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1.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35105803

RESUMEN

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Femenino , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Células MCF-7 , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Proteínas de Neoplasias/genética , Factores de Transcripción/genética
2.
J Am Chem Soc ; 146(42): 28783-28794, 2024 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-39394087

RESUMEN

Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO4 and TriPEX-PF6) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial mitochondria-derived vacuolation, accompanied by reactive oxygen species generation, decreased mitochondrial membrane potential, and intracellular Ca2+ overload, thereby disrupting metabolisms and inducing nonapoptotic cell death. In vivo imaging revealed that TriPEX-ClO4 and TriPEX-PF6 successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy postintravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to Temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases.


Asunto(s)
Antineoplásicos , Barrera Hematoencefálica , Ferroptosis , Colorantes Fluorescentes , Glioblastoma , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/diagnóstico por imagen , Glioblastoma/patología , Glioblastoma/metabolismo , Ferroptosis/efectos de los fármacos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Animales , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Paraptosis
3.
Pharmacogenet Genomics ; 34(6): 175-183, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38640061

RESUMEN

OBJECTIVES: Reference materials for in-vitro diagnostic reagents play a critical role in determining the quality of reagents and ensuring the accuracy of clinical test results. This study aimed to establish a national reference material (NRM) for detecting cytochrome P450 (CYP) genes related to drug metabolism by screening databases on the Chinese population to identify CYP gene polymorphism characteristics. METHODS: To prepare the NRM, we used DNA extracted from healthy human immortalized B lymphoblastoid cell lines as the raw material. Samples of these cell lines were obtained from the Chinese Population PGx Gene Polymorphism Biobank. Further, we used Sanger sequencing, next-generation sequencing, and commercial assay kits to validate the polymorphic genotypes. RESULTS: Among the CYP superfamily genes, we confirmed 24 riboswitch loci related to drug metabolism, with evidence levels of 1A, 2A, 3, and 4. We confirmed the polymorphic loci and validated their genotypes using various sequencing techniques. Our results were consistent with the polymorphism information of samples obtained from the biobank, thus demonstrating high precision and stability of the established NRM. CONCLUSION: An NRM (360 056-202 201) for CYP genetic testing covering 24 loci related to drug metabolism was established and approved to assess in-vitro diagnostic reagents containing CYP family gene polymorphisms and perform clinical inter-room quality evaluations.


Asunto(s)
Sistema Enzimático del Citocromo P-450 , Pruebas Genéticas , Humanos , Línea Celular , China , Sistema Enzimático del Citocromo P-450/genética , Pruebas Genéticas/normas , Pruebas Genéticas/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Polimorfismo Genético , Estándares de Referencia , Pueblos del Este de Asia/genética
4.
Small ; : e2403295, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39268807

RESUMEN

Lead-free perovskite materials have received extensive attention due to their non-toxicity, super environmental stability and adjustable photoelectric properties. However, the inherent problems of low luminous efficiency and low photoluminescence quantum yields (PLQYs) limit its development in multifunctional applications. Here, Te4+ doped Cs2ZrCl6 with high luminous efficiency and stability for multifunctional applications are developed. Te4+ ions are used as emission centers to improve the optical properties of Cs2ZrCl6 to make efficient and stable single-component white light-emitting diodes (WLEDs), and can be used as scintillator materials to improve scintillation performance to achieve high-resolution and low-dose X-ray imaging detection. In addition, it is found for the first time that Te4+ ions can be introduced into the trap center, so that the Cs2ZrCl6:Te4+ perovskite material exhibits excellent persistent luminescence (PersL) and mechanoluminescence (ML) after X-ray radiation, which has potential applications in the fields of delayed imaging and stress sensing. This work provides a method for designing lead-free perovskites with high optical performance and scintillating properties, as well as developing multifunctional applications.

5.
J Med Virol ; 96(6): e29765, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38924102

RESUMEN

This study aims to investigate the significant relationship between serum heavy metals (lead [Pb], cadmium [Cd], mercury [Hg]) and the risk of herpes simplex virus type 1 (HSV-1) infection. Data were derived from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States from 2007 to 2016. This nationally representative survey, conducted by the National Center for Health Statistics, assessed the health status of participants through interviews, physical examinations, and laboratory tests. After excluding participants lacking serum Pb, Cd, and Hg data, as well as those missing HSV-1 testing data and pregnant women, the analysis included 13 772 participants, among whom 3363 were adolescents. A survey-weighted multivariate logistic regression model was used to evaluate the association between heavy metal exposure and the risk of HSV-1 infection, and to explore the dose-response relationship between them. In adults and adolescents, serum concentrations of Pb and Cd were higher in those infected with HSV-1 than in those not infected. However, an increase in serum Hg concentration was observed only in infected adolescents. After adjusting for potential confounders, elevated serum Pb and Cd concentrations in adults were associated with an increased risk of HSV-1 infection. Higher serum Pb and Cd concentrations were associated with an increased risk of HSV-2 infection, irrespective of HSV-1 infection status. In adults, serum concentrations of Pb and Hg showed an approximately linear relationship with HSV-1 infection risk (p for nonlinearity > 0.05), whereas the dose-response relationship between serum Cd concentration and HSV-1 infection was nonlinear (p for nonlinearity = 0.004). In adolescents, serum concentrations of heavy metals (Pb, Cd, Hg) showed an approximately linear relationship with HSV-1 infection (p for nonlinearity > 0.05). Furthermore, the study examined the relationship between serum heavy metal levels and the risk of HSV-1 infection across different genders, races, income levels, weight statuses, and immune statuses. In conclusion, there is a significant association between serum heavy metal concentrations and HSV-1 infection, which warrants further investigation into the causal relationship between them.


Asunto(s)
Herpes Simple , Herpesvirus Humano 1 , Metales Pesados , Encuestas Nutricionales , Humanos , Femenino , Masculino , Estudios Transversales , Adolescente , Metales Pesados/sangre , Metales Pesados/efectos adversos , Herpes Simple/epidemiología , Herpes Simple/sangre , Adulto , Adulto Joven , Persona de Mediana Edad , Estados Unidos/epidemiología , Cadmio/sangre , Cadmio/efectos adversos , Plomo/sangre , Mercurio/sangre , Niño , Factores de Riesgo , Exposición a Riesgos Ambientales/efectos adversos , Anciano
6.
Opt Lett ; 49(12): 3412-3415, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38875633

RESUMEN

Photoionization is one of the most fundamental processes in light-matter interaction. Advanced attosecond photoelectron spectroscopy provides the possibility to characterize the ultrafast photoemission process in an extremely short attosecond time scale. Following scattering symmetry rules, residual ions encode ultrafast photoionization prints at the instant of electron removal forming an alternative electron emission chronoscope. Here, we experimentally illustrate the attosecond ion reconstruction of attosecond beating by interference of two-photon transition (RABBIT)-like interferometry through the development of high-resolution ion momentum detection in atomic photoionization processes. Our ion interferometry presents identical momentum- and time-dependent scattering phase shift, as we observed in photoelectron spectroscopy, and thus demonstrates that ion interferometry can be a possible alternative attosecond approach to resolve the photoionization process, without the electron homogeneity limitation.

7.
Mol Genet Genomics ; 298(2): 375-387, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36580169

RESUMEN

The yellow colour of ornamental varieties of tree peony originated from Paeonia delavayi. However, but P. delavayi and Paeonia suffruticosa belong to different subgroups, so hybridization is difficult and results in a long breeding cycle. However, no comprehensive transcriptomic profiling has focused on the colour formation mechanisms of yellow tree peony petals. Analysing the colour formation mechanism of yellow petals in P. delavayi is very important for directional molecular breeding. In this study, the transcriptional map of yellow pigment development in petals was used to analyse the mechanism of petal colour formation. We analysed the genes related to the metabolism of flavonoids and carotenoids and the transcription factors (TFs) involved in P. delavayi var. lutea (pure yellow individual) yellow pigment development using transcriptome sequence profiling. Transcriptome sequence profiles revealed three and four differentially expressed transcripts (DETs) involved in flavonoid biosynthesis and carotenoid biosynthesis, respectively. An analysis of DETs in the flavonoid pathway showed that chalcone synthase (CHS) and chalcone 2´-glucosyltransferases (THC2'GT) act in synergy to synthesize isosalipurposide (ISP). CHS and flavonol synthase (FLS) synergistically synthesize quercetin and kaempferol. DEG analysis of the carotenoid pathway revealed that phytoene synthase (PSY), carotenoid isomerase (CRTISO) and ß-carotene hydroxylases (CHYB) play a key role in regulating lutein formation, and carotenoid cleavage dioxygenase (CCD) plays an important role in the degradation of carotenoids. These two pathways may be regulated by TF families such as bHLH, ARF, and MYB. The results of the transient overexpression of genes showed that CHS and CHI are regulated by PdMYB2. In this study, the molecular mechanism of ISP synthesis was analysed in depth, and the complete metabolic pathway of carotenoids in Paeonia L. was reported for the first time. By studying the formation mechanism of yellow pigment in P. delavayi petals, a breeding strategy for improving flavonol and carotenoid contents and reducing anthocyanin synthesis by genetic engineering was suggested.


Asunto(s)
Paeonia , Humanos , Paeonia/genética , Paeonia/metabolismo , Antocianinas/metabolismo , Pigmentación/genética , Fitomejoramiento , Perfilación de la Expresión Génica , Flavonoides/metabolismo , Flores/genética , Flores/metabolismo , Transcriptoma/genética , Carotenoides/metabolismo , Regulación de la Expresión Génica de las Plantas
8.
Small ; 19(22): e2206943, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36755211

RESUMEN

Developing a facile, efficient, and versatile polyphenol coating strategy and exploring its novel applications are of great significance in the fields of material surfaces and interfaces. Herein, a one-step assembly strategy for constructing novel tannic acid (TA) coatings via a solvent evaporation method is reported using TA and polycyclodextrin (PCD) particles (TPP). TPP with a high phenolic group activity of 88% integrates the advantages of host-guest and polyphenol chemistry. The former can drive TPP dynamically assemble into a large and collective aggregation activated by high temperature or density, and the latter provides excellent adhesion properties to substrates (0.9 mg cm-2 ). TPP can assemble into a coating (TPC) rapidly on various substrates within 1 h at 37 °C while with a high availability of feed TPP (≈90%). The resulting TPC is not only high-temperature steam-sensitive for use as an anti-fake mask but also pH-sensitive for transforming into a free-standing film under physiological conditions. Moreover, various metal ions and functional particles can incorporate into TPC to extend its versatile properties including antibacterial activity, enhanced stability, and conductivity. This work expands the polyphenol coating strategy and builds up a one-step and efficient preparation platform of polyphenol coating for multiapplication prospects in various fields.

9.
J Med Virol ; 95(3): e28561, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36755358

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III interferons (IFNs) by targeting the RIG-I/MDA5, Toll-like receptor (TLR3)-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3-5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF- and STING-induced IFN responses. Mechanistically, NSP7 associated with RIG-I and MDA5 prevented the formation of the RIG-I/MDA5-MAVS signalosome and interacted with TRIF and STING to inhibit TRIF-TBK1 and STING-TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nuclear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS-CoV-2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG-I/MDA5-MAVS, TLR3-TRIF, and cGAS-STING signaling pathways, thus providing novel insights into the interactions between SARS-CoV-2 and innate antiviral immunity.


Asunto(s)
COVID-19 , Interferón Tipo I , Humanos , SARS-CoV-2/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Transducción de Señal , Interferones , Inmunidad Innata , Nucleotidiltransferasas/metabolismo , Antivirales , Proteínas Adaptadoras del Transporte Vesicular/genética
10.
J Med Virol ; 95(4): e28680, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36929724

RESUMEN

SARS-CoV-2 has developed a variety of approaches to counteract host innate antiviral immunity to facilitate its infection, replication and pathogenesis, but the molecular mechanisms that it employs are still not been fully understood. Here, we found that SARS-CoV-2 NSP8 inhibited the production of type I and III interferons (IFNs) by acting on RIG-I/MDA5 and the signaling molecules TRIF and STING. Overexpression of NSP8 downregulated the expression of type I and III IFNs stimulated by poly (I:C) transfection and infection with SeV and SARS-CoV-2. In addition, NSP8 impaired IFN expression triggered by overexpression of the signaling molecules RIG-I, MDA5, and MAVS, instead of TBK1 and IRF3-5D, an active form of IRF3. From a mechanistic view, NSP8 interacts with RIG-I and MDA5, and thereby prevents the assembly of the RIG-I/MDA5-MAVS signalosome, resulting in the impaired phosphorylation and nuclear translocation of IRF3. NSP8 also suppressed the TRIF- and STING- induced IFN expression by directly interacting with them. Moreover, ectopic expression of NSP8 promoted virus replications. Taken together, SARS-CoV-2 NSP8 suppresses type I and III IFN responses by disturbing the RIG-I/MDA5-MAVS complex formation and targeting TRIF and STING signaling transduction. These results provide new insights into the pathogenesis of COVID-19.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Proteínas Adaptadoras del Transporte Vesicular/genética , Helicasa Inducida por Interferón IFIH1/genética , Interferones , SARS-CoV-2/metabolismo , Transducción de Señal
11.
Opt Express ; 31(16): 25467-25476, 2023 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-37710432

RESUMEN

Driven by intense laser fields, the outgoing photoelectrons in molecules possess a quiver motion, resulting in the rise of the effective ionization potential. The coupling of the field-dressed ionization potential with abundant molecular dynamics complicates the laser-molecule interactions. Here, we demonstrate an approach to resolve photoelectron releasing order in the dissociative and non-dissociative channels of multiphoton ionization driven by an orthogonally polarized two-color femtosecond laser pulse. The photoelectron kinetic energy releases and the regular nodes in the photoelectron angular distributions due to the participation of different continuum partial waves allow us to deduce the field-dressed ionization potential of various channels. It returns the ponderomotive energy experienced by the outgoing electron and reveals the corresponding photoionization instants within the laser pulse. Our results provide a route to explore the complex strong-field ionization dynamics of molecules using two-dimensional photoelectron momentum spectroscopy.

12.
Phys Rev Lett ; 131(20): 203201, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-38039486

RESUMEN

Multiphoton light-matter interactions invoke a so-called "black box" in which the experimental observations contain the quantum interference between multiple pathways. Here, we employ polarization-controlled attosecond photoelectron metrology with a partial wave manipulator to deduce the pathway interference within this quantum 'black box" for the two-photon ionization of neon atoms. The angle-dependent and attosecond time-resolved photoelectron spectra are measured across a broad energy range. Two-photon phase shifts for each partial wave are reconstructed through the comprehensive analysis of these photoelectron spectra. We resolve the quantum interference between the degenerate p→d→p and p→s→p two-photon ionization pathways, in agreement with our theoretical simulations. Our approach thus provides an attosecond time-resolved microscope to look inside the "black box" of pathway interference in ultrafast dynamics of atoms, molecules, and condensed matter.

13.
Exp Mol Pathol ; 134: 104877, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37952894

RESUMEN

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease without early diagnostic and specific therapeutic approaches. Podocyte apoptosis and loss play important roles in the pathological process of DKD. This study aimed to explore whether urinary exosomes from type 2 diabetes patients with DKD could induce podocyte apoptosis and the underlying pathological mechanisms. The exosomes were isolated from the urine samples of patients with DKD (DKD-Exo). Later, they were taken up and internalized by MPC5 cells. MPC5 cells were co-cultured with DKD-Exo (45 µg/ml) for 24 h in the presence or absence of microRNA-145-5p (miR-145-5p) inhibitor, fasudil and pcDNA-Srgap2 transfection. MiR-145-5p and Srgap2 expression was evaluated using real-time quantitative PCR. The protein levels of Srgap2, Bcl-2, Bax, and cleaved caspase-3, as well as ROCK activity were determined using Western blotting. Cell apoptosis was measured using flow cytometry and the TUNEL assay. miR-145-5p expression in MPC5 cells exposed to DKD-Exo was markedly upregulated. miR-145-5p negatively regulated Srgap2 levels. Exposure of MPC5 cells to DKD-Exo reduced Srgap2 expression and activated ROCK, which was partly reversed by the presence of the miR-145-5p inhibitor or Srgap2 overexpression. The apoptosis of MPC5 cells exposed to DKD-Exo increased significantly, which was counteracted by the addition of the miR-145-5p inhibitor and fasudil. The results showed that urinary exosomal miR-145-5p from patients with DKD induced podocyte apoptosis by inhibiting Srgap2 and activating the RhoA/ROCK pathway, suggesting that urinary exosomal miR-145-5p is involved in the pathological process of DKD and could become a noninvasive diagnostic biomarker for DKD.


Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Exosomas , MicroARNs , Podocitos , Humanos , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , MicroARNs/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Podocitos/patología , Exosomas/metabolismo , Apoptosis/genética
14.
Nucleic Acids Res ; 49(8): 4421-4440, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33849069

RESUMEN

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention.


Asunto(s)
Carcinogénesis , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Peptidasa Específica de Ubiquitina 7/metabolismo , Animales , Femenino , Proteína Forkhead Box O1/metabolismo , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Células Sf9 , Ubiquitinación , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Int J Mol Sci ; 25(1)2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38203307

RESUMEN

PFOA, a newly emerging persistent organic pollutant, is widely present in various environmental media. Previous reports have proved that PFOA exposure can accumulate in the ovary and lead to reproductive toxicity in pregnant mice. However, the potential mechanism of PFOA exposure on fertility remains unclear. In this study, we explore how PFOA compromises fertility in the zebrafish. The data show that PFOA (100 mg/L for 15 days) exposure significantly impaired fertilization and hatching capability. Based on tissue sections, we found that PFOA exposure led to ovarian damage and a decrease in the percentage of mature oocytes. Moreover, through in vitro incubation, we determined that PFOA inhibits oocyte development. We also sequenced the transcriptome of the ovary of female zebrafish and a total of 284 overlapping DEGs were obtained. Functional enrichment analysis showed that 284 overlapping DEGs function mainly in complement and coagulation cascades signaling pathways. In addition, we identified genes that may be associated with immunity, such as LOC108191474 and ZGC:173837. We found that exposure to PFOA can cause an inflammatory response that can lead to ovarian damage and delayed oocyte development.


Asunto(s)
Caprilatos , Fluorocarburos , Ovario , Pez Cebra , Femenino , Embarazo , Animales , Ratones , Fertilidad , Oocitos
16.
Pak J Med Sci ; 39(3): 656-661, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37250586

RESUMEN

Objective: To determine the changes in serum bone metabolism indexes and ultrasonic bone mineral density (BMD) in patients with diabetic nephropathy at different stages, and their effects on diabetic renal microvascular complications. Methods: This is a clinical comparative study. One hundred twenty two diabetic patients admitted to the Baoding No.1 Central Hospital from January 2020 to March 2022 were selected as subjects and divided into three groups according to their actual condition: the simple diabetes (Group-A, 40 cases), diabetic nephropathy with micro urinary protein (Group-B, 40 cases) and diabetic nephropathy with massive proteinuria (Group-C, 42 cases). Another 36 healthy subjects were selected as the control group. Differences in serum bone metabolism indexes and ultrasound BMD levels were compared. Results: Twenty five hydroxy-vitamin D, BGP, T-PINP and ultrasound BMD levels in the control group were > Group-A > Group-B > Group-C, PTH and ß-CTX in the control group were < Group-A < Group-B < Group-C, statistically significant differences (p<0.05). The urinary albumin to urinary creatinine ratio (ACR) value in Group-B was significantly lower than Group-C (p<0.05). Logistic regression analysis showed that 25-hydroxy-vitamin D, PTH, BGP, ß-CTX, T-PINP and ultrasound BMD were the influencing factors of diabetic renal microvascular complications (p<0.05). Conclusion: Bone metabolism indexes and ultrasound bone mineral density are abnormally expressed in patients with diabetic nephropathy at different stages, which are closely related to the urine protein of patients. They have important clinical value in the diagnosis of early diabetic nephropathy.

17.
Angew Chem Int Ed Engl ; 62(2): e202211550, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36336656

RESUMEN

Optimized theranostic strategies for Alzheimer's disease (AD) remain almost absent from bench to clinic. Current probes and drugs attempting to prevent ß-amyloid (Aß) fibrosis encounter failures due to the blood-brain barrier (BBB) penetration challenge and blind intervention time window. Herein, we design a near-infrared (NIR) aggregation-induced emission (AIE) probe, DNTPH, via balanced hydrophobicity-hydrophilicity strategy. DNTPH binds selectively to Aß fibrils with a high signal-to-noise ratio. In vivo imaging revealed its excellent BBB permeability and long-term tracking ability with high-performance AD diagnosis. Remarkably, DNTPH exhibits a strong inhibitory effect on Aß fibrosis and promotes fibril disassembly, thereby attenuating Aß-induced neurotoxicity. DNTPH treatment significantly reduced Aß plaques and rescued learning deficits in AD mice. Thus, DNTPH serves as the first AIE in vivo theranostic agent for real-time NIR imaging of Aß plaques and AD therapy simultaneously.


Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Medicina de Precisión , Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Imagen Óptica/métodos
18.
Crit Rev Eukaryot Gene Expr ; 32(8): 1-8, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36017911

RESUMEN

Long noncoding RNA (lncRNA) PCAT29 has been characterized as a tumor suppressor in several types of cancer, although its involvement in neuroblastoma (NB) is unknown. In this study, we analyzed the role of PCAT29 in NB. In paired NB and nontumor tissues from 56 patients with NB, microRNA (miR)-21 and PCAT29 expression was determined with reverse transcription quantitative PCR. Correlation between miR-21 and PCAT29 was evaluated with linear regression. The interaction between miR-21 and PCAT29 was predicted by the IntaRNA 2.0 program. In NB cells, miR-21 and PCAT29 were overexpressed to explore their relationship. In NB cell proliferation, the roles of miR-21 and PCAT29 were analyzed with propidium iodide staining and Ki67 staining assays. The results showed that PCAT29 was downregulated and miR-21 was upregulated in NB. MiR-21 was inversely correlated with PCAT29. RNA-RNA interaction prediction revealed that miR-21 might target PCAT29. MiR-21 overexpression reduced PCAT29 expression and increased NB cell proliferation, whereas PCAT29 overexpression inhibited NB cell proliferation. PCAT29 overexpression promoted NB cell apoptosis, while miR-21 overexpression inhibited NB cell apoptosis and attenuated PCAT29 overexpression-mediated NB cell apoptosis. In conclusion, MiR-21 may target PCAT29 to promote cell apoptosis in NB.


Asunto(s)
MicroARNs , Neuroblastoma , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , ARN Largo no Codificante/genética
19.
J Med Virol ; 94(11): 5174-5188, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35765167

RESUMEN

A characteristic feature of COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is the dysregulated immune response with impaired type I and III interferon (IFN) expression and an overwhelming inflammatory cytokine storm. RIG-I-like receptors (RLRs) and cGAS-STING signaling pathways are responsible for sensing viral infection and inducing IFN production to combat invading viruses. Multiple proteins of SARS-CoV-2 have been reported to modulate the RLR signaling pathways to achieve immune evasion. Although SARS-CoV-2 infection also activates the cGAS-STING signaling by stimulating micronuclei formation during the process of syncytia, whether SARS-CoV-2 modulates the cGAS-STING pathway requires further investigation. Here, we screened 29 SARS-CoV-2-encoded viral proteins to explore the viral proteins that affect the cGAS-STING signaling pathway and found that SARS-CoV-2 open reading frame 10 (ORF10) targets STING to antagonize IFN activation. Overexpression of ORF10 inhibits cGAS-STING-induced interferon regulatory factor 3 phosphorylation, translocation, and subsequent IFN induction. Mechanistically, ORF10 interacts with STING, attenuates the STING-TBK1 association, and impairs STING oligomerization and aggregation and STING-mediated autophagy; ORF10 also prevents the endoplasmic reticulum (ER)-to-Golgi trafficking of STING by anchoring STING in the ER. Taken together, these findings suggest that SARS-CoV-2 ORF10 impairs the cGAS-STING signaling by blocking the translocation of STING and the interaction between STING and TBK1 to antagonize innate antiviral immunity.


Asunto(s)
COVID-19 , Interferón Tipo I , Autofagia , Humanos , Inmunidad Innata , Interferón Tipo I/genética , Interferones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/genética , Sistemas de Lectura Abierta , Proteínas Serina-Treonina Quinasas/genética , SARS-CoV-2 , Proteínas Virales/metabolismo
20.
Bioconjug Chem ; 33(5): 829-838, 2022 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-35413182

RESUMEN

Tyrosine, a simple and well-available natural amino acid, is featured by the small size of the compound that contains multiple reactive groups. This study developed an efficient bioconjugation strategy using tyrosine-based dual-functional interfaces. When tyrosine molecules are immobilized on the surface of a supporting material through amino groups, their carboxyl groups can function as an attracting trap due to their anionic nature at neutral pH and ability to chelate nickel(II) ions (Ni2+), allowing the capture and enrichment of cationic proteins and histidine (His)-tagged proteins on the surface. The trapped proteins can be further covalently immobilized on site through ruthenium-mediated photochemical cross-linking, which has been found to be highly efficient and can be completed within minutes. This strategy was successfully applied to two different material systems. We found that tyrosine-modified agarose beads had a binding capacity of the His-tagged enhanced green fluorescent protein comparable to that of commonly used nitrilotriacetic acid-based resins, and further covalent coupling via dityrosine cross-linking achieved a yield of 85% within 5 min, without compromising much on its fluorescence activity. On the surface of tyrosine-modified 316L stainless steel, lysozyme was captured through electrostatic interaction and further immobilized. The resultant surface exhibited remarkable antibacterial activity against both Staphylococcus aureus and Escherichia coli. Such a tyrosine-based capture-then-coupling method is featured by its simplicity, high coupling efficiency, and high utilization rate of target molecules, making it particularly suitable for the proteins that are highly priced or vulnerable to general immobilization chemistry.


Asunto(s)
Histidina , Ácido Nitrilotriacético , Histidina/química , Indicadores y Reactivos , Níquel/química , Ácido Nitrilotriacético/química , Tirosina/química
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