Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 585
Filtrar
Más filtros

Tipo del documento
Intervalo de año de publicación
1.
Cell ; 187(12): 2969-2989.e24, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38776919

RESUMEN

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.


Asunto(s)
Hongos , Microbioma Gastrointestinal , Micobioma , Animales , Humanos , Masculino , Ratones , Heces/microbiología , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Genoma Fúngico/genética , Genómica , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/genética , Metagenoma , Filogenia , Femenino , Adulto , Persona de Mediana Edad
2.
Cell ; 184(1): 257-271.e16, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33417862

RESUMEN

Hardwired circuits encoding innate responses have emerged as an essential feature of the mammalian brain. Sweet and bitter evoke opposing predetermined behaviors. Sweet drives appetitive responses and consumption of energy-rich food sources, whereas bitter prevents ingestion of toxic chemicals. Here we identified and characterized the neurons in the brainstem that transmit sweet and bitter signals from the tongue to the cortex. Next we examined how the brain modulates this hardwired circuit to control taste behaviors. We dissect the basis for bitter-evoked suppression of sweet taste and show that the taste cortex and amygdala exert strong positive and negative feedback onto incoming bitter and sweet signals in the brainstem. Finally we demonstrate that blocking the feedback markedly alters responses to ethologically relevant taste stimuli. These results illustrate how hardwired circuits can be finely regulated by top-down control and reveal the neural basis of an indispensable behavioral response for all animals.


Asunto(s)
Amígdala del Cerebelo/fisiología , Encéfalo/fisiología , Mamíferos/fisiología , Gusto/fisiología , Animales , Tronco Encefálico/fisiología , Calbindina 2/metabolismo , Corteza Cerebral/fisiología , Retroalimentación Fisiológica , Ratones Endogámicos C57BL , Mutación/genética , Inhibición Neural/fisiología , Neuronas/fisiología , Núcleo Solitario/fisiología , Somatostatina/metabolismo
3.
Cell ; 179(2): 392-402.e15, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31543264

RESUMEN

The ability to sense sour provides an important sensory signal to prevent the ingestion of unripe, spoiled, or fermented foods. Taste and somatosensory receptors in the oral cavity trigger aversive behaviors in response to acid stimuli. Here, we show that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system. We demonstrate that knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs). In addition, we show that mice engineered to express otopetrin-1 in sweet TRCs have sweet cells that also respond to sour stimuli. Next, we genetically identified the taste ganglion neurons mediating each of the five basic taste qualities and demonstrate that sour taste uses its own dedicated labeled line from TRCs in the tongue to finely tuned taste neurons in the brain to trigger aversive behaviors.


Asunto(s)
Encéfalo/fisiología , Proteínas de la Membrana/metabolismo , Papilas Gustativas/metabolismo , Gusto , Ácidos/farmacología , Vías Aferentes/citología , Vías Aferentes/metabolismo , Vías Aferentes/fisiología , Animales , Encéfalo/citología , Encéfalo/metabolismo , Femenino , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Papilas Gustativas/efectos de los fármacos , Papilas Gustativas/fisiología , Percepción del Gusto
4.
Nature ; 630(8017): 695-703, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38692285

RESUMEN

The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here we show that a peripheral immune insult strongly activates the body-brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.


Asunto(s)
Encéfalo , Citocinas , Inflamación , Neuroinmunomodulación , Animales , Femenino , Masculino , Ratones , Encéfalo/citología , Encéfalo/inmunología , Encéfalo/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Ratones Endogámicos C57BL , Neuroinmunomodulación/inmunología , Neuroinmunomodulación/fisiología , Neuronas/fisiología , Nervio Vago/citología , Nervio Vago/fisiología , Análisis de Expresión Génica de una Sola Célula
5.
Nature ; 580(7804): 511-516, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32322067

RESUMEN

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1-3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.


Asunto(s)
Encéfalo/fisiología , Conducta de Elección/fisiología , Azúcares de la Dieta/metabolismo , Preferencias Alimentarias/fisiología , Glucosa/metabolismo , Intestinos/fisiología , Animales , Encéfalo/citología , Azúcares de la Dieta/química , Glucosa/análogos & derivados , Glucosa/química , Masculino , Metilglucósidos/química , Metilglucósidos/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Gusto/fisiología , Tiazinas/metabolismo , Agua/metabolismo
6.
FASEB J ; 38(4): e23492, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38363564

RESUMEN

Lineage specification and X chromosome dosage compensation are two crucial biological processes that occur during preimplantation embryonic development. Although extensively studied in mice, the timing and regulation of these processes remain elusive in other species, including humans. Previous studies have suggested conserved principles of human and bovine early development. This study aims to provide fundamental insights into these programs and the regulation using a bovine embryo model by employing single-cell transcriptomics and genome editing approaches. The study analyzes the transcriptomes of 286 individual cells and reveals that bovine trophectoderm/inner cell mass transcriptomes diverge at the early blastocyst stage, after cavitation but before blastocyst expansion. The study also identifies transcriptomic markers and provides the timing of lineage specification events in the bovine embryo. Importantly, we find that SOX2 is required for the first cell decision program in bovine embryos. Moreover, the study shows the occurrence of X chromosome dosage compensation from morula to late blastocyst and reveals that this compensation results from downregulation of X-linked genes in female embryonic cells. The transcriptional atlas generated by this study is expected to be widely useful in improving our understanding of mammalian early embryo development.


Asunto(s)
Blastocisto , Análisis de Expresión Génica de una Sola Célula , Embarazo , Bovinos , Animales , Femenino , Humanos , Ratones , Embrión de Mamíferos , Desarrollo Embrionario/genética , Cromosoma X/genética , Regulación del Desarrollo de la Expresión Génica , Linaje de la Célula/genética , Mamíferos
7.
Mol Med ; 30(1): 58, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720283

RESUMEN

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Exenatida , Receptor del Péptido 1 Similar al Glucagón , Mitofagia , Transducción de Señal , Calcificación Vascular , Animales , Mitofagia/efectos de los fármacos , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Calcificación Vascular/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Humanos , Exenatida/farmacología , Exenatida/uso terapéutico , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
8.
Anal Chem ; 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38976239

RESUMEN

Both solitary and tandem applications of residual chemical shift anisotropy (RCSA) and residual dipolar coupling (RDC) show great potential for the structural and configurational determination of organic molecules. A critical component of both RDC and RCSA methodologies is the alignment medium, whose availability is limited, especially for RCSA measurement. Moreover, reported RDC and RCSA acquisitions mainly rely on two experiments conducted under two different conditions, which are relatively time-consuming and easily cause experimental errors. Herein, a biphasic supramolecular lyotropic liquid crystalline (LLC) system was developed through the self-assembly of C21H43-CONH-V4K3-CONH2, which could act as an alignment medium for not only RDC but also RCSA extraction in DMSO-d6. Notably, the RCSA extraction was easily achieved via one-shot measurement from a single one-dimensional 13C NMR experiment, with no need for special instruments, devices, and correction. Relying on the biphasic LLC medium, meanwhile, RDC data were simply extracted from a single F1-coupled HSQC experiment, different from the standard protocol that requires two spectral acquisitions corresponding to the isotropic and anisotropic conditions. Collectively, the biphasic LLC medium is applicable for tandem RCSA and RDC measurements in one single sample, advancing the stereochemical elucidation of molecules of interest.

9.
Anal Chem ; 96(12): 4978-4986, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38471057

RESUMEN

Bioaccumulation of nanoplastic particles has drawn increasing attention regarding environmental sustainability and biosafety. How nanoplastic particles interact with the cellular milieu still remains elusive. Herein, we exemplify a general approach to profile the composition of a "protein corona" interacting with nanoparticles via the photocatalytic protein proximity labeling method. To enable photocatalytic proximity labeling of the proteome interacting with particles, iodine-substituted BODIPY (I-BODIPY) is selected as the photosensitizer and covalently conjugated onto amino-polystyrene nanoparticles as a model system. Next, selective proximity labeling of interacting proteins is demonstrated using I-BODIPY-labeled nanoplastic particles in both Escherichia coli lysate and live alpha mouse liver 12 cells. Mechanistic studies reveal that the covalent modifications of proteins by an aminoalkyne substrate are conducted via a reactive oxygen species photosensitization pathway. Further proteomic analysis uncovers that mitochondria-related proteins are intensively involved in the protein corona, indicating substantial interactions between nanoplastic particles and mitochondria. In addition, proteostasis network components are also identified, accompanied by consequent cellular proteome aggregation confirmed by fluorescence imaging. Together, this work exemplifies a general strategy to interrogate the composition of the protein corona of nanomaterials by endowing them with photooxidation properties to enable photocatalytic protein proximity labeling function.


Asunto(s)
Compuestos de Boro , Nanopartículas , Corona de Proteínas , Animales , Ratones , Microplásticos , Proteoma , Proteómica , Poliestirenos
10.
J Nat Prod ; 87(2): 297-303, 2024 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-38308643

RESUMEN

Three nor-sesquiterpenes, phellinharts A-C (1-3), isolated from Phellinus hartigii, exhibited unprecedented protoilludane and cerapicane-type structures. The structures of compounds 1-3 were elucidated via spectroscopic analysis, quantum chemical calculations, and X-ray diffraction. Potential biogenic pathways involving demethylation, ring cleavage, and rearrangement were proposed. Compounds 1-3 displayed potent anti-hypertrophic activities with low cytotoxicity (CC50 > 50 µM) in rat cardiomyocytes, underscoring their therapeutic potential.


Asunto(s)
Miocitos Cardíacos , Phellinus , Sesquiterpenos Policíclicos , Sesquiterpenos , Animales , Ratas , Estructura Molecular , Sesquiterpenos/química
11.
Bioorg Chem ; 148: 107491, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38788365

RESUMEN

As a consequence of somatosensory nervous system injury or disease, neuropathic pain is commonly associated with chemotherapies, known as chemotherapy-induced peripheral neuropathy (CIPN). However, the mechanisms underlying CIPN-induced proteome aggregation in neuronal cells remain elusive due to limited detection tools. Herein, we present series sensors for fluorescence imaging (AggStain) and proteomics analysis (AggLink) to visualize and capture aggregated proteome in CIPN neuronal cell model. The environment-sensitive AggStain imaging sensor selectively binds and detects protein aggregation with 12.3 fold fluorescence enhancement. Further, the covalent AggLink proteomic sensor captures cellular aggregated proteins and profiles their composition via LC-MS/MS analysis. This integrative sensor platform reveals the presence of proteome aggregation in CIPN cell model and highlights its potential for broader applications in assessing proteome stability under various cellular stress conditions.


Asunto(s)
Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Proteoma , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Humanos , Proteoma/análisis , Proteoma/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Estructura Molecular , Agregado de Proteínas/efectos de los fármacos , Imagen Óptica , Relación Dosis-Respuesta a Droga , Proteómica , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología
12.
J Dairy Sci ; 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38825103

RESUMEN

Traditional fermented milks are produced through an inoculation process that involves the deliberate introduction of microorganisms that have been adapted and perpetuated across successive generations. However, the changes in the microbiota of traditional fermented milk during long-term inoculation fermentation in a laboratory environment remain unclear. In this study, we collected 5 samples of traditional fermented milk samples from 5 different counties in Tibet (3 kurut products) and Xinjiang (2 tarag products) of China, which served as starter cultures for a 9-mo continuous inoculation fermentation experiment. We analyzed the inter- and intra-population variations in the microbial communities of the collected samples, representing their macrodiversity and microdiversity, using shotgun metagenomic sequencing. Across all samples, we obtained a total of 186 high-quality metagenomic-assembled genomes, including 7 genera and 13 species with a relative abundance of more than 1%. The majority of these genomes were annotated as Lactobacillus helveticus (60.46%), Enterococcus durans (9.52%), and Limosilactobacillus fermentum (6.23%). We observed significant differences in species composition and abundance among the 5 initial inoculants. During the long-term inoculation fermentation, we found an overall increasing trend in species diversity, composition, and abundances of carbohydrate metabolism module-encoding genes in the fermented milk bacterial metagenome, while the fermented milk virome exhibited a relatively narrow range of variation. Lactobacillus helveticus, a dominant species in traditional fermented milk, displayed high stability during the long-term inoculation fermentation. Our study provides valuable insights for the industrial production of traditional fermented milk.

13.
Nano Lett ; 23(24): 11669-11677, 2023 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-38060996

RESUMEN

Supramolecular aggregation has provided the archetype concept to understand the variants in an emerging systems property. Herein, we have achieved the supramolecular assembly of carbon nanodots (CDs) for the first time and employ supramolecular aggregation to understand their alteration in photophysical properties. In detail, we have employed the CDs as a block to construct the supramolecular assembly of aggregates in the CDs' antisolvent of ethanol. The CD-based aggregates exhibit complex and organized morphologies with another long-wavelength excitation-dependent emission band. The experimental results and density functional theoretical calculations reveal that the supramolecular assembly of CDs can decrease the energy gap between the ground and excited states, contributing to the new long-wavelength excitation-dependent emission. The supramolecular aggregation can be employed as one universal strategy to manipulate and understand the luminescence of CDs. These findings cast new light to build the emerging systems and understand the light emission of CDs through supramolecular chemistry.

14.
J Environ Manage ; 356: 120750, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38520849

RESUMEN

The nitrate denitrifying anaerobic methane oxidation-anaerobic ammonia oxidation (DAMO-anammox) can accomplish nitrogen removal and methane (CH4) reduction. This process greatly contributes to carbon emission mitigation and carbon neutrality. In this study, we investigated the electron transfer process of functional microorganisms in the iron-mediated DAMO-anammox system. Fe3+ could be bound to several functional groups (-CH3, COO-, -CH) in extracellular polymeric substance (EPS), and the functional groups bound were different at different iron concentration. Fe3+ underwent reduction reactions to produce Fe2+. Most Fe3+ and Fe2+ react with microorganisms and formed chelates with EPS. Three-dimensional fluorescence spectra showed that Fe3+ affected the secretion of tyrosine and tryptophan, which were essential for cytochrome synthesis. The presence of Fe3+ accelerated c-type cytochrome-mediated extracellular electron transfer (EET), and when more Fe3+ existed, the more cytochrome C expressed. DAMO archaea (M. nitroreducens) in the system exhibited a high positive correlation with the functional genes (resa and ccda) for cytochrome c synthesis. Some denitrifying microorganisms showed positive correlations with the abundance of riboflavin. This finding showed that riboflavin secreted by functional microorganisms acted as an electron shuttle. In addition, DAMO archaea were positively correlated with the hair synthesis gene pily1, which indicated that direct interspecies electron transfer (DIET) may exist in the iron-mediated DAMO-anammox system.


Asunto(s)
Compuestos de Amonio , Hierro , Oxidación Anaeróbica del Amoníaco , Matriz Extracelular de Sustancias Poliméricas/metabolismo , Citocromos c/metabolismo , Electrones , Desnitrificación , Anaerobiosis , Archaea , Oxidación-Reducción , Metano , Carbono/metabolismo , Riboflavina/metabolismo , Reactores Biológicos , Compuestos de Amonio/metabolismo , Nitrógeno/metabolismo , Nitritos/metabolismo
15.
Lancet Oncol ; 24(7): 798-810, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37290468

RESUMEN

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.


Asunto(s)
Neoplasias Nasofaríngeas , Neutropenia , Adolescente , Masculino , Humanos , Femenino , Adulto , Cisplatino , Carcinoma Nasofaríngeo/tratamiento farmacológico , Gemcitabina , China , Desoxicitidina , Quimioradioterapia , Fluorouracilo , Neutropenia/inducido químicamente , Neoplasias Nasofaríngeas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante
16.
J Am Chem Soc ; 145(1): 160-170, 2023 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-36542745

RESUMEN

Ferroptosis provides an innovative theoretical basis and method for tumor therapy but is limited by the low efficiency of conventional iron delivery systems. Herein, an efficient supramolecular iron delivery system (SIDS) is demonstrated upon the hydrolysis of FeCl3, condensation of amino acids, and self-assembly of iron-containing components. The as-assembled SIDS possesses a shuttle-like core/shell structure with ß-FeOOH as the core and Fe3+/polyamino acid coordinated networks as shells. The iron content of SIDS is up to 42 wt %, which is greatly higher than that of ferritin. The iron-containing protein-mimic structure and shuttle-like morphology of SIDS facilitate tumor accumulation and cell internalization. Once exposed to the tumor microenvironment with overexpressed glutathione (GSH), the SIDS will disassemble, accompanied by the depletion of GSH and the release of Fe2+, leading to dual amplified ferroptosis. Primary studies indicate that SIDS exhibits outstanding antitumor efficacy on bladder cancer.


Asunto(s)
Ferroptosis , Hierro , Hierro/química , Ferritinas , Línea Celular Tumoral
17.
Int J Cancer ; 152(9): 1933-1946, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36691829

RESUMEN

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities. We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.


Asunto(s)
Proteínas de la Membrana , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Microdominios de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo
18.
Anal Chem ; 95(15): 6358-6366, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-37017602

RESUMEN

Stress induced amorphous proteome aggregation is a hallmark for diseased cells, with the proteomic composition intimately associated with disease pathogenicity. Due to its particularly dynamic, reversible, and dissociable nature, as well as lack of specific recognition anchor, it is difficult to capture aggregated proteins in situ. In this work, we develop a chemical proteomics method (AggLink) to capture amorphous aggregated proteins in live stressed cells and identify the proteomic contents using LC-MS/MS. Our method relies on an affinity-based chemical probe (AggLink 1.0) that is optimized to selectively bind to and covalently label amorphous aggregated proteins in live stressed cells. Especially, chaotrope-compatible ligation enables effective enrichment of labeled aggregated proteins under urea denaturation and dissociation conditions. Compared to conventional fractionation-based method to profile aggregated proteome, our method showed improved enrichment selectivity, detection sensitivity, and identification accuracy. In HeLa cells, the AggLink method reveals the constituent heterogeneity of aggregated proteome induced by inhibition of pro-folding (HSP90) or pro-degradation (proteasome) pathway, which uncovers a synergistic strategy to reduce cancer cell viability. In addition, the unique fluorogenicity of our probe upon labeling aggregated proteome detects its cellular location and morphology. Together, the AggLink method may help to expand our knowledge of the previously nontargetable amorphous aggregated proteome.


Asunto(s)
Proteoma , Proteómica , Humanos , Proteoma/química , Células HeLa , Cromatografía Liquida/métodos , Proteómica/métodos , Espectrometría de Masas en Tándem/métodos
19.
Anal Chem ; 95(48): 17759-17765, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-37996077

RESUMEN

Multiple independent sets of residual dipolar couplings (RDCs) acquired by relying on different alignment media show the great potential for de novo structure determination of organic compounds. However, this methodology is severely compromised by the limited availability of multialignment media. In this work, an engineering strategy was developed to program the oligopeptide amphiphiles (OPAs) to create different peptide liquid crystal (LC) media for the acquisition of independent sets of RDCs. With no need for de novo design on peptide sequences, the molecular alignment can be simply modulated by varying the length of the hydrophobic tails within OPAs. Relying on these programmed peptide LC media, five independent sets of RDCs were extracted in a highly efficient and accurate manner. Because of the similar bulk composition of OPAs, this approach offers the significant advantage in circumventing the possible incompatibilities of analytes with one or several different alignment media, therefore avoiding the analysis complication. Notably, these peptide LC media show enantiodifferentiating properties, and the enantiodiscriminating capabilities could also be optimized through the programmed strategy. Furthermore, we show that these media are compatible with different polar solvents, allowing the possible de novo structure elucidation of organic compounds with varied polarities and solubilities.

20.
Small ; 19(14): e2206262, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36642832

RESUMEN

The upsurge of new materials that can be used for near-infrared (NIR) photodetectors operated without cooling is crucial. As a novel material with a small bandgap of ≈0.28 eV, the topological crystalline insulator SnTe has attracted considerable attention. Herein, this work demonstrates self-driven NIR photodetectors based on SnTe/Si and SnTe:Si/Si heterostructures. The SnTe/Si heterostructure has a high detectivity D* of 3.3 × 1012 Jones. By Si doping, the SnTe:Si/Si heterostructure reduces the dark current density and increases the photocurrent by ≈1 order of magnitude simultaneously, which improves the detectivity D* by ≈2 orders of magnitude up to 1.59 × 1014 Jones. Further theoretical analysis indicates that the improved device performance may be ascribed to the bulk photovoltaic effect (BPVE), in which doped Si atoms break the inversion symmetry and thus enable the generation of additional photocurrents beyond the heterostructure. In addition, the external quantum efficiency (EQE) measured at room temperature at 850 nm increases by a factor of 7.5 times, from 38.5% to 289%. A high responsivity of 1979 mA W-1 without bias and fast rising time of 8 µs are also observed. The significantly improved photodetection achieved by the Si doping is of great interest and may provide a novel strategy for superior photodetectors.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA