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Cell size is tightly controlled in healthy tissues, but it is unclear how deviations in cell size affect cell physiology. To address this, we measured how the cell's proteome changes with increasing cell size. Size-dependent protein concentration changes are widespread and predicted by subcellular localization, size-dependent mRNA concentrations, and protein turnover. As proliferating cells grow larger, concentration changes typically associated with cellular senescence are increasingly pronounced, suggesting that large size may be a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative, DNA-damage-induced, and CDK4/6i-induced senescence. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by an increase in ploidy. Together, our findings show how cell size could impact many aspects of cell physiology by remodeling the proteome and provide a rationale for cell size control and polyploidization.
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Senescencia Celular , Proteoma , Tamaño de la Célula , Senescencia Celular/fisiología , Daño del ADN , Proteoma/genéticaRESUMEN
BACKGROUND: The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. RESULTS: Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P = 0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group. CONCLUSIONS: In older patients with hypertension, intensive treatment with a systolic blood-pressure target of 110 to less than 130 mm Hg resulted in a lower incidence of cardiovascular events than standard treatment with a target of 130 to less than 150 mm Hg. (Funded by the Chinese Academy of Medical Sciences and others; STEP ClinicalTrials.gov number, NCT03015311.).
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Antihipertensivos/administración & dosificación , Hipertensión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Femenino , Humanos , Hipertensión/complicaciones , Hipotensión/inducido químicamente , Incidencia , Masculino , Persona de Mediana Edad , Nivel de Atención , SístoleRESUMEN
In the chemical investigation of Inula japonica, a total of 29 sesquiterpenoids (1-29) were obtained, including pseudoguaine-, xanthane-, eudesmane-, and 1,10-secoeudesmane-type compounds, as well as their dimers. Among them, six new dimeric sesquiterpenoids, bisinulains A-F (1-5, 7), characterized by a [4 + 2] biogenetic pathway between different sesquiterpenoid monomers were identified. Additionally, three new monomers named inulaterins A-C (13, 18 and 21) were discovered. The structures of these compounds were determined through analysis of spectroscopic data, X-ray crystallographic data, and ECD experiments. To assess their potential anti-inflammatory activities, the sesquiterpenoid dimers were tested for their ability to inhibit NO production in LPS-stimulated RAW 264.7 cells. Furthermore, the compounds that exhibited anti-inflammatory effects underwent evaluation for their anti-fibrotic potential using a TGF-ß-induced epithelial-mesenchymal transition model in A549 cells. As a result, bisinulain B (2) was screened out to significantly inhibit the production of cytokines involved in pulmonary fibrosis such as NO, α-SMA, collagen I and fibronectin.
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Inula , Sesquiterpenos , Animales , Ratones , Humanos , Inula/química , Estructura Molecular , Células RAW 264.7 , Antiinflamatorios/farmacología , Antiinflamatorios/química , Células A549 , Sesquiterpenos/farmacología , Sesquiterpenos/químicaRESUMEN
A series of pyrimidine-2,4-diamine analogues were designed and synthesized. Their anticancer activity and the underlying mechanism against colorectal cancer (CRC) HCT116 cells and non-small cell lung cancer (NSCLC) A549 cells were investigated. The results demonstrated that the active compound Y18 significantly inhibited cancer cell proliferation by inducing robust cell cycle arrest and cell senescence through the persistence of DNA damage. Additionally, Y18 exhibited significant inhibitory effects on the adhesion, migration and invasion of cancer cells in vitro. Mechanistically, Y18 achieved these anticancer activities by suppressing GTSE1 transcription and expression. Y18 also effectively inhibited tumor growth in vivo with minimal side effects. Furthermore, Y18 exhibited a suitable half-life and oral bioavailability (16.27%), with limited inhibitory activity on CYP isoforms. Taken together, these results suggested that Y18 could be a potential chemotherapeutic drug for cancer treatment, particularly in cases of GTSE1 overexpressed cancers.
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Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.
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Senescencia Celular , Neoplasias Hepáticas , Acortamiento del Telómero , Proteína 2 de Unión a Repeticiones Teloméricas , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/antagonistas & inhibidores , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Acortamiento del Telómero/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ratones , Ratones Desnudos , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Masculino , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The prognosis of advanced ovarian cancer is often poor. Although there are several treatment options for stage IV epithelial ovarian cancer, it is not clear which treatment will benefit the patient's prognosis.We conducted an analysis using the SEER database to compare the impact of different treatment modalities on the prognosis of advanced ovarian cancer. METHODS: The present study conducts a retrospective analysis of relevant data from the SEER database pertaining to patients diagnosed with stage IV epithelial ovarian cancer between 2011 and 2020 (n = 5345). Statistical methods including Kaplan-Meier curves, log-rank tests, and Cox regression analysis are employed to ascertain the impact of different treatment regimens on the prognosis of patients with stage IV epithelial ovarian cancer. RESULTS: Among patients with stage IV epithelial ovarian cancer, age ≥ 60 and the presence of lung metastases or multiple metastases were identified as poor prognostic factors. Conversely, being Asian or Pacific Islander, married, and testing negative for CA125 were associated with favorable prognoses. In terms of the choice of treatment for patients, surgery plus chemotherapy was the best treatment modality, and timely surgery could significantly improve the prognosis of patients, but there was no difference between chemoradiotherapy alone and the surgery group among patients with lung metastases. CONCLUSION: The prognosis of patients with stage IV epithelial ovarian cancer is influenced by many factors. In terms of the choice of treatment, patients with surgery plus chemotherapy have the best prognosis. In cases where lung metastases are inoperable, a combination of radiotherapy and chemotherapy can be used. In other cases, radiotherapy does not improve outcomes in patients with stage IV epithelial ovarian cancer. This study provides a basis for the choice of treatment for patients with stage IV epithelial ovarian cancer.
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Carcinoma Epitelial de Ovario , Estadificación de Neoplasias , Neoplasias Ováricas , Programa de VERF , Humanos , Femenino , Carcinoma Epitelial de Ovario/terapia , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/mortalidad , Persona de Mediana Edad , Neoplasias Ováricas/terapia , Neoplasias Ováricas/patología , Estudios Retrospectivos , Pronóstico , Anciano , Adulto , Terapia Combinada , Bases de Datos Factuales , Estimación de Kaplan-Meier , Estados Unidos/epidemiologíaRESUMEN
The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here, we describe a new mouse model to investigate the consequences of RB depletion and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to Rb knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo.
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Neoplasias Hipofisarias/genética , Proteínas de Unión a Retinoblastoma/genética , Neoplasias de la Tiroides/genética , Animales , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Factores de Transcripción E2F/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Ratones Transgénicos , Células 3T3 NIH , Neoplasias Hipofisarias/patología , ARN Interferente Pequeño/metabolismo , Neoplasias de la Tiroides/patologíaRESUMEN
At present, there is a research gap concerning the specific functions and mechanisms of the Notch gene family and its signaling pathway in jawless vertebrates. In this study, we identified a Notch1 homologue (Lr. Notch1) in the Lethenteron reissneri database. Through bioinformatics analysis, we identified Lr. Notch1 as the likely common ancestor gene of the Notch gene family in higher vertebrates, indicating a high degree of conservation in the Notch gene family and its signaling pathways. To validate the biological function of Lr. Notch1, we conducted targeted silencing of Lr. Notch1 in L. reissneri and analyzed the resultant gene expression profile before and after silencing using transcriptome analysis. Our findings revealed that the silencing of Lr. Notch1 resulted in differential expression of pathways and genes associated with signal transduction, immune regulation, and metabolic regulation, mirroring the biological function of the Notch signaling pathway in higher vertebrates. This article systematically elucidated the origin and evolution of the Notch gene family while also validating the biological function of Lr. Notch1. These insights offer valuable clues for understanding the evolution of the Notch signaling pathway and establish a foundation for future research on the origin of the Notch signaling pathway, as well as its implications in human diseases and immunomodulation.
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Biología Computacional , Perfilación de la Expresión Génica , Humanos , Animales , Filogenia , Bases de Datos Factuales , Inmunomodulación , Receptores NotchRESUMEN
The metabotropic glutamate receptor (mGluR, GRM) family is involved in multiple signaling pathways and regulates neurotransmitter release. However, the evolutionary history, distribution, and function of the mGluRs family in lampreys have not been determined. Therefore, we identified the mGluRs gene family in the genome of Lethenteron reissneri, which has been conserved throughout vertebrate evolution. We confirmed that Lr-GRM3, Lr-GRM5, and Lr-GRM7 encode three types of mGluRs in lamprey. Additionally, we investigated the distribution of Lr-GRM3 within this species by qPCR and Western blotting. Furthermore, we conducted RNA sequencing to investigate the molecular function of Lr-GRM3 in lamprey. Our gene expression profile revealed that, similar to that in jawed vertebrates, Lr-GRM3 participates in multiple signal transduction pathways and influences synaptic excitability in lampreys. Moreover, it also affects intestinal motility and the inflammatory response in lampreys. This study not only enhances the understanding of mGluRs' gene evolution but also highlights the conservation of GRM3's role in signal transduction while expanding our knowledge of its functions specifically within lampreys. In summary, our experimental findings provide valuable insights for studying both the evolution and functionality of the mGluRs family.
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Evolución Molecular , Lampreas , Receptores de Glutamato Metabotrópico , Animales , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Lampreas/genética , Lampreas/metabolismo , Filogenia , Transducción de SeñalRESUMEN
The frequently mutated phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene is associated with multiple tumors and endocytosis of viruses. Identification of muted nucleotides at the hotspot can help in finding the susceptible people who are vulnerable to cancers and viruses. Herein, a simple enzyme-free colorimetric method is developed for the quick detection of PIK3CA gene mutations. The main mechanism lies in the dissimilar interactions between praseodymia nanorods and different nucleotides, as well as the underlying oxidase-mimicking characteristics of praseodymia. With rational designs of probes and processes, this method has great potential for expanded applications in the screening of mutations in other genes of interest.
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Colorimetría , Neoplasias , Humanos , Dominio Catalítico , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genética , NucleótidosRESUMEN
Arbuscular mycorrhizal (AM) fungi can form mutualistic endosymbiosis with > 70% of land plants for obtaining fatty acids and sugars, in return, AM fungi promote plant nutrients and water acquisition to enhance plant fitness. However, how AM fungi orchestrate its own signaling components in response to drought stress remains elusive. Here, we identify a transcription factor containing C2H2 zinc finger domains, RiMsn2 from Rhizophagus irregularis. To characterize the RiMsn2, we combined heterologous expression, subcellular localization in yeasts, and biochemical and molecular studies with reverse genetics approaches during the in planta phase. The results indicate that RiMsn2 is highly conserved across AM fungal species and induced during the early stages of symbiosis. It is significantly upregulated in mycorrhizal roots under severe drought conditions. The nucleus-localized RiMsn2 regulates osmotic homeostasis and trehalose contents of yeasts. Importantly, gene silencing analyses indicate that RiMsn2 is essential for arbuscule formation and enhances plant tolerance to drought stress. Results from yeasts and biochemical experiments suggest that the RiHog1-RiMsn2-STREs module controls the drought stress-responsive genes in AM fungal symbiont. In conclusion, our findings reveal that a module centered on the transcriptional activator RiMsn2 from AM fungus regulates drought stress tolerance in host plant.
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Micorrizas , Micorrizas/fisiología , Sequías , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Simbiosis/genética , Raíces de Plantas/metabolismo , Levaduras , Regulación de la Expresión Génica de las PlantasRESUMEN
Biliary tract cancer (BTC) is a highly malignant tumor that originates from bile duct epithelium and is categorized into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA) and gallbladder cancer (GBC) according to the anatomic location. Inflammatory cytokines generated by chronic infection led to an inflammatory microenvironment which influences the carcinogenesis of BTC. Interleukin-6 (IL-6), a multifunctional cytokine secreted by kupffer cells, tumor-associated macrophages, cancer-associated fibroblasts (CAFs) and cancer cells, plays a central role in tumorigenesis, angiogenesis, proliferation, and metastasis in BTC. Besides, IL-6 serves as a clinical biomarker for diagnosis, prognosis, and monitoring for BTC. Moreover, preclinical evidence indicates that IL-6 antibodies could sensitize tumor immune checkpoint inhibitors (ICIs) by altering the number of infiltrating immune cells and regulating the expression of immune checkpoints in the tumor microenvironment (TME). Recently, IL-6 has been shown to induce programmed death ligand 1 (PD-L1) expression through the mTOR pathway in iCCA. However, the evidence is insufficient to conclude that IL-6 antibodies could boost the immune responses and potentially overcome the resistance to ICIs for BTC. Here, we systematically review the central role of IL-6 in BTC and summarize the potential mechanisms underlying the improved efficacy of treatments combining IL-6 antibodies with ICIs in tumors. Given this, a future direction is proposed for BTC to increase ICIs sensitivity by blocking IL-6 pathways.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , Humanos , Interleucina-6 , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/terapia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Citocinas , Anticuerpos , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Microambiente TumoralRESUMEN
The wireless communication system is used to provide dispatching, control, communication and other services for rail transit operations. In practice, interference from other wireless communication systems will affect the normal operation of trains, so it is an urgent problem to study the interference detection algorithms for rail transit applications. In this paper, the fourth-order cyclic cumulant (FOCC) of signals with different modulation modes is analyzed for the narrow-band wireless communications system of rail transit. Based on the analysis results, an adjacent-frequency interference detection algorithm is proposed according to the FOCC of the received signal within the predetermined cyclic frequency range. To detect interference with the same carrier frequency, a same-frequency interference detection algorithm using the relationship between the FOCC and the received power is proposed. The performance of the proposed detection algorithms in terms of correct rate and computational complexity is analyzed and compared with the traditional second-order statistical methods. Simulation results show that when an interference signal coexists with the expected signal, the correct rates of the adjacent-frequency and the same-frequency interference detection algorithms are greater than 90% when the signal-to-noise ratio (SNR) is higher than 2 dB and -4 dB, respectively. Under the practical rail transit wireless channel with multipath propagation and the Doppler effect, the correct rates of the adjacent-frequency and the same-frequency interference detection algorithms are greater than 90% when the SNR is higher than 3 dB and 7 dB, respectively. Compared with the existing second-order statistical methods, the proposed method can detect both the adjacent-frequency and the same-frequency interference when the interference signals coexist with the expected signal. Although the computational complexity of the proposed method is increased, it is acceptable in the application of rail transit wireless communication interference detection.
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Although multitargeted PtIV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. Herein, we report the synthesis of PtIV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted PtIV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumor in vivo. This research adds to the array of synthetic methods for accessing PtIV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a PtIV center.
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Antineoplásicos , Profármacos , Platino (Metal) , Ligandos , Profármacos/farmacología , Antineoplásicos/farmacología , Línea Celular TumoralRESUMEN
miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal-binding protein-interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination-mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer.
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Transformación Celular Neoplásica , Neoplasias del Colon/patología , Endodesoxirribonucleasas/metabolismo , MicroARNs/genética , Animales , Línea Celular Tumoral , Humanos , Ratones , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas pp60(c-src)RESUMEN
Elevated serum uric acid (UA) level has been shown to be influenced by multiple genetic variants, but it remains uncertain how UA-associated variants differ in their influence on hyperuricemia risk in people taking antihypertensive drugs. We examined a total of 43 UA-related variants at 29 genes in 1840 patients with hypertension from a community-based longitudinal cohort during a median 2.25-year follow-up (including 1031 participants with normal UA, 440 prevalent hyperuricemia at baseline, and 369 new-onset hyperuricemia). Compared with the wild-type genotypes, patients carrying the SLC2A9 rs3775948G allele or the rs13129697G allele had decreased risk of hyperuricemia, while patients carrying the SLC2A9 rs11722228T allele had increased risk of hyperuricemia, after adjustment for cardiovascular risk factors and correction for multiple comparisons; moreover, these associations were modified by the use of diuretics, ß-blockers, or angiotensin converting enzyme inhibitors. The rs10821905A allele of A1CF gene was associated with increased risk of hyperuricemia, and this risk was enhanced by diuretics use. The studied variants were not observed to confer risk for incident cardiovascular events during the follow-up. In conclusion, the genes SLC2A9 and A1CF may serve as potential genetic markers for hyperuricemia risk in relation to antihypertensive drugs therapy in Chinese hypertensive patients.
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Hipertensión , Hiperuricemia , Antihipertensivos/efectos adversos , Diuréticos/efectos adversos , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hiperuricemia/complicaciones , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/genética , Estudios Longitudinales , Factores de Riesgo , Ácido Úrico/uso terapéuticoRESUMEN
Zirconium-89 (89Zr) has been explored for molecularly targeted positron emission tomography (PET) imaging of various diseases. We synthesized and evaluated a novel chelator (DA-18C6-BHA) for 89Zr. The new chelator is structured on a macrocyclic backbone (1,10-diaza-18-crown-6) and contains hydroxamates as acyclic donor groups. The new chelator ((DA-18C6-BHA) was rapidly labeled with 89Zr under mild conditions. The 89Zr-labeled DA-18C6-BHA complex remained stable in human serum and apotransferrin for 7 days. When challenged with excess EDTA solution, 89Zr-labeled DA-18C6-BHA was shown to hold 89Zr without losing considerable radioactivity to EDTA. The 89Zr-labeled DA-18C6-BHA complex displayed high complex stability in normal mice as evidenced by low bone uptake.
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Quelantes , Éteres Corona , Animales , Hidroxianisol Butilado , Ácido Edético , Humanos , Ácidos Hidroxámicos , Ratones , Tomografía de Emisión de Positrones/métodos , Radioisótopos , CirconioRESUMEN
BACKGROUND: Results regarding the association between migraine and risk of stroke are inconsistent. METHODS: A literature search of the databases (Web of Science, Google Scholar and PubMed) was made before December 2021. STATA 12.0 software was used. Odds ratios (ORs) or relative risks (RRs) and their 95% confidence intervals (CIs) regarding migraine and risk of stroke were computed. RESULTS: Migraine was associated with increased risks of total stroke, ischemic stroke (IS) and haemorrhagic stroke (HS) (total stroke: OR/RR = 1.62; 95% CI: 1.44-1.83, I2 = 95.8%, p < 0.001; IS: OR/RR = 1.70; 95% CI: 1.47-1.98, I2 = 96.1%, p < 0.001; HS: OR/RR = 1.35; 95% CI: 1.11-1.63, I2 = 85.7%, p < 0.001). Migraine with aura was related to increased risks of total stroke, IS and HS (total stroke: OR/RR = 1.95; 95% CI: 1.62-2.34, I2 = 89.7%, p < 0.001; IS: OR/RR = 2.17; 95% CI: 1.78-2.64, I2 = 89.2%, p < 0.001; HS: OR/RR = 1.30; 95% CI: 1.04-1.62, I2 = 46.3%, p = 0.114). Migraine without aura was related to increased risks of total stroke, IS and HS (total stroke: OR/RR = 1.35; 95% CI: 1.18-1.55, I2 = 85.4%, p < 0.001; IS: OR/RR = 1.34; 95% CI: 1.11-1.62, I2 = 87.8%, p < 0.001; HS: OR/RR = 1.29; 95% CI: 1.04-1.61, I2 = 64.8%, p = 0.023). CONCLUSIONS: Migraine is associated with a higher risk of total stroke and IS. However, the association between migraine and risk of HS is with more uncertainty.
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Accidente Cerebrovascular Hemorrágico , Accidente Cerebrovascular Isquémico , Trastornos Migrañosos , Accidente Cerebrovascular , Humanos , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/epidemiología , Oportunidad Relativa , Riesgo , Factores de Riesgo , Accidente Cerebrovascular/complicacionesRESUMEN
Aero-optical effect correction has become a crucial issue in airborne infrared imaging. However, it is impractical to test the correction algorithm using flight tests and numerical simulation because of its high cost. This study proposes a dynamic imaging simulation method for the infrared aero-optical effect based on a continuously varying Gaussian superposition model. The influence of infrared image degradation under different high-speed aerodynamic flow fields was investigated in detail. A continuously varying Gaussian superposition model was established for flight speed, altitude, and attitude. A dynamic infrared scene simulation model was constructed. Experimental results show that the proposed method can realistically simulate actual aero-optical effects of any flight case. Moreover, it can simulate continuous frames of aerodynamically degraded infrared images. The method uses a simpler model than numerical simulation and provides more data for multitype tasks.
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OBJECTIVE: To investigate the effect and mechanism of piceatannol on cerebral ischemia-reperfusion injury. METHODS: The oxygen-glucose deprivation reperfusion (OGD/R) model was constructed in primary cultured suckling rat cortical neuron cells. After 2â h of oxygen-glucose deprivation, the cells were treated with piceatannol for 24â h. The cell survival rate was detected by MTT assay, and the degree of cell damage was detected by intracellular lactate dehydrogenase (LDH) release assay. The activity of superoxide dismutase (SOD) and the content of adenosine triphosphate (ATP) were detected by colorimetric method. The content of reactive oxygen species (ROS) was detected by flow cytometry or observed with inverted fluorescence microscope. The ultrastructure of mitochondria was observed with transmission electron microscopy. Western blotting was used to detect the phosphorylation levels of protein kinase B (AKT) and glycogen synthase kinase (GSK)-3ß. Immunofluorescence staining was used to observe the nuclear localization of nuclear factor-erythroid 2-related factor (Nrf) 2. After OGD/R neuron cells were pretreated with Nrf2 inhibitor ML385 for 24â h, the effect of Nrf2 on the improvement of cell activity and antioxidant activity of piceatannol were investigated. Western blotting was used to detect the protein expression levels of Nrf2, heme oxygenase (HO) 1 and NADPH quinone oxidoreductase (NQO) 1. RESULTS: Piceatannol significantly increased the survival rate of OGD/R neurons, decreased LDH release and reactive oxygen species content, increased SOD activity, ameliorated mitochondrial ultrastructural damage, increased mitochondrial membrane potential and ATP level (all P<0.05), increased phosphorylation of AKT and GSK-3ß protein, up-regulated the expression of Nrf2, HO-1 and NQO1 protein, increased the nuclear-to-plasma ratio of Nrf2, and promoted the nuclear transfer of Nrf2 (all P<0.05). ML385 could significantly reverse the rescue effect of paclitaxel on the model cells and the regulatory activities of SOD, ROS and LDH (all P<0.05). CONCLUSION: Piceatannol can regulate Nrf2 by activating GSK-3ß signaling pathway, promote its nuclear translocation, exert corresponding antioxidant effect, and protect mitochondrial structure and function in rat neuron cells.