RESUMEN

BACKGROUND: Stroke and traumatic intracranial hemorrhage (tICH) are major causes of disability worldwide, with stroke exerting significant negative effects on the brain, potentially elevating tICH risk. In this study, we investigated tICH risk in stroke survivors. METHODS AND RESULTS: Using relevant data (2017-2019) from Taiwan's National Health Insurance Research Database, we conducted a population-based retrospective cohort study. Patients were categorized into stroke and nonstroke groups, and tICH risk was compared using a Cox proportional-hazards model. Among 164 628 patients with stroke, 1004 experienced tICH. Patients with stroke had a higher tICH risk than nonstroke counterparts (adjusted hazard ratio [HR], 3.49 [95% CI, 3.17-3.84]). Subgroup analysis by stroke type revealed higher tICH risk in hemorrhagic stroke survivors compared with ischemic stroke survivors (HR, 5.64 [95% CI, 4.97-6.39] versus 2.87 [95% CI, 2.58-3.18], respectively). Older patients (≥45 years) with stroke had a higher tICH risk compared with their younger counterparts (<45 years), in contrast to younger patients without stroke (HR, 7.89 [95% CI, 6.41-9.70] versus 4.44 [95% CI, 2.99-6.59], respectively). Dementia and Parkinson disease emerged as significant tICH risk factors (HR, 1.69 [95% CI, 1.44-2.00] versus 2.17 [95% CI, 1.71-2.75], respectively). In the stroke group, the highest tICH incidence density occurred 3 months after stroke, particularly in patients aged >65 years. CONCLUSIONS: Stroke survivors, particularly those with hemorrhagic stroke and those aged ≥45 years, face elevated tICH risk. Interventions targeting the high-risk period are vital, with fall injuries potentially contributing to tICH incidence.

RESUMEN

The requirement to improve the efficiency of pesticide utilization has led to the development of sustainable and smart stimuli-responsive pesticide delivery systems. Herein, a novel avermectin nano/micro spheres (AVM@HPMC-Oxalate) with sensitive stimuli-response function target to the Lepidoptera pests midgut microenvironment (pH 8.0-9.5) was constructed using hydroxypropyl methylcellulose (HPMC) as the cost-effective and biodegradable material. The avermectin (AVM) loaded nano/micro sphere was achieved with high AVM loading capacity (up to 66.8 %). The simulated release experiment proved the rapid stimuli-responsive and pesticides release function in weak alkaline (pH 9) or cellulase environment, and the release kinetics were explained through release models and SEM characterization. Besides, the nano/micro sphere size made AVM@HPMC-Oxalate has higher foliar retention rate (1.6-2.1-fold higher than commercial formulation) which is beneficial for improving the utilization of pesticides. The in vivo bioassay proved that AVM@HPMC-Oxalate could achieve the long-term control of Plutella xylostella by extending UV shielding performance (9 fold higher than commercial formulation). After 3 h of irradiation, the mortality rate of P. xylostella treated by AVM@HPMC-Oxalate still up to 56.7 % ± 5.8 %. Moreover, AVM@HPMC-Oxalate was less toxic to non-target organisms, and the acute toxicity to zebrafish was reduced by 2-fold compared with AVM technical.

Asunto(s)

Ivermectina , Mariposas Nocturnas , Rayos Ultravioleta , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacología , Ivermectina/toxicidad , Animales , Mariposas Nocturnas/efectos de los fármacos , Insecticidas/química , Insecticidas/farmacología , Insecticidas/toxicidad , Celulosa/química , Celulosa/análogos & derivados , Derivados de la Hipromelosa/química , Concentración de Iones de Hidrógeno , Liberación de Fármacos

RESUMEN

BACKGROUND: Alleviating the sore throat caused by acute pharyngitis is a primary patient concern. However, antibiotics are not commonly recommended drugs, and abuse can lead to serious consequences such as drug resistance. Therefore, seeking alternative treatments is necessary. PURPOSE: To investigate the efficacy and safety of Kegan Liyan (KGLY) oral liquid for patients with acute pharyngitis. STUDY DESIGN: Randomized, double-blinded, placebo-controlled, multi-center study. METHODS: Participants from 17 hospitals were randomly assigned 1:1 to receive KGLY oral liquid or placebo for five days. Assessments occurred at baseline, day 3, and day 6. The primary outcome was the recovery rate. Secondary outcomes included sore throat and cough visual analogue scale (VAS), the area under the curve (AUC) of sore throat VAS, time to sore throat relief and recovery, proportion of participants with sore throat relief and recovery, traditional Chinese medicine (TCM) syndrome score, single TCM manifestation score and use of acetaminophen. RESULTS: Involving 239 participants (120 in KGLY and 119 in placebo group), the study found a significantly higher recovery rate on day 6 in the KGLY group (between-group difference, 27.20 % [15.00 % to 39.40 %], p < 0.001). On day 3 and 6, the KGLY group showed significantly larger reductions in sore throat (-3.02 vs -2.37, p = 0.001; -4.66 vs -3.64, p < 0.001) and cough VAS scores (-1.55 vs -1.05, p = 0.004; -2.28 vs -1.56, p < 0.001) from baseline. KGLY oral liquid lowered the AUC of sore throat VAS score (-2.33 [-4.10 to -0.56], p = 0.011), shortened time to sore throat recovery (hazard ratio, 0.42 [0.30 to 0.59], p < 0.001), increased sore throat recovery rate at day 6 (75.00 % vs 42.86 %, p < 0.001), decreased the TCM syndrome score (-2.03 [-2.69 to -1.37], p < 0.001), and improved individual TCM symptoms compared to placebo. No significant differences between the groups in acetaminophen usage. KGLY oral liquid was safe and tolerated. CONCLUSION: KGLY oral liquid may be a beneficial and safe alternative treatment for acute pharyngitis, which can alleviate symptoms such as sore throat, swollen throat, cough, and phlegm production.

RESUMEN

Fluid shear stress (FSS) from blood flow, sensed by the vascular endothelial cells (ECs) that line all blood vessels, regulates vascular development during embryogenesis, controls adult vascular physiology and determines the location of atherosclerotic plaque formation. Although a number of papers have reported a crucial role for cell-cell adhesions or adhesion receptors in these processes, a recent publication has challenged this paradigm, presenting evidence that ECs can very rapidly align in fluid flow as single cells without cell-cell contacts. To address this controversy, four independent laboratories assessed EC alignment in fluid flow across a range of EC cell types. These studies demonstrate a strict requirement for cell-cell contact in shear stress sensing over timescales consistent with previous literature and inconsistent with the newly published data.

Asunto(s)

Células Endoteliales , Uniones Intercelulares , Mecanotransducción Celular , Estrés Mecánico , Humanos , Uniones Intercelulares/metabolismo , Células Endoteliales/metabolismo , Animales , Resistencia al Corte , Adhesión Celular/fisiología

RESUMEN

Endothelial tissues are essential mechanosensors in the vasculature and facilitate adaptation to various blood flow-induced mechanical cues. Defects in endothelial mechanoresponses can perturb tissue remodelling and functions leading to cardiovascular disease progression. In this context, the precise mechanisms of endothelial mechanoresponses contributing to normal and diseased tissue functioning remain elusive. Here, we sought to uncover how flow-mediated transcriptional regulation drives endothelial mechanoresponses in healthy and atherosclerotic-prone tissues. Using bulk RNA sequencing, we identify novel mechanosensitive genes in response to healthy unidirectional flow (UF) and athero-prone disturbed flow (DF). We find that the transcription as well as protein expression of Four-and-a-half LIM protein 2 (FHL2) are enriched in athero-prone DF both in vitro and in vivo. We then demonstrate that the exogenous expression of FHL2 is necessary and sufficient to drive discontinuous adherens junction morphology and increased tissue permeability. This athero-prone phenotype requires the force-sensitive binding of FHL2 to actin. In turn, the force-dependent localisation of FHL2 to stress fibres promotes microtubule dynamics to release the RhoGEF, GEF-H1, and activate the Rho-ROCK pathway. Thus, we unravelled a novel mechanochemical feedback wherein force-dependent FHL2 localisation promotes hypercontractility. This misregulated mechanoresponse creates highly permeable tissues, depicting classic hallmarks of atherosclerosis progression. Overall, we highlight crucial functions for the FHL2 force-sensitivity in tuning multi-scale endothelial mechanoresponses.

RESUMEN

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Quimioterapia de Inducción , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Persona de Mediana Edad , Masculino , Femenino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/tratamiento farmacológico , Adulto , China/epidemiología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/terapia , Quimioradioterapia/métodos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anciano , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Adulto Joven , Adolescente , Supervivencia sin Progresión

RESUMEN

Olaquindox (OLA) and quinocetone (QCT) have been prohibited in aquatic products due to their significant toxicity and side effects. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) were developed for the simultaneous quantitative detection of OLA, QCT, and 3-methyl-quinoxaline-2-carboxylic acid (MQCA) in fish feed and tissue. The EuNP-LFSBs enabled sensitive detection for OLA, QCT, and MQCA with a limit of detection of 0.067, 0.017, and 0.099 ng/mL (R2 ≥ 0.9776) within 10 min. The average recovery of the EuNP-LFSBs was 95.13%, and relative standard deviations were below 9.38%. The method was verified by high-performance liquid chromatography (HPLC), and the test results were consistent. Therefore, the proposed LFSBs serve as a powerful tool to monitor quinoxalines in fish feeds and their residues in fish tissues.

Asunto(s)

Alimentación Animal , Antibacterianos , Técnicas Biosensibles , Europio , Peces , Quinoxalinas , Quinoxalinas/análisis , Animales , Antibacterianos/análisis , Alimentación Animal/análisis , Nanopartículas , Cromatografía Líquida de Alta Presión , Nanopartículas del Metal

RESUMEN

GABBR1 receptors have been implicated in the progression of rheumatoid arthritis (RA), and p38 MAP kinase (MAPK) was shown to be downregulated by GABA and result in unchecked production of pro-inflammatory cytokine. GABBR1 is a member of GABA receptors, and it is known to be upregulated and plays a vital role in RA. Glucocorticoids are efficient therapeutics in rheumatoid arthritis (RA) and are known to regulate GABA actions; therefore, we intended to investigate the potential of glucocorticoids in RA concerning the potential pathway GABBR1/MAPK. Joint specimens were obtained from collagen-induced arthritis mouse model. A double-blind semi-quantitative analysis of vascularity, cell infiltration, as well as lining thickness by help of a 4-point scale setting was used to assess joint inflammation. Expression of GABBR1 and p38 was evaluated immunohistochemically. In vitro peripheral blood (PB), synovial fluid (SF), and mononuclear cells (MCs) were acquired from RA mice. Western blotting was used for detecting expression of GABBR1 and p38 proteins. The presence of high levels of GABBR1 and p38 was prevalent in RA joints relative to healthy joints and related to the inflammation level. Glucocorticoid treatment alters GABBR1 along with p38 protein expression in joints while reducing joint inflammation. Ex vivo and in vitro assays revealed glucocorticoids have a direct impact on p38, such as the decreased GABBR1 expression level after dexamethasone incubation with SFMC. GABBR1 together with p38 expression in RA joints depends on local inflammation and can be targeted by glucocorticoids.

Asunto(s)

Artritis Experimental , Artritis Reumatoide , Glucocorticoides , Proteínas Quinasas p38 Activadas por Mitógenos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Animales , Glucocorticoides/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Artritis Experimental/patología , Ratones , Masculino , Articulaciones/patología , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Ratones Endogámicos DBA , Líquido Sinovial/metabolismo , Líquido Sinovial/efectos de los fármacos , Microambiente Celular/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.

Asunto(s)

Factores de Transcripción ARNTL , Animales Recién Nacidos , Hiperoxia , Animales , Hiperoxia/metabolismo , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Ratones , Femenino , Masculino , Pulmón/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Caracteres Sexuales

RESUMEN

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Asunto(s)

Receptores Opioides kappa , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Animales , Ratones , Relación Estructura-Actividad , Masculino , Humanos , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/síntesis química , Hipnóticos y Sedantes/química , Ratas , Analgésicos/farmacología , Analgésicos/síntesis química , Analgésicos/química , Descubrimiento de Drogas , Ratas Sprague-Dawley , Cricetulus

RESUMEN

BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.

Asunto(s)

Proteína Similar al Receptor de Calcitonina , Enfermedad de la Arteria Coronaria , Células Endoteliales , Elementos de Facilitación Genéticos , Polimorfismo de Nucleótido Simple , Estrés Mecánico , Humanos , Células Endoteliales/metabolismo , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Proteína Similar al Receptor de Calcitonina/genética , Proteína Similar al Receptor de Calcitonina/metabolismo , Factores de Transcripción del Choque Térmico/genética , Factores de Transcripción del Choque Térmico/metabolismo , Mecanotransducción Celular , Células Cultivadas , Regulación de la Expresión Génica , Unión Proteica , Predisposición Genética a la Enfermedad , Sitios de Unión

RESUMEN

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.

RESUMEN

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/µL v 335 cells/µL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Asunto(s)

Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/mortalidad , Adulto , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/mortalidad , Anciano , Cuello

RESUMEN

Diosgenin, a natural steroidal sapogenin, has recently attracted a high amount of attention, as an effective anticancer agent in ovarian cancer. However, diosgenin mediated anticancer impacts are still not completely understood. Thus, the present study evaluated the effect of diosgenin on the proliferation, apoptosis, and metastasis of ovarian cancer cells. OVCAR-3 and SKOV-3 cells were treated with diosgenin, cellular viability was assessed by MTT assay and apoptosis was measured by ELISA and evaluated the protein expression levels of apoptotic markers through western blotting. Cell migration was examined by measuring the mRNA levels of genes involved in the cell invasion. The protein expression levels of main components of PI3K signaling were evaluated via western blotting. Diosgenin led to significant inhibition of cellular proliferation in a dose-dependent manner. It also induced apoptosis through upregulating pro-apoptotic markers and downregulating antiapoptotic mediators. In addition, OVCAR-3 cells exposure to diosgenin decreased cell migration and invasion. More importantly, diosgenin downregulated the expression levels of main proteins in PI3K signaling including PI3K, Akt, mTOR, and GSK3. Diosgenin inhibited the proliferation and migration of OVCAR-3 ovarian cancer cells and induced apoptosis, which may be mediated by targeting PI3K signaling.

Asunto(s)

Diosgenina , Neoplasias Ováricas , Fosfohidrolasa PTEN , Femenino , Humanos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Diosgenina/farmacología , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfohidrolasa PTEN/efectos de los fármacos , Fosfohidrolasa PTEN/metabolismo , Regulación hacia Arriba

RESUMEN

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Asunto(s)

Asma , COVID-19 , Humanos , Tos Crónica , Estudios Longitudinales , COVID-19/complicaciones , SARS-CoV-2 , Asma/complicaciones , Asma/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Tos , Disnea/tratamiento farmacológico , Administración por Inhalación

RESUMEN

The increasing demand for improving pesticide utilization efficiency has prompted the development of sustainable, targeted, and stimuli-responsive delivery systems. Herein, a multi-stimuli-responsive nano/microcapsule bidirectional delivery system loaded with pyraclostrobin (Pyr) is prepared through interfacial cross-linking from a lignin-based Pickering emulsion template. During this process, methacrylated alkali lignin nanoparticles (LNPs) are utilized as stabilizers for the tunable oil-water (O/W) Pickering emulsion. Subsequently, a thiol-ene radical reaction occurs with the acid-labile cross-linkers at the oil-water interface, leading to the formation of lignin nano/microcapsules (LNCs) with various topological shapes. Through the investigation of the polymerization process and the structure of LNC, it was found that the amphiphilicity-driven diffusion and distribution of cyclohexanone impact the topology of LNC. The obtained Pyr@LNC exhibits high encapsulation efficiency, tunable size, and excellent UV shielding to Pyr. Additionally, the flexible topology of the Pyr@LNC shell enhances the retention and adhesion of the foliar surface. Furthermore, Pyr@LNC exhibits pH/laccase-responsive targeting against Botrytis disease, enabling the intelligent release of Pyr. The in vivo fungicidal activity shows that efficacy of Pyr@LNC is 53% ± 2% at 14 days postspraying, whereas the effectiveness of Pyr suspension concentrate is only 29% ± 4%, and the acute toxicity of Pyr@LNC to zebrafish is reduced by more than 9-fold compared with that of Pyr technical. Moreover, confocal laser scanning microscopy shows that the LNCs can be bidirectionally translocated in plants. Therefore, the topology-regulated bidirectional delivery system LNC has great practical potential for sustainable agriculture.

Asunto(s)

Lignina , Plaguicidas , Estrobilurinas , Animales , Lignina/química , Plaguicidas/farmacología , Cápsulas/química , Emulsiones/química , Pez Cebra , Agua

RESUMEN

Strawberry anthracnose (Colletotrichum gloeosporioides) exhibits a high pathogenicity, capable of directly infecting leaves through natural openings, resulting in devastating impacts on strawberries. Here, nanocomposite (CuS@Cu-MOF) was prepared with a high photothermal conversion efficiency of 35.3% and a strong response to near-infrared light (NIR) by locally growing CuS nanoparticles on the surface of a copper-based metal-organic framework (Cu-MOF) through in situ sulfurization. The porosity of Cu-MOF facilitated efficient encapsulation of the pesticide difenoconazole within CuS@Cu-MOF (DIF/CuS@Cu-MOF), achieving a loading potential of 19.18 ± 1.07%. Under NIR light irradiation, DIF/CuS@Cu-MOF showed an explosive release of DIF, which was 2.7 times higher than that under dark conditions. DIF/CuS@Cu-MOF exhibited a 43.9% increase in efficacy against C. gloeosporioides compared to difenoconazole microemulsion (DIF ME), demonstrating prolonged effectiveness. The EC50 values for DIF and DIF/CuS@Cu-MOF were 0.219 and 0.189 µg/mL, respectively. Confocal laser scanning microscopy demonstrated that the fluorescently labeled CuS@Cu-MOF acted as a penetrative carrier for the uptake of hyphae. Furthermore, DIF/CuS@Cu-MOF exhibited more substantial resistance to rainwater wash-off than DIF ME, with retention levels on the surfaces of cucumber leaves (hydrophilicity) and peanut leaves (hydrophobicity) increasing by 36.5-fold and 9.4-fold, respectively. These findings underscore the potential of nanocomposite to enhance pesticide utilization efficiency and leaf retention.

Asunto(s)

Fragaria , Nanopartículas , Plaguicidas , Cobre , Rayos Infrarrojos

RESUMEN

The leaching of ionic rare earth elements has caused serious environmental pollution and ecological damage. Microorganisms play a crucial role in soil ecosystems and are one of the most important components of these systems. However, there are fewer studies related to the changes that occur in microbial community structure and diversity before and after leaching in ionic rare earth mines. In this study, Illumina high-throughput sequencing was used to examine the diversity and composition of soil microorganisms on the summit, hillside, and foot valley surfaces of unleached and leached mines after in situ leaching. The results showed that microbial diversity and abundance in the surface soil of the unleached mine were higher than those in the leached mine, and leaching had a significant impact on the microbial community of mining soil. pH was the main factor affecting the microbial community. Proteobacteria, Actinobacteriota, and Chloroflexi were phyla that showed high abundance in the soil. Network analysis showed that microbial interactions can improve microbial adaptation and stability in harsh environments. PICRUSt2 predictions indicate functional changes and linkages in soil microbial communities.

Asunto(s)

Metales de Tierras Raras , Microbiota , Contaminantes del Suelo , Metales de Tierras Raras/análisis , Suelo/química , Microbiología del Suelo , Contaminantes del Suelo/análisis

RESUMEN

Vascular homeostasis and pathophysiology are tightly regulated by mechanical forces generated by hemodynamics. Vascular disorders such as atherosclerotic diseases largely occur at curvatures and bifurcations where disturbed blood flow activates endothelial cells while unidirectional flow at the straight part of vessels promotes endothelial health. Integrated analysis of the endothelial transcriptome, the 3D epigenome, and human genetics systematically identified the SNP-enriched cistrome in vascular endothelium subjected to well-defined atherosclerosis-prone disturbed flow or atherosclerosis-protective unidirectional flow. Our results characterized the endothelial typical- and super-enhancers and underscored the critical regulatory role of flow-sensitive endothelial super-enhancers. CRISPR interference and activation validated the function of a previously unrecognized unidirectional flow-induced super-enhancer that upregulates antioxidant genes NQO1, CYB5B, and WWP2, and a disturbed flow-induced super-enhancer in endothelium which drives prothrombotic genes EDN1 and HIVEP in vascular endothelium. Our results employing multiomics identify the cis-regulatory architecture of the flow-sensitive endothelial epigenome related to atherosclerosis and highlight the regulatory role of super-enhancers in mechanotransduction mechanisms.

Asunto(s)

Aterosclerosis , Células Endoteliales , Mecanotransducción Celular , Humanos , Aterosclerosis/genética , Endotelio Vascular

RESUMEN

The development of effective multifunctional nano-delivery approaches for pesticide absorption remains a challenge. Here, a dextran-based pesticide delivery system (MBD) is constructed to deliver tebuconazole for multidimensionally enhancing its effective utilization on tomato plants. Spherical MBD nanoparticles are obtained through two-step esterification of dextran, followed by tebuconazole loading using the Michael addition reaction. Confocal laser scanning microscopy shows that fluorescein isothiocyanate-labeled MBD nanoparticles can be bidirectionally transported in tomato plants and a modified quick, easy, cheap, effective, rugged, and safe-HPLC approach demonstrates the capacity to carry tebuconazole to plant tissues after 24 h of root uptake and foliar spray, respectively. Additionally, MBD nanoparticles could increase the retention of tebuconazole on tomato leaves by up to nearly 2.1 times compared with the tebuconazole technical material by measuring the tebuconazole content retained on the leaves. In vitro antifungal and pot experiments show that MBD nanoparticles improve the inhibitory effect of tebuconazole against botrytis cinerea by 58.4% and the protection against tomato gray molds by 74.9% compared with commercial suspensions. Furthermore, the MBD nanoparticles do not affect the healthy growth of tomato plants. These results underline the potential for the delivery system to provide a strategy for multidimensional enhancement of pesticide efficacy.

Asunto(s)

Plaguicidas , Solanum lycopersicum , Dextranos , Plantas