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1.
Cell ; 171(2): 358-371.e9, 2017 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-28985563

RESUMEN

Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ácido Láctico/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Análisis Químico de la Sangre , Línea Celular Tumoral , Ciclo del Ácido Cítrico , Modelos Animales de Enfermedad , Femenino , Ácidos Glicéricos/metabolismo , Xenoinjertos , Humanos , Masculino , Ratones , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Trasplante de Neoplasias , Simportadores/genética , Simportadores/metabolismo
2.
Cell ; 164(4): 681-94, 2016 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-26853473

RESUMEN

Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative (13)C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Ciclo del Ácido Cítrico , Femenino , Glucólisis , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones
3.
Cell ; 155(3): 552-66, 2013 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-24243015

RESUMEN

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Indoles/farmacología , Neoplasias Pulmonares/metabolismo , Triazinas/farmacología , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Portadoras , Línea Celular Tumoral , Proteína Coatómero/metabolismo , Femenino , Genes ras , Xenoinjertos , Humanos , Neoplasias Pulmonares/patología , Lisosomas/metabolismo , Ratones , Terapia Molecular Dirigida , Proteína con Dominio Pirina 3 de la Familia NLR , Trasplante de Neoplasias , Fosforilación Oxidativa
4.
Mol Cell ; 76(5): 838-851.e5, 2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31564558

RESUMEN

Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral/metabolismo , Metaboloma/fisiología , Biomarcadores de Tumor/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos , Regulación Neoplásica de la Expresión Génica/fisiología , Glucosa/metabolismo , Glutamina/metabolismo , Humanos , Redes y Vías Metabólicas/genética , Metabolómica/métodos , Neoplasias/metabolismo
5.
Proc Natl Acad Sci U S A ; 121(28): e2319994121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38959032

RESUMEN

Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.


Asunto(s)
Asma , Factor 2 Relacionado con NF-E2 , Células Th2 , Animales , Femenino , Humanos , Ratones , Asma/inmunología , Asma/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/metabolismo , Glucólisis , Interleucina-33/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación Oxidativa , PPAR gamma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Th2/inmunología , Células Th2/metabolismo
6.
Proc Natl Acad Sci U S A ; 120(15): e2220770120, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-37011211

RESUMEN

The canonical role of the transcription factor E2F is to control the expression of cell cycle genes by binding to the E2F sites in their promoters. However, the list of putative E2F target genes is extensive and includes many metabolic genes, yet the significance of E2F in controlling the expression of these genes remains largely unknown. Here, we used the CRISPR/Cas9 technology to introduce point mutations in the E2F sites upstream of five endogenous metabolic genes in Drosophila melanogaster. We found that the impact of these mutations on both the recruitment of E2F and the expression of the target genes varied, with the glycolytic gene, Phosphoglycerate kinase (Pgk), being mostly affected. The loss of E2F regulation on the Pgk gene led to a decrease in glycolytic flux, tricarboxylic acid cycle intermediates levels, adenosine triphosphate (ATP) content, and an abnormal mitochondrial morphology. Remarkably, chromatin accessibility was significantly reduced at multiple genomic regions in PgkΔE2F mutants. These regions contained hundreds of genes, including metabolic genes that were downregulated in PgkΔE2F mutants. Moreover, PgkΔE2F animals had shortened life span and exhibited defects in high-energy consuming organs, such as ovaries and muscles. Collectively, our results illustrate how the pleiotropic effects on metabolism, gene expression, and development in the PgkΔE2F animals underscore the importance of E2F regulation on a single E2F target, Pgk.


Asunto(s)
Proteínas de Drosophila , Drosophila , Factores de Transcripción E2F , Fosfoglicerato Quinasa , Animales , Cromatina , Drosophila/genética , Factores de Transcripción E2F/genética , Fosfoglicerato Quinasa/genética , Fosfoglicerato Quinasa/metabolismo , Regiones Promotoras Genéticas , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
7.
Proc Natl Acad Sci U S A ; 120(9): e2213793120, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36802434

RESUMEN

Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRß-deficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRß-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/ß-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3ß-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.


Asunto(s)
Células T Auxiliares Foliculares , Linfocitos T Colaboradores-Inductores , Ratones , Humanos , Animales , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Centro Germinal , Factor 1 de Transcripción de Linfocitos T/genética , Diferenciación Celular
8.
Nat Immunol ; 14(6): 611-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23644504

RESUMEN

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.


Asunto(s)
Proteínas Proto-Oncogénicas c-akt/inmunología , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/inmunología , Células Th17/inmunología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/inmunología , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Citometría de Flujo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Immunoblotting , Interleucina-17/inmunología , Interleucina-17/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Complejos Multiproteicos/inmunología , Complejos Multiproteicos/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Células Th17/metabolismo
9.
Nature ; 566(7743): 254-258, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30728500

RESUMEN

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.


Asunto(s)
Colesterol/metabolismo , Familia 7 del Citocromo P450/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Osteoartritis/metabolismo , Esteroide Hidroxilasas/metabolismo , Animales , Transporte Biológico , Condrocitos/enzimología , Condrocitos/metabolismo , Masculino , Ratones , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Osteoartritis/enzimología , Osteoartritis/patología , Oxiesteroles/metabolismo , Esteroide Hidroxilasas/deficiencia , Regulación hacia Arriba
10.
Nature ; 569(7756): E4, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31043737

RESUMEN

Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method revealed that the level of carbamoyl phosphate in these NSCLC extracts is below the detection threshold of approximately 10 nanomoles. These findings do not alter the overall conclusions of the Letter; see associated Amendment for full details. The Letter has not been corrected online.

11.
J Am Chem Soc ; 146(20): 14012-14021, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38738871

RESUMEN

Plasmonic nanoparticles with an externally open nanogap can localize the electromagnetic (EM) field inside the gap and directly detect the target via the open nanogap with surface-enhanced Raman scattering (SERS). It would be beneficial to design and synthesize the open gap nanoprobes in a high yield for obtaining uniform and quantitative signals from randomly oriented nanoparticles and utilizing these particles for direct SERS analysis. Here, we report a facile strategy to synthesize open cross-gap (X-gap) nanocubes (OXNCs) with size- and EM field-tunable gaps in a high yield. The site-specific growth of Au budding structures at the corners of the AuNC using the principle that the Au deposition rate is faster than the surface diffusion rate of the adatoms allows for a uniform X-gap formation. The average SERS enhancement factor (EF) for the OXNCs with 2.6 nm X-gaps was 1.2 × 109, and the EFs were narrowly distributed within 1 order of magnitude for ∼93% of the measured OXNCs. OXNCs consistently displayed strong EM field enhancement on large particle surfaces for widely varying incident light polarization directions, and this can be attributed to the symmetric X-gap geometry and the availability of these gaps on all 6 faces of a cube. Finally, the OXNC probes with varying X-gap sizes have been utilized in directly detecting biomolecules with varying sizes without Raman dyes. The concept, synthetic method, and biosensing results shown here with OXNCs pave the way for designing, synthesizing, and utilizing plasmonic nanoparticles for selective, quantitative molecular-fingerprint Raman sensing and imaging applications.

12.
Breast Cancer Res ; 26(1): 13, 2024 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-38238761

RESUMEN

BACKGROUND: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). METHODS: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. RESULTS: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2- mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2- mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2- mBC. CONCLUSIONS: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.


Asunto(s)
Neoplasias de la Mama , Ácidos Nucleicos Libres de Células , Células Neoplásicas Circulantes , Humanos , Femenino , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Ácidos Nucleicos Libres de Células/uso terapéutico , Pronóstico , Molécula de Adhesión Celular Epitelial/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Fosfatidilinositol 3-Quinasa Clase I/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
13.
Anal Chem ; 96(26): 10765-10771, 2024 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-38904303

RESUMEN

The nuclear pore complex (NPC) is a proteinaceous nanopore that solely and selectively regulates the molecular transport between the cytoplasm and nucleus of a eukaryotic cell. The ∼50 nm-diameter pore of the NPC perforates the double-membrane nuclear envelope to mediate both passive and facilitated molecular transport, thereby playing paramount biological and biomedical roles. Herein, we visualize single NPCs by scanning electrochemical microscopy (SECM). The high spatial resolution is accomplished by employing ∼25 nm-diameter ion-selective nanopipets to monitor the passive transport of tetrabutylammonium at individual NPCs. SECM images are quantitatively analyzed by employing the finite element method to confirm that this work represents the highest-resolution nanoscale SECM imaging of biological samples. Significantly, we apply the powerful imaging technique to address the long-debated origin of the central plug of the NPC. Nanoscale SECM imaging demonstrates that unplugged NPCs are more permeable to the small probe ion than are plugged NPCs. This result supports the hypothesis that the central plug is not an intrinsic transporter, but is an impermeable macromolecule, e.g., a ribonucleoprotein, trapped in the nanopore. Moreover, this result also supports the transport mechanism where the NPC is divided into the central pathway for RNA export and the peripheral pathway for protein import to efficiently mediate the bidirectional traffic.


Asunto(s)
Microscopía Electroquímica de Rastreo , Poro Nuclear , Poro Nuclear/metabolismo , Poro Nuclear/química , Compuestos de Amonio Cuaternario/química , Nanoporos
14.
Langmuir ; 40(6): 3004-3014, 2024 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-38294191

RESUMEN

Unequivocally, Pb2+ as a harmful substance damaging children's brain and nerve systems, thereby causing behavior and learning disabilities, should be detected much lower than the elevated blood lead for children, 240 nM, endorsed by US CDC considering the unknown neurotoxic effects, yet the ultralow detection limit up to sub-ppb level remains a challenge due to the intrinsically insufficient sensitivity in the current analytical techniques. Here, we present nanoemulsion (NE)-integrated single-entity electrochemistry (NI-SEE) toward ultrasensitive sensing of blood lead using Pb-ion-selective ionophores inside a NE, i.e., Pb2+-selective NE. Through the high thermodynamic selectivity between Pb2+ and Pb-ionophore IV, and the extremely large partition coefficient for the Pb2+-Pb-ionophore complex inside NEs, we modulate the selectivity and sensitivity of NI-SEE for Pb2+ sensing up to an unprecedentedly low detection limit, 20 ppt in aqueous solutions, and lower limit of quantitation, 40 ppb in blood serums. This observation is supported by molecular dynamics simulations, which clearly corroborate intermolecular interactions, e.g., H-bonding and π*-n, between the aromatic rings of Pb-ionophore and lone pair electrons of oxygen in dioctyl sebacate (DOS), plasticizers of NEs, subsequently enhancing the current intensity in NI-SEE. Moreover, the highly sensitive sensing of Pb2+ is enabled by the appropriate suppression of hydroxyl radical formation during NI-SEE under a cathodic potential applied to a Pt electrode. Overall, the experimentally demonstrated NI-SEE approach and the results position our new sensing technology as potential sensors for practical environmental and biomedical applications as well as a platform to interrogate the stoichiometry of target ion-ionophore recognition inside a NE as nanoreactors.


Asunto(s)
Plomo , Agua , Niño , Humanos , Electroquímica/métodos , Ionóforos/química , Electrodos
15.
J Korean Med Sci ; 39(25): e208, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38952349

RESUMEN

A 30-year-old Korean man with myelodysplastic syndrome admitted hospital due to undifferentiated fever and recurrent skin lesions. He received combination therapy with high doses of meropenem, tigecycline and amikacin, yielding carbapenem resistant Klebsiella pneumoniae (CRKP) harboring K. pneumoniae carbapenemase (KPC)-2 from blood cultures on hospital day (HD) 23. Ceftazidime/avibactam was started at HD 37 and CRKP was eradicated from blood cultures after 5 days. However, ceftazidime/avibactam-resistant CRKP carrying KPC-44 emerged after 26 days of ceftazidime/avibactam treatment and then ceftazidime/avibactam-resistant, carbapenem-susceptible K. pneumoniae carrying KPC-135 was isolated on HD 65. The 3-D homology of KPC protein showed that hot spot changes in the omega loop could be attributed to ceftazidime/avibactam resistance and loss of carbapenem resistance. Whole genome sequencing of serial isolates supported that phenotypic variation was due to clonal evolution than clonal replacement. The treatment regimen was changed from CAZ/AVI to meropenem-based therapy (meropenem 1 g iv q 8 hours and amikacin 600 mg iv per day) starting with HD 72. CAZ/AVI-susceptible CRKP was presented again from blood cultures on HD 84, and the patient expired on HD 85. This is the first Korean report on the acquisition of ceftazidime/avibactam resistance through the emergence of blaKPC variants.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Bacteriemia , Ceftazidima , Combinación de Medicamentos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , Humanos , Ceftazidima/uso terapéutico , Ceftazidima/farmacología , Klebsiella pneumoniae/aislamiento & purificación , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Compuestos de Azabiciclo/uso terapéutico , Adulto , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Secuenciación Completa del Genoma , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Meropenem/uso terapéutico , Meropenem/farmacología , Farmacorresistencia Bacteriana Múltiple/genética
16.
Nano Lett ; 23(16): 7593-7598, 2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37561947

RESUMEN

The use of DNA triplex association is advantageous for the reconfiguration of dynamic DNA nanostructures through pH alteration and can provide environmental control for both structural changes and molecular signaling. The combination of pH-induced triplex-forming oligonucleotide (TFOs) binding with toehold-mediated strand displacement has recently garnered significant attention in the field of structural DNA nanotechnology. While most previous studies use single-stranded DNA to displace or replace TFOs within the triplex, here we demonstrate that pH alteration allows a DNA duplex, with a toehold assistance, to displace TFOs from the components of another DNA duplex. We examined the dependence of this process on toehold length and show that the pH changes allow for cyclic oscillations between two molecular formations. We implemented the duplex/triplex design onto the surface of 2D DNA origami in the form outlining binary digits 0 or 1 and verified the oscillatory conformational changes between the two formations with atomic force microscopy.


Asunto(s)
ADN , Nanoestructuras , ADN/química , Oligonucleótidos/química , ADN de Cadena Simple , Microscopía de Fuerza Atómica , Conformación de Ácido Nucleico
17.
Int J Mol Sci ; 25(4)2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38396979

RESUMEN

Gallic acid (GA), a phenolic compound naturally found in many plants, exhibits potential preventive and therapeutic roles. However, the underlying molecular mechanisms of its diverse biological activities remain unclear. Here, we investigated possible mechanisms of GA function through a transcriptome-based analysis using LINCS L1000, a publicly available data resource. We compared the changes in the gene expression profiles induced by GA with those induced by FDA-approved drugs in three cancer cell lines (A549, PC3, and MCF7). The top 10 drugs exhibiting high similarity with GA in their expression patterns were identified by calculating the connectivity score in the three cell lines. We specified the known target proteins of these drugs, which could be potential targets of GA, and identified 19 potential targets. Next, we retrieved evidence in the literature that GA likely binds directly to DNA polymerase ß and ribonucleoside-diphosphate reductase. Although our results align with previous studies suggesting a direct and/or indirect connection between GA and the target proteins, further experimental investigations are required to fully understand the exact molecular mechanisms of GA. Our study provides insights into the therapeutic mechanisms of GA, introducing a new approach to characterizing therapeutic natural compounds using transcriptome-based analyses.


Asunto(s)
Neoplasias , Transcriptoma , Humanos , Ácido Gálico/farmacología , Ácido Gálico/metabolismo , Perfilación de la Expresión Génica
18.
Int J Mol Sci ; 25(4)2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38396634

RESUMEN

Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects.


Asunto(s)
Interleucina-8 , Enfermedad Pulmonar Obstructiva Crónica , Animales , Humanos , Ratones , Antiinflamatorios/farmacología , Apoptosis/genética , Células Endoteliales/metabolismo , Inflamación/metabolismo , Inflamación/patología , Interleucina-8/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Fumar Tabaco/efectos adversos , Proteínas de Unión al Calcio/metabolismo , Moléculas de Adhesión Celular/metabolismo
19.
J Environ Manage ; 360: 121010, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38749135

RESUMEN

Numerous unique flora and fauna inhabit the Lower Florida Keys, including the endangered Florida Key deer, found nowhere else. In this vulnerable habitat of flat islands with low elevation, accelerated sea level rise poses a threat. Predicting the impact of sea level rise on vegetation and wildlife is crucial. This study used 5 Intergovernmental Panel on Climate Change (IPCC) sea level rise scenarios to assess their effects on No Name Key, Florida. The goal was to estimate changes in the Florida Key deer population relative to sea level rise using a lidar-derived elevation data and a vegetation map. The method used 2 cases to model the sea level rise impact. In Case 1, total non-submerged area at current sea level was determined. Using 5 IPCC scenarios, a new total non-submerged land area was estimated, and deer numbers were predicted for each scenario. In Case 2, upward migration of coastal vegetation combined with the coastal squeeze process was modeled. A distinct elevation range for each vegetation type at the current sea level was determined. Vegetation ranges were redistributed based on respective elevation ranges in the sea level rise scenarios. Areas for each vegetation type were recalculated, and Key deer numbers were estimated for each sea level rise scenario. Results under the worst emission scenario showed the following: (1) for case 1, the land area was reduced to 30 % of the current land area, corresponding to having about 27 deer, and (2) for case 2, the land area was reduced to 70 % of the current land area, having about 54 deer on No Name Key. The results indicated reduced non-submerged land area and less upland vegetation, particularly hardwoods/hammocks, by the year 2100. As less land area is available, a decline in Key deer population is expected as sea levels rise. Since Key deer favor upland vegetation, habitat affected by sea level rise will likely support a smaller deer population. The findings emphasize the need for precise, timely predictions of sea level rise impacts and long-term conservation strategies. Specifically designed measures are required to protect and maintain endangered wildlife, such as the Florida Key deer, residing on these vulnerable islands.


Asunto(s)
Ecosistema , Modelos Teóricos , Elevación del Nivel del Mar , Elevación del Nivel del Mar/estadística & datos numéricos , Florida , Dinámica Poblacional/estadística & datos numéricos , Distribución Animal , Simulación por Computador , Dispersión de las Plantas
20.
Comput Inform Nurs ; 42(2): 118-126, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38129321

RESUMEN

This study aims to develop a virtual reality-based education program for managing behavioral and psychological symptoms of dementia for family carers of persons living with dementia and investigate the feasibility for users. The program was developed through literature review, interviews with family carers, surveys, and expert content validity assessment. User feasibility was evaluated quantitatively through a questionnaire on usefulness, ease of use, and satisfaction, and qualitatively through participant interviews. The program was produced in two parts, Type 1 and Type 2, consisting of three and six episodes, respectively. Participants showed a high level of satisfaction with overall program scores of 4.28 ± 0.66 and 4.34 ± 0.41 for the two evaluations. Participants also expressed that both programs were helpful, Type 1 for achieving changes in attitude associated with more understanding of persons living with dementia and Type 2 for acquiring coping methods through communication training. Use of the virtual reality device was not inconvenient and was identified as helpful due to the high immersion experience. Results of this study confirmed that family carers had no resistance to education using new technologies such as virtual reality devices and that virtual reality-based education could be effective for training family carers.


Asunto(s)
Demencia , Realidad Virtual , Humanos , Estudios de Factibilidad , Cuidadores/psicología , Comunicación , Demencia/terapia , Demencia/psicología
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