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1.
Anal Chem ; 96(5): 1965-1976, 2024 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-38267074

RESUMEN

Exosomes have been established as a valuable tool for clinical applications for the purpose of liquid biopsy and therapy. However, the clinical practice of exosomes as cancer biopsy markers is still to a very low extent. Active mode optical microcavity with microlaser emission has aroused as a versatile approach for chemical and biological sensing due to its benefits of larger photon population, increased effective Q-factor, decreased line width, and improved sensitivity. Herein, we report a label-free and precise quantification of exosome vesicles and surface protein profiling of breast cancer exosomes using functionalized active whispering gallery mode (WGM) microlaser probes. A detection limit of 40 exosomes per microresonator was achieved. The proposed system enabled a pilot assay of quantitative exosome analysis in cancer patients' blood with only a few microliters of sample consumption, holding good potential for large-scale cancer liquid biopsy. Multiplexed functionalization of the optical microresonator allowed us to profile cancer exosomal surface markers and distinct subclasses of breast cancer-associated exosomes and monitor drug treatment outcomes. Our findings speak volumes about the advantages of the WGM microlaser sensor, including very small sample consumption, low detection limit, high specificity, and ease of operation, offering a promising means for precious clinical sample analysis.


Asunto(s)
Neoplasias de la Mama , Exosomas , Humanos , Femenino , Exosomas/metabolismo , Biopsia Líquida , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Rayos Láser
2.
Nat Mater ; 22(8): 999-1006, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37202488

RESUMEN

Ultralow thermal conductivity and fast ionic diffusion endow superionic materials with excellent performance both as thermoelectric converters and as solid-state electrolytes. Yet the correlation and interdependence between these two features remain unclear owing to a limited understanding of their complex atomic dynamics. Here we investigate ionic diffusion and lattice dynamics in argyrodite Ag8SnSe6 using synchrotron X-ray and neutron scattering techniques along with machine-learned molecular dynamics. We identify a critical interplay of the vibrational dynamics of mobile Ag and a host framework that controls the overdamping of low-energy Ag-dominated phonons into a quasi-elastic response, enabling superionicity. Concomitantly, the persistence of long-wavelength transverse acoustic phonons across the superionic transition challenges a proposed 'liquid-like thermal conduction' picture. Rather, a striking thermal broadening of low-energy phonons, starting even below 50 K, reveals extreme phonon anharmonicity and weak bonding as underlying features of the potential energy surface responsible for the ultralow thermal conductivity (<0.5 W m-1 K-1) and fast diffusion. Our results provide fundamental insights into the complex atomic dynamics in superionic materials for energy conversion and storage.

3.
Immunopharmacol Immunotoxicol ; 45(5): 581-588, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36995149

RESUMEN

BACKGROUND: Imperatorin (IMP) is a secondary metabolite of plants and is the most abundant in Angelica dahurica. Previous studies showed that IMP exhibited anti-inflammatory activity in RAW264.7 cell line. Here, we aim to investigate the roles and mechanisms of IMP in bone marrow-derived macrophages (BMDMs), in view of the difference between primary macrophages and cell lines. METHODS: BMDMs were stimulated with LPS for the inflammation model. Flow cytometry was performed with BMDMs treated with different doses of IMP (0-20mg/L) within staining Annexin V-APC for 5 min. The cytokines and inflammatory mediators were detected by RT-PCR or ELISA. RNA-seq was performed in IMP-treated BMDMs or control, stimulated with LPS for 6h. Western blotting is carried out to determine the phosphorylation of p65, ERK1/2, JNK1, p38, and Akt. RESULTS: Our results showed that IMP inhibited IL-12p40, IL-6, TNF-α and IL-1ß in LPS-stimulated BMDMs. RNA-seq analysis suggested that IMP inhibits Toll-like receptor signaling pathway (KEGG), TNF signaling pathway (KEGG), NF-κB signaling pathway (KEGG), Inflammatory Response (GO). In addition, IMP inhibited myd88, tpl2, cxcl1, ptgs2(COX-2) expression in mRNA level. Finally, we found decreased phosphorylation of NF-κB p65 in IMP-treated BMDMs, after stimulated with LPS. CONCLUSION: IMP inhibits IL-12p40, IL-6, TNF-α, and IL-1ß expression in LPS-stimulated BMDMs. IMP inhibits macrophage activation, which maybe resulted in decreased phosphorylation of NF-κB p65. Furthermore, IMP may protect against the progress of inflammatory-related diseases.


Asunto(s)
Lipopolisacáridos , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Subunidad p40 de la Interleucina-12/efectos adversos , Subunidad p40 de la Interleucina-12/metabolismo , Interleucina-6/metabolismo , Fosforilación , Factor de Necrosis Tumoral alfa/metabolismo , Macrófagos/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo
4.
J Med Virol ; 94(11): 5345-5353, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35854470

RESUMEN

Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of critically ill COVID-19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (ß = 0.0075, 95% confidence interval [CI]: -0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio = 1.00, 95% CI: 0.79-1.28, p = 0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction.


Asunto(s)
COVID-19 , Estudio de Asociación del Genoma Completo , COVID-19/genética , Enfermedad Crítica , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Telómero/genética
5.
AAPS PharmSciTech ; 22(7): 226, 2021 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-34426942

RESUMEN

The postprandial glycemic regulation is essential for diabetic patients to reduce the risk of long-term microvascular and macrovascular complications. Herein, we designed a glucose-responsive oral insulin delivery system based on polyelectrolyte complexes (PECs) for controlling the increasing postprandial glucose concentrations. Briefly, alginate-g-3-aminophenylboronic acid (ALG-g-APBA) and chitosan-g-3-fluoro-4-carboxyphenylboronic acid (CS-g-FPBA) were wrapped on mesoporous silica (MSN) to form the negative charged ALG-g-APBA@MSN and the positive charged CS-g-FPBA@MSN nanoparticles, with an optimum insulin loading capacity of 124 mg/g and 295 mg/g, respectively. ALG-g-APBA@MSN was further cross-linked with CS-g-FPBA@MSN to form PECs through electrostatic interaction and borate esters. The dense polyelectrolyte network wrapped on MSN was capable of preventing insulin from diffusion and regulating its release. The in vitro insulin release of PECs demonstrated an obvious glucose response profile in different glucose concentrations (0 mg/mL, 2 mg/mL, 5 mg/mL) and presented a switch "on" and "off" release regulation at hyperglycemic or normal state. The CCK-8 assay showed that none of the MSN, ALG-g-APBA@MSN, CS-g-FPBA@MSN, and PECs possessed cytotoxicity to Caco-2 cells. For in vivo tests, the oral PECs exhibited a significant hypoglycemic effect and maintained in the euglycemic levels up to approximately 12 h on diabetic rats. Overall, the PECs directly triggered by postprandial glucose in the intestine have a good potential to be applied in intelligent insulin delivery by the oral route.


Asunto(s)
Diabetes Mellitus Experimental , Glucosa , Hipoglucemiantes , Insulina , Animales , Células CACO-2 , Diabetes Mellitus Experimental/tratamiento farmacológico , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Polielectrolitos , Ratas , Dióxido de Silicio
6.
J Mater Sci Mater Med ; 31(12): 124, 2020 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-33247776

RESUMEN

As traditional root canal obturation leads to the loss of the biological activity of the tooth, it is necessary to develop a material that promotes the regeneration of dental tissue. However, this remains a challenging task. Our study aims to construct a mineralized material to support the proliferation and differentiation of dental pulp stem cells (DPSCs), and to explore a new strategy for the treatment of pulp tissue necrosis. Mineralized keratin (M-keratin), defined as keratin that has been mineralized in simulated body fluid, was first harvested to construct the root canal filling material. Characterizations indicated that new substances or components were formed on the surface of keratin particles after mineralization, and the morphology of the keratin was changed. M-keratin promoted the growth, proliferation, and differentiation of DPSCs. After cultivation with M-keratin, DPSCs exhibited more extracellular matrix proteins interacting with the culture interface, the number of these cells increased significantly, and the 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyltetrazolium bromide values of cells in the experimental group also increased. Meanwhile, signs that the DPSCs began to differentiate into odontoblasts were observed or detected by alizarin red S staining, ELISA, RNA-Seq, and western blot. We hope that this study will contribute to the development of a new material that promotes the regeneration of dental tissue as well as providing new ideas and strategies for the treatment of dental pulp disease.


Asunto(s)
Microambiente Celular/efectos de los fármacos , Queratinas/farmacología , Odontoblastos/efectos de los fármacos , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Líquidos Corporales/química , Calcificación Fisiológica/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Implantes Dentales , Pulpa Dental/citología , Pulpa Dental/fisiología , Humanos , Queratinas/química , Nanoestructuras/química , Odontoblastos/citología , Odontoblastos/fisiología , Ratas , Células Madre/efectos de los fármacos , Células Madre/fisiología
7.
Fish Physiol Biochem ; 46(5): 1729-1741, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32533395

RESUMEN

To understand the physiological response of estuarine fish to acidification, barramundi (Lates calcarifer) juveniles were exposed to acidified seawater in experimental conditions. The molecular response of barramundi to acidification stress was assessed by RNA-seq analysis. A total of 2188 genes were identified as differential expression genes. The gene ontology classification system and Kyoto Encyclopedia of Genes and Genomes database analysis showed that acidification caused differential expressions of genes and pathways in the gills of barramundi. Acidification had a great influence on the signal transduction pathway in cell process. Furthermore, we detected that numerous unigenes involved in the pathways associated with lipid metabolism, carbohydrate metabolism, amino acid metabolism, glycan biosynthesis and metabolism specific and non-specific immunity were changed. This study indicates that the physiological responses in barramundi especially the immune system and energy allocation correspond to the variation of environmental pH. This study reveals the necessity for assessment of the potential of estuarine fishes to cope with acidification of the environment and the need to develop strategies for fish conservation in coastal areas.


Asunto(s)
Estuarios , Peces/fisiología , Agua de Mar/química , Estrés Fisiológico/genética , Transcripción Genética/fisiología , Adaptación Fisiológica/genética , Animales , Peces/genética , Branquias/citología , Concentración de Iones de Hidrógeno
8.
Bioorg Med Chem Lett ; 29(3): 435-440, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30455146

RESUMEN

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.


Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/química , Receptores CCR1/metabolismo , Relación Estructura-Actividad
9.
Fish Shellfish Immunol ; 89: 127-131, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30930278

RESUMEN

To understand the physiological responses of euryhaline fish to reared salinity, the gut microbiota composition and antioxidant enzymes activity of same batch barramundi Lates calcarifer reared in two extreme salinity condition (seawater and freshwater) were studied, under laboratory condition. The gut bacterial composition was analyzed using high-throughput Illumina sequencing. Acid phosphatase (ACP), catalase (CAT), glutathione peroxidase (GSH-Px), lipid peroxide (LPO), lysozyme (LZM), malonaldehyde (MDA), peroxidase (POD), and superoxide dismutase (SOD) were used as biochemical indicators. The reared salinity did not change the major composition of barramundi gut bacteria under circulating aquaculture system. Proteobacteria, Firmicutes were the most phylum in barramundi gut microbiota community, and Exiguobacterium, Citrobacter, Acinetobacter, Pseudomonas were the dominate genus. CAT and ACP activity in barramundi liver were found significantly different between freshwater and seawater group. GSH-Px, LZM, POD, SOD activity and MDA, LPO levels were not significantly affected by reared salinity. This study is the first high-throughput analyses of the gut microbiota diversity in barramundi from same batch of siblings reared under two extreme salinity condition. And the findings in the present study can be instructive to the management of animal health in barramundi circulating farming activities, and further euryhaline fish gut microecology research.


Asunto(s)
Antioxidantes/metabolismo , Microbioma Gastrointestinal , Hígado/enzimología , Perciformes/metabolismo , Perciformes/microbiología , Animales , Bacterias/genética , Agua Dulce , ARN Bacteriano/análisis , ARN Ribosómico 16S/análisis , Agua de Mar , Análisis de Secuencia de ARN/veterinaria
10.
J Biol Chem ; 292(28): 11618-11630, 2017 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-28546429

RESUMEN

The nuclear receptor retinoid acid receptor-related orphan receptor γt (RORγt) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORγt has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORγt. Here, we report the crystal structures for the ligand-binding domain of RORγt in both apo and ligand-bound states. We show that apo RORγt adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORγt in the active state in the absence of a ligand. The structures of ligand-bound RORγt reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORγt toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Agonismo Inverso de Drogas , Modelos Moleculares , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Apoproteínas/antagonistas & inhibidores , Apoproteínas/química , Apoproteínas/genética , Apoproteínas/metabolismo , Sitios de Unión , Unión Competitiva , Células Cultivadas , Genes Reporteros/efectos de los fármacos , Células HEK293 , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-17/metabolismo , Ligandos , Conformación Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/metabolismo , Fenilalanina/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Compuestos de Fenilurea/farmacología , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Replegamiento Proteico , Estabilidad Proteica , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo
11.
J Endocr Soc ; 8(6): bvae063, 2024 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-38623382

RESUMEN

Context: Iron is an essential element in the human body and plays a critical role in many physiological and cellular processes. However, the association between iron status and the risk of all-cause or cause-specific mortality has not been well-investigated. And it is unclear whether the association between iron metabolic biomarkers and the risk of mortality differs between people with and without diabetes mellitus (DM). Objective: This work aimed to investigate associations between iron metabolic biomarkers and all-cause and cause-specific mortality risk in the general population, and heterogeneities in the associations among population with and without DM.. Methods: A total of 29 166 adults from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999 to 2010 were included, with linkage to the National Death Index to December 31, 2019. Cox proportional-hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between iron metabolic biomarkers and outcomes. Results: During a median follow-up of 18.83 years, 9378 deaths were observed, including 3420 cardiovascular disease (CVD) deaths and 1969 cancer deaths. A significant linear association between serum ferritin (SF) and all-cause mortality was observed among the overall population and those without DM. J-shaped associations between transferrin saturation (TSAT) and all-cause and CVD mortality were observed among all populations. In the overall population, compared to the first quartile (Q1) group, the adjusted hazard ratio (HR) (95% CI) for all-cause mortality was 1.07 (1.00-1.15), 1.05 (0.98-1.12), 1.13 (1.05-1.21) in Q2, Q3, and Q4 groups for SF, while the HR was 0.94 (0.88-0.99), 0.92 (0.86-0.97), and 0.93 (0.88-0.99) for TSAT. In individuals without DM, the adjusted HR of the Q4 of SF were 1.19 (1.03-1.37) for CVD mortality and 1.25 (1.05-1.48) for cancer mortality. In individuals with DM, the adjusted HRs of the Q4 of TSAT were 0.76 (0.62-0.93) for CVD mortality and 1.47 (1.07-2.03) for cancer mortality. Conclusion: Iron metabolism abnormalities increase mortality risk in the general population. The associations of iron status with mortality were significantly different between individuals with and without DM, which indicated tailored strategies for iron homeostasis are needed.

12.
J Mater Chem B ; 11(8): 1808-1817, 2023 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-36734460

RESUMEN

Photodynamic therapy (PDT) has attracted much attention in recent years for its favorable therapeutic efficacy in cancer therapy. However, PDT alone is insufficient to improve the therapeutic efficiency mainly due to the limited penetration depth of light, the insufficient O2 supply in the hypoxic microenvironment, and the high level of reducing substances in cancer cells. To overcome these limitations, a multifunctional MnO2 nanoparticle was constructed with honeycomb MnO2 which was loaded with the photosensitizer Ce6 and modified with polydopamine on its surface (HMnO2/C&P) to achieve efficient PDT/mild photothermal treatment (PTT) combination therapy. HMnO2/C&P had high drug loading contents (11.2% Ce6) and can be responsive to the tumor microenvironment (TME), supply O2 to alleviate the hypoxic microenvironment, and clear GSH to reduce the consumption of ROS, thus enhancing the PDT effect. The introduction of PDA can improve the stability of HMnO2/C&P, and further give the ability of PTT to act as nanomedicine. The results of in vitro and in vivo experiments show that HMnO2/C&P based PDT/mild PTT combination therapy has an excellent inhibitory effect on tumor growth. Meanwhile, HMnO2/C&P can act as a fluorescence imaging reagent and a TME triggerable magnetic resonance imaging (MRI) contrast agent, thus having excellent multimodal self-tracking abilities. Collectively, this study provides a new perspective on the design of multifunctional theranostic nanomedicine to maximize the efficacy of cancer phototherapy.


Asunto(s)
Fotoquimioterapia , Nanomedicina Teranóstica , Nanomedicina Teranóstica/métodos , Compuestos de Manganeso , Óxidos , Fototerapia , Fotoquimioterapia/métodos , Medios de Contraste
13.
Int Immunopharmacol ; 117: 109944, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36871536

RESUMEN

Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Myc is a key regulator of immune cell activity and function, but little is known about how Myc controls NK cell activation and function. In this study, we found that c-Myc is involved in the regulation of NK cell immune activity. In the development of colon cancer, the energy generation disorder of tumor cells promotes the plunder of polyamines of NK cells by tumor cells, resulting in the inhibition of NK cell c-Myc. After inhibition of c-Myc, glycolysis of NK cells was impaired, resulting in decreased killing activity. There are three main types of polyamines: putrescine (Put), spermidine (Spd) and spermine (Spm). We found that the NK cells could reverse the inhibition state of c-Myc and glycolysis energy supply disorder and recover the killing activity of NK cells after giving certain spermidine. These results suggest that polyamine content and glycolysis supply under the regulation of c-Myc play a crucial role in the immune activity of NK cells.


Asunto(s)
Neoplasias Colorrectales , Poliaminas , Humanos , Poliaminas/metabolismo , Poliaminas/farmacología , Espermidina/farmacología , Espermidina/metabolismo , Glucólisis , Células Asesinas Naturales/metabolismo
14.
Artículo en Inglés | MEDLINE | ID: mdl-35479514

RESUMEN

Background: Tao-He-Cheng-Qi Formula (THCQF) is a traditional Chinese medicine that has been proven to have antitumor effects. The aim of this study was to elucidate the molecular targets and mechanisms of THCQF against colon cancer and construct a prognostic model based on network pharmacology, bioinformatics analysis, and in vitro experiments. Methods: Potential THCQF compounds and targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine databases. Differentially expressed genes for colon cancer were screened in The Cancer Genome Atlas and Gene Expression Omnibus databases. The anticolon cancer mechanisms of THCQF were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking simulations and molecular dynamics analysis were used to evaluate the binding between target proteins and active compounds. Finally, the identified compounds were used to treat colon cancer cells from the HCT116 cell line, and expression of mRNA and protein after relevant posttreatment were tested using real-time polymerase chain reaction and western blotting. Results: A total of 27 anticolon cancer targets of THCQF were selected, among which four genes (CCNB1, CCNA2, IL1A, and MMP3) were shown to effectively predict patient outcomes in a prognostic colon cancer model. GO and KEGG enrichment analyses indicated that the activity against colon cancer of THCQF was associated with the interleukin (IL)-4 and IL-3 signaling pathways. Two compounds in THCQF, aloe emodin (AE) and quercetin (QR), were shown to efficiently bind to cyclin B1, the protein encoded by CCNB1. Finally, incubation of HCT116 cells with AE and QR significantly decreased CCNB1 mRNA expression and cyclin B1 levels. Conclusions: Taken together, the results indicate that AE and QR are the pivotal active compounds of THCQF, and CCNB1 is the main molecular target through which THCQF exerts its anticolon cancer effects. The study findings provide insight for studies investigating the anticancer effects of other traditional Chinese medicines.

15.
Nat Commun ; 13(1): 237, 2022 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-35017505

RESUMEN

Low-grade heat accounts for >50% of the total dissipated heat sources in industries. An efficient recovery of low-grade heat into useful electricity not only reduces the consumption of fossil-fuels but also releases the subsequential environmental-crisis. Thermoelectricity offers an ideal solution, yet low-temperature efficient materials have continuously been limited to Bi2Te3-alloys since the discovery in 1950s. Scarcity of tellurium and the strong property anisotropy cause high-cost in both raw-materials and synthesis/processing. Here we demonstrate cheap polycrystalline antimonides for even more efficient thermoelectric waste-heat recovery within 600 K than conventional tellurides. This is enabled by a design of Ni/Fe/Mg3SbBi and Ni/Sb/CdSb contacts for both a prevention of chemical diffusion and a low interfacial resistivity, realizing a record and stable module efficiency at a temperature difference of 270 K. In addition, the raw-material cost  to the output power ratio in this work is reduced to be only 1/15 of that of conventional Bi2Te3-modules.

16.
MAbs ; 14(1): 2104153, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35916739

RESUMEN

An in-house antibody generation campaign identified a diverse, high affinity set of anti-interleukin-11 (IL-11) monoclonal antibodies (mAbs) to enable successful development of novel, custom ultra-sensitive target engagement assays for detection of "free" (unbound to the dosed anti-IL-11 therapeutic mAb) and "total" (free and mAb-IL-11 complexed form) IL-11 in preclinical species and human. Antibody hits from distinct epitope communities were screened on various platforms, including enzyme-linked immunosorbent assay, Meso Scale Discovery, Simoa HD-1 and Simoa Planar Array (SP-X), and used for assay development and sensitivity optimization. The ultra-sensitive SP-X format achieved a lower limit of quantitation of 0.006 pg/mL, enabling the first reported baseline levels of IL-11 in healthy control plasma determined by custom bioanalytical assays. These newly established baseline levels supported mechanistic pharmacokinetic/pharmacodynamic modeling in mouse, cynomolgus monkey, and human for a greater understanding of preclinical study design and in vivo dynamic interaction of soluble IL-11 with an anti-IL-11 antibody therapeutic candidate. Modeling and simulation also helped refine the utility of assays with respect to their potential use as target engagement biomarkers in the clinic.Abbreviations IL-11: Interleukin-11, TE: Target engagement, PK/PD: Pharmacokinetic/pharmacodynamic, mAb: Monoclonal antibody, NHP: Non-human primate, IgG: Immunoglobulin G, Cyno: Cynomolgulus monkey, GFR: Glomerular filtration rate, BQL: Below quantitation levels, DRM: Disease relevant model, kDa: kilodaltons, SPR: Surface plasmon resonance, pSTAT3: phosphorylated STAT3, IL-11R: Interleukin-11 receptor, TPP: Target product protein, LLOQ: Lower limit of quantitation, RLU: Relative light units.


Asunto(s)
Anticuerpos Monoclonales , Inmunoglobulina G , Animales , Simulación por Computador , Ensayo de Inmunoadsorción Enzimática , Macaca fascicularis , Ratones
17.
Sci Adv ; 7(19)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33962945

RESUMEN

GeTe alloys have recently attracted wide attention as efficient thermoelectrics. In this work, a single-leg thermoelectric device with a conversion efficiency as high as 14% under a temperature gradient of 440 K was fabricated on the basis of GeTe-Cu2Te-PbSe alloys, which show a peak thermoelectric figure of merit (zT) > 2.5 and an average zT of 1.8 within working temperatures. The high performance of the material is electronically attributed to the carrier concentration optimization and thermally due to the strengthened phonon scattering, the effects of which all originate from the defects in the alloys. A design of Ag/SnTe/GeTe contact successfully enables both a prevention of chemical diffusion and an interfacial contact resistivity of 8 microhm·cm2 for the realization of highly efficient devices with a good service stability/durability. Not only the material's high performance but also the device's high efficiency demonstrated the extraordinariness of GeTe alloys for efficient thermoelectric waste-heat recovery.

18.
Sci Adv ; 6(46)2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33188018

RESUMEN

Development of thermoelectrics usually involves trial-and-error investigations, including time-consuming synthesis and measurements. Here, we identify the electronic quality factor BE for determining the maximum thermoelectric power factor, which can be conveniently estimated by a single measurement of Seebeck coefficient and electrical conductivity of only one sample, not necessarily optimized, at an arbitrary temperature. We demonstrate that thousands of experimental measurements in dozens of materials can all be described by a universal curve and a single material parameter BE for each class of materials. Furthermore, any deviation in BE with temperature or doping indicated new effects such as band convergence or additional scattering. This makes BE a powerful tool for evaluating and guiding the development of thermoelectrics. We demonstrate the power of BE to show both p-type GeTe alloys and n-type Mg3SbBi alloys as highly competitive materials, at near room temperature, to state-of-the-art Bi2Te3 alloys used in nearly all commercial applications.

19.
Research (Wash D C) ; 2020: 8151059, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32025663

RESUMEN

Maximizing band degeneracy and minimizing phonon relaxation time are proven to be successful for advancing thermoelectrics. Alloying with monotellurides has been known to be an effective approach for converging the valence bands of PbTe for electronic improvements, while the lattice thermal conductivity of the materials remains available room for being further reduced. It is recently revealed that the broadening of phonon dispersion measures the strength of phonon scattering, and lattice dislocations are particularly effective sources for such broadening through lattice strain fluctuations. In this work, a fine control of MnTe and EuTe alloying enables a significant increase in density of electron states near the valence band edge of PbTe due to involvement of multiple transporting bands, while the creation of dense in-grain dislocations leads to an effective broadening in phonon dispersion for reduced phonon lifetime due to the large strain fluctuations of dislocations as confirmed by synchrotron X-ray diffraction. The synergy of both electronic and thermal improvements successfully leads the average thermoelectric figure of merit to be higher than that ever reported for p-type PbTe at working temperatures.

20.
Adv Sci (Weinh) ; 6(16): 1802286, 2019 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-31453051

RESUMEN

Over the past years, thermoelectric Mg3Sb2 alloys particularly in n-type conduction, have attracted increasing attentions for thermoelectric applications, due to the multivalley conduction band, abundance of constituents, and less toxicity. However, the high vapor pressure, causticity of Mg, and the high melting point of Mg3Sb2 tend to cause the inclusion in the materials of boundary phases and defects that affect the transport properties. In this work, a utilization of tantalum-sealing for melting enables n-type Mg3Sb2 alloys to show a substantially higher mobility than ever reported, which can be attributed to the purification of phases and to the coarse grains. Importantly, the inherently high mobility successfully enables the thermoelectric figure of merit in optimal compositions to be highly competitive to that of commercially available n-type Bi2Te3 alloys and to be higher than that of other known n-type thermoelectrics at 300-500 K. This work reveals Mg3Sb2 alloys as a top candidate for near-room-temperature thermoelectric applications.

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