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1.
Food Chem ; 462: 141011, 2025 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-39226643

RESUMEN

Chlorogenic acid (CGA) is a well-known plant secondary metabolite exhibiting multiple physiological functions. The present study focused on screening for synergistic antibacterial combinations containing CGA. The combination of CGA and p-coumaric acid (pCA) exhibited remarkably enhanced antibacterial activity compared to that when administering the treatment only. Scanning electron microscopy revealed that a low-dose combination treatment could disrupt the Shigella dysenteriae cell membrane. A comprehensive analysis using nucleic acid and protein leakage assay, conductivity measurements, and biofilm formation inhibition experiments revealed that co-treatment increased the cell permeability and inhibited the biofilm formation substantially. Further, the polyacrylamide protein- and agarose gel-electrophoresis indicated that the proteins and DNA genome of Shigella dysenteriae severely degraded. Finally, the synergistic bactericidal effect was established for fresh-cut tomato preservation. This study demonstrates the remarkable potential of strategically selecting antibacterial agents with maximum synergistic effect and minimum dosage exhibiting excellent antibacterial activity in food preservation.


Asunto(s)
Antibacterianos , Ácido Clorogénico , Ácidos Cumáricos , Sinergismo Farmacológico , Shigella dysenteriae , Antibacterianos/farmacología , Antibacterianos/química , Ácidos Cumáricos/farmacología , Ácidos Cumáricos/química , Ácido Clorogénico/farmacología , Ácido Clorogénico/química , Shigella dysenteriae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Biopelículas/efectos de los fármacos , Propionatos/farmacología , Solanum lycopersicum/química , Solanum lycopersicum/microbiología , Conservación de Alimentos/métodos
2.
Prev Med Rep ; 46: 102877, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39309699

RESUMEN

Background: The α-klotho (αKl) is widely accepted as an anti-aging and anti-inflammatory protein. However, it is rarely reported on the function and mechanism of αKl in the overall population (including healthy people and those with history of chronic disease). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are established as predictors of systemic inflammation. This study aims to investigate the relationship between NLR, PLR, and αKl levels in the overall population. Methods: Data from 10,124 adults aged 40 years old and above, collected from NHANES 2007-2016, were analyzed. Associations between NLR, PLR, and αKl levels were assessed by weighted multivariate linear regression analyses, adjusting for potential confounders. Subgroup analysis was conducted by gender, age, diabetes, cardiovascular disease, and chronic kidney disease. Results: Weighted linear regression models showed that a significant negative correlation was observed between both NLR and PLR with αKl levels. Subgroup analysis revealed that the negative correlation between NLR and serum αKl levels was not significant in individuals aged 40-59 years and males, while this relationship remained stable across most other subgroups. The negative correlation between PLR and serum αKl levels was consistent across most subgroups but not significant in individuals with cardiovascular disease. Conclusion: Our study revealed a significant negative relationship between inflammatory markers (NLR and PLR) and serum αKl levels, suggesting systemic inflammation may be linked to reduced αKl expression. Subgroup analyses showed that the relationship varies across different demographic and health-related factors. We provided insight into the significance of managing inflammation and preserving αKl levels.

3.
Molecules ; 29(18)2024 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-39339490

RESUMEN

A Dy(III) coordination polymer (CP), [Dy(spasds)(H2O)2]n (1) (Na2Hspasds = 5-(4-sulfophenylazo)salicylic disodium salt), has been synthesized using a hydrothermal method and characterized. 1 features a 2D layered structure, where the spasda3- anions act as pentadentate ligands, adopting carboxylate, sulfonate and phenolate groups to bridge with four Dy centers in η3-µ1: µ2, η2-µ1: µ1, and monodentate coordination modes, respectively. It possesses a unique (4,4)-connected net with a Schläfli symbol of {44·62}{4}2. The luminescence study revealed that 1 exhibited a broad fluorescent emission band at 392 nm. Moreover, the visual blue color has been confirmed by the CIE plot. 1 can serve as a dual-functional luminescent sensor toward Fe3+ and MnO4- through the luminescence quenching effect, with limits of detection (LODs) of 9.30 × 10-7 and 1.19 × 10-6 M, respectively. The LODs are relatively low in comparison with those of the reported CP-based sensors for Fe3+ and MnO4-. In addition, 1 also has high selectivity and remarkable anti-interference ability, as well as good recyclability for at least five cycles. Furthermore, the potential application of the sensor for the detection of Fe3+ and MnO4- was studied through simulated wastewater samples with different concentrations. The possible sensing mechanisms were investigated using Ultraviolet-Visible (UV-Vis) absorption spectroscopy and density functional theory (DFT) calculations. The results revealed that the luminescence turn-off effects toward Fe3+ and MnO4- were caused by competitive absorption and photoinduced electron transfer (PET), and competitive absorption and inner filter effect (IFE), respectively.

4.
IEEE J Transl Eng Health Med ; 12: 558-568, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39155920

RESUMEN

Vital signs are important indicators to evaluate the health status of patients. Channel state information (CSI) can sense the displacement of the chest wall caused by cardiorespiratory activity in a non-contact manner. Due to the influence of clutter, DC components, and respiratory harmonics, it is difficult to detect reliable heartbeat signals. To address this problem, this paper proposes a robust and novel method for simultaneously extracting breath and heartbeat signals using software defined radios (SDR). Specifically, we model and analyze the signal and propose singular value decomposition (SVD)-based clutter suppression method to enhance the vital sign signals. The DC is estimated and compensated by the circle fitting method. Then, the heartbeat signal and respiratory signal are obtained by the modified variational modal decomposition (VMD). The experimental results demonstrate that the proposed method can accurately separate the respiratory signal and the heartbeat signal from the filtered signal. The Bland-Altman analysis shows that the proposed system is in good agreement with the medical sensors. In addition, the proposed system can accurately measure the heart rate variability (HRV) within 0.5m. In summary, our system can be used as a preferred contactless alternative to traditional contact medical sensors, which can provide advanced patient-centered healthcare solutions.


Asunto(s)
Frecuencia Cardíaca , Procesamiento de Señales Asistido por Computador , Programas Informáticos , Humanos , Frecuencia Cardíaca/fisiología , Masculino , Adulto , Algoritmos , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/instrumentación , Femenino , Respiración , Adulto Joven
5.
Nat Commun ; 15(1): 6867, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39127753

RESUMEN

Artificial Intelligence (AI) techniques have made great advances in assisting antibody design. However, antibody design still heavily relies on isolating antigen-specific antibodies from serum, which is a resource-intensive and time-consuming process. To address this issue, we propose a Pre-trained Antibody generative large Language Model (PALM-H3) for the de novo generation of artificial antibodies heavy chain complementarity-determining region 3 (CDRH3) with desired antigen-binding specificity, reducing the reliance on natural antibodies. We also build a high-precision model antigen-antibody binder (A2binder) that pairs antigen epitope sequences with antibody sequences to predict binding specificity and affinity. PALM-H3-generated antibodies exhibit binding ability to SARS-CoV-2 antigens, including the emerging XBB variant, as confirmed through in-silico analysis and in-vitro assays. The in-vitro assays validate that PALM-H3-generated antibodies achieve high binding affinity and potent neutralization capability against spike proteins of SARS-CoV-2 wild-type, Alpha, Delta, and the emerging XBB variant. Meanwhile, A2binder demonstrates exceptional predictive performance on binding specificity for various epitopes and variants. Furthermore, by incorporating the attention mechanism inherent in the Roformer architecture into the PALM-H3 model, we improve its interpretability, providing crucial insights into the fundamental principles of antibody design.


Asunto(s)
Anticuerpos Antivirales , COVID-19 , Regiones Determinantes de Complementariedad , Epítopos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , Humanos , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Regiones Determinantes de Complementariedad/inmunología , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , COVID-19/inmunología , COVID-19/virología , Epítopos/inmunología , Anticuerpos Neutralizantes/inmunología , Inteligencia Artificial
6.
Molecules ; 29(12)2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38931007

RESUMEN

A novel coordination polymer [Zn(atyha)2]n (1) (Hatyha = 2-(2-aminothiazole-4-yl)-2- hydroxyiminoacetic acid) was constructed by hydrothermal reaction of Zn2+ with Hatyha ligand. CP 1 exhibits a 2D (4,4)-connected topological framework with Schläfli symbol of {44·62}, where atyha- anions serve as tridentate ligands, bridging with Zn2+ through carboxylate, thiazole and oxime groups. CP 1 displays a strong ligand-based photoluminescence at 390 nm in the solid state, and remains significantly structurally stable in water. Interestingly, it can be utilized as a fluorescent probe for selective and sensitive sensing of Fe3+, Cr2O72- and MnO4- through the fluorescent turn-off effect with limit of detection (LOD) of 3.66 × 10-6, 2.38 × 10-5 and 2.94 × 10-6 M, respectively. Moreover, the efficient recyclability for detection of Fe3+ and Cr2O72- is better than that for MnO4-. The mechanisms of fluorescent quenching involve reversible overlap of UV-Vis absorption bands of the analytes (Fe3+, Cr2O72- and MnO4-) with fluorescence excitation and emission bands for CP 1, respectively.

7.
Mar Drugs ; 22(6)2024 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-38921594

RESUMEN

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.


Asunto(s)
Plaquetas , Células Endoteliales de la Vena Umbilical Humana , Sepsis , Factor de von Willebrand , Animales , Sepsis/tratamiento farmacológico , Factor de von Willebrand/metabolismo , Humanos , Ratones , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Masculino , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/antagonistas & inhibidores , Permeabilidad Capilar/efectos de los fármacos
8.
Int J Clin Pharmacol Ther ; 62(6): 284-292, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38577751

RESUMEN

AIMS: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. MATERIALS AND METHODS: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. RESULTS: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. CONCLUSION: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.


Asunto(s)
Área Bajo la Curva , Estudios Cruzados , Ayuno , Interacciones Alimento-Droga , Hidroxicloroquina , Comprimidos , Equivalencia Terapéutica , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/sangre , Masculino , Adulto , Femenino , Adulto Joven , Voluntarios Sanos , Pueblo Asiatico , Semivida , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Administración Oral , China , Pueblos del Este de Asia
9.
IEEE Trans Pattern Anal Mach Intell ; 46(10): 6731-6747, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38602857

RESUMEN

In this paper, we propose a general deep learning training framework XGrad which introduces weight prediction into the popular gradient-based optimizers to boost their convergence and generalization when training the deep neural network (DNN) models. In particular, ahead of each mini-batch training, the future weights are predicted according to the update rule of the used optimizer and are then applied to both the forward pass and backward propagation. In this way, during the whole training period, the optimizer always utilizes the gradients w.r.t. the future weights to update the DNN parameters, making the gradient-based optimizer achieve better convergence and generalization compared to the original optimizer without weight prediction. XGrad is rather straightforward to implement yet pretty effective in boosting the convergence of gradient-based optimizers and the accuracy of DNN models. Empirical results concerning five popular optimizers including SGD with momentum, Adam, AdamW, AdaBelief, and AdaM3 demonstrate the effectiveness of our proposal. The experimental results validate that XGrad can attain higher model accuracy than the baseline optimizers when training the DNN models.

11.
Nature ; 626(7997): 33, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38291139
12.
Water Res ; 250: 121094, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38183799

RESUMEN

The biological safety of drinking water plays a crucial role in public health protection. However, research on the drinking water microbiome remains in its infancy, especially little is known about the potentially pathogenic bacteria in and functional characteristics of the microbiome in household tap water that people are directly exposed to. In this study, we used a genomic-centric approach to construct a genetic catalogue of the drinking water microbiome by analysing 116 metagenomic datasets of household tap water worldwide, spanning nine countries/regions on five continents. We reconstructed 859 high-quality metagenome-assembled genomes (MAGs) spanning 27 bacterial and 2 archaeal phyla, and found that the core MAGs belonging to the phylum Proteobacteria encoded the highest metabolic functional diversity of the 33 key complete metabolic modules. In particular, we found that two core MAGs of Brevibacillus and Methylomona encoded genes for methane metabolism, which may support the growth of heterotrophic organisms observed in the oligotrophic ecosystem. Four MAGs of complete ammonia oxidation (comammox) Nitrospira were identified and functional metabolic analysis suggested these may enable mixotrophic growth and encode genes for reactive oxygen stress defence and arsenite reduction that could aid survival in the environment of oligotrophic drinking water systems. Four MAGs were annotated as potentially pathogenic bacteria (PPB) and thus represented a possible public health concern. They belonged to the genera Acinetobacter (n = 3) and Mycobacterium (n = 1), with a total relative abundance of 1.06 % in all samples. The genomes of PPB A. junii and A. ursingii were discovered to contain antibiotic resistance genes and mobile genetic elements that could contribute to antimicrobial dissemination in drinking water. Further network analysis suggested that symbiotic microbes which support the growth of pathogenic bacteria can be targets for future surveillance and removal.


Asunto(s)
Agua Potable , Microbiota , Humanos , Agua Potable/metabolismo , Bacterias/metabolismo , Archaea/genética , Metagenoma
13.
Sensors (Basel) ; 23(21)2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37960463

RESUMEN

With the development of deepfake technology, deepfake detection has received widespread attention. Although some deepfake forensics techniques have been proposed, they are still very difficult to implement in real-world scenarios. This is due to the differences in different deepfake technologies and the compression or editing of videos during the propagation process. Considering the issue of sample imbalance with few-shot scenarios in deepfake detection, we propose a multi-feature channel domain-weighted framework based on meta-learning (MCW). In order to obtain outstanding detection performance of a cross-database, the proposed framework improves a meta-learning network in two ways: it enhances the model's feature extraction ability for detecting targets by combining the RGB domain and frequency domain information of the image and enhances the model's generalization ability for detecting targets by assigning meta weights to channels on the feature map. The proposed MCW framework solves the problems of poor detection performance and insufficient data compression resistance of the algorithm for samples generated by unknown algorithms. The experiment was set in a zero-shot scenario and few-shot scenario, simulating the deepfake detection environment in real situations. We selected nine detection algorithms as comparative algorithms. The experimental results show that the MCW framework outperforms other algorithms in cross-algorithm detection and cross-dataset detection. The MCW framework demonstrates its ability to generalize and resist compression with low-quality training images and across different generation algorithm scenarios, and it has better fine-tuning potential in few-shot learning scenarios.

14.
Trials ; 24(1): 767, 2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38017543

RESUMEN

BACKGROUND: Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI. METHODS AND DESIGN: This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up. DISCUSSION: In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline. TRIAL REGISTRATION: Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.


Asunto(s)
Disfunción Cognitiva , Demencia , Humanos , Anciano , Pueblos del Este de Asia , China , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/prevención & control , Cognición , Audición , Demencia/diagnóstico , Demencia/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto
15.
IUCrJ ; 10(Pt 6): 671-677, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37721769

RESUMEN

Five coordination polymers [TM1(absa)(H2O)4]n and [TM2(absa)(bipy)(H2O)]n [TM1 = Zn (1), Co (2); TM2 = Zn (3), Co (4), Cu (5); Na2absa = 5,5'-azobissalicylic acid disodium salt; bipy = 4,4'-bipyride] were synthesized by solvent evaporation under a magnetic field. It is evident that magnetic fields bring significant and noticeable changes to the absa2- ligand orientation and the component movement behaviors to construct coordination polymers. The absa2- ligands bind to the metal ions in bridging coordination mode through the carboxylate groups, in addition to the bipy molecules adopting bridging modes. Photoluminescence measurements indicate that the emissions of compounds 1-5 are at 626, 600, 632, 658 and 682 nm in the solid state, respectively.

16.
Biochem Biophys Res Commun ; 678: 1-10, 2023 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-37603967

RESUMEN

Bladder cancer (BC) invasion is a critical factor that impacts the prognosis and quality of life of patients. However, the underlying mechanisms of BC invasion is far from clear. Fibroblast growth factor 13 (FGF13), a non-secretory FGF, has been found to be ectopically expressed in various tumors and implicated in tumor development, but its potential association to BC has not been investigated. Here, we reported that the expression of FGF13A, one nucleolar isoform of FGF13, was downregulated in BC patients and negatively associated with tumor invasion. Additionally, we demonstrated that overexpression of FGF13A could inhibit the migration and invasion of BC 5637 and T24 cells. We also confirmed the localization of FGF13A in the nucleolus and its interaction with nucleoproteins NPM1 and UBP. Subsequently, we identified that the N-terminal region of FGF13A was essential for its nucleolus location and interaction with NPM1. Furthermore, we found that FGF13A inhibited the generation of nascent ribosomal RNA and suppressed the migration and invasion of BC cells through its N-terminal region. Our research establishes, for the first time, a correlation between the expression of FGF13A and the onset and progression of BC. This provides novel insights into the role of FGF13A in the development of BC.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Células Epiteliales , Proteínas Nucleares/genética , Isoformas de Proteínas/metabolismo , Calidad de Vida , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo
18.
Aging (Albany NY) ; 15(11): 5164-5189, 2023 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-37310469

RESUMEN

BACKGROUND: Mounting evidence has underscored the pivotal role of the competitive endogenous RNA (ceRNA) regulatory networks among various cancers. However, the behavior characteristics and complexity of the ceRNA network in Gastric cancer (GC) remains unclear. In this study, we aimed to clarify a Microsatellite instability (MSI)-related ceRNA regulatory network and identify potential prognostic markers associated with GC. METHODS AND RESULTS: We extracted transcriptome data of GC patients from The Cancer Genome Atlas (TCGA) and identified differentially expressed lncRNAs, miRNAs and mRNAs based on MSI status. A hub ceRNA network including 1 lncRNAs (MIR99AHG), 2 miRNAs and 26 mRNAs specific to MSI was established in GC. We further constructed a prognostic model with seven target mRNAs by Lasso Cox regression, which yielded AUC values of 0.76. The prognostic model was further validated in an external independent dataset that integrated three GEO datasets. The characterization of immune cell infiltration and immunotherapy effects between high-risk and low-risk groups were then analyzed. Immune cell infiltration was significantly different between high- and low-risk groups based on risk scores. GC patients with lower risk scores correlated with better immune checkpoint inhibitor therapy (ICI) response. We further validated the expression and regulatory relationship of the ceRNA network in vitro experiments, and also confirmed the relationship between MIR99AHG and PD-L1. CONCLUSIONS: Our research provides in-depth insights on the role of MSI-related ceRNA in GC and the prognosis and ICIs therapy response of GC patients can be assessed by the risk model based on MSI-related ceRNA network.


Asunto(s)
MicroARNs , ARN Largo no Codificante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Inestabilidad de Microsatélites , Redes Reguladoras de Genes , MicroARNs/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Inmunoterapia , Pronóstico
19.
EBioMedicine ; 92: 104614, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37229906

RESUMEN

BACKGROUND: Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy. METHODS: Here, we report two different methods for generating melanoma patient-derived organoids (MPDOs), one is embedded in collagen gel, and the other is inlaid in Matrigel. MPDOs in Matrigel are used for assessing the therapeutic effects of anti-PD-1 antibodies (αPD-1), autochthonous tumor infiltrating lymphocytes (TILs), and small molecule compounds. MPDOs in collagen gel are used for evaluating the chemotaxis and migratory capacity of TILs. FINDING: The MPDOs in collagen gel and Matrigel have similar morphology and immune cell composition to their parental melanoma tissues. MPDOs show inter- and intra-tumoral heterogeneity and contain diverse immune cells such as CD4+, CD8+ T, Treg, CD14+ monocytic, CD15+, and CD11b+ myeloid cells. The tumor microenvironment (TME) in MPDOs is highly immunosuppressive, and the lymphoid and myeloid lineages express similar levels of PD-1, PD-L1, and CTLA-4 as their parental melanoma tissues. Anti-PD-1 antibodies (αPD-1) reinvigorate CD8+ T cells and induce melanoma cell death in the MPDOs. TILs expanded by IL-2 and αPD-1 show significantly lower expression of TIM-3, better migratory capacity and infiltration of autochthonous MPDOs, and more effective killing of melanoma cells than TILs expanded by IL-2 alone or IL-2 with αCD3. A small molecule screen discovers that Navitoclax increases the cytotoxicity of TIL therapy. INTERPRETATION: MPDOs may be used to test immune checkpoint inhibitors and cellular and targeted therapies. FUNDING: This work was supported by the NIH grants CA114046, CA261608, CA258113, and the Tara Miller Melanoma Foundation.


Asunto(s)
Linfocitos T CD8-positivos , Melanoma , Humanos , Interleucina-2/metabolismo , Melanoma/tratamiento farmacológico , Inmunoterapia/métodos , Organoides/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Microambiente Tumoral
20.
Cell Mol Biol (Noisy-le-grand) ; 69(2): 157-161, 2023 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-37224029

RESUMEN

This study was performed to analyze the biological behavior of childhood leukemia cells regulated by miR-708 by binding to the 3' UTR end of the target gene and reducing the level of the target gene. In this regard, human leukemia Jurkat cell lines were selected and divided into a control group, miR-708 overexpression group and miR-708 inhibition group. MTT assay was used to detect the cell proliferation inhibition rate, flow cytometry was used to detect the apoptosis rate and cell cycle change, the scratch test was used to detect the cell migration capacity, and Western Blot assay was used to detect the expression of CNTFR, apoptosis and JAK/STAT pathway related proteins. To verify the binding site of miR-708 and target gene CNTFR. The results showed that the cell proliferation inhibition rate, apoptosis rate, G1 phase ratio, Bax protein, and CNTFR protein in the miR-708 overexpression group were significantly lower than those in the control group at each time point, while the S phase ratio, Bcl-2 protein, cell migration ability, JAK3 and STAT3 protein were significantly higher than those in the control group (P<0.05). The results of the miR-708 inhibition group were contrary to those of the miR-708 overexpression group. The binding sites of miR-708 and CNTFR were predicted by TargetScan bioinformatics software. It was found that there were two binding sites of miR-708 and CNTFR, 394-400 bp and 497-503 bp respectively. In conclusion, miR-708 can reduce the expression of CNTFR by binding to the target gene CNTFR3' UTR, activate the JAK/STAT pathway to regulate apoptosis-related proteins, reduce apoptosis, and enhance the migration ability of leukemia cells.


Asunto(s)
Subunidad alfa del Receptor del Factor Neurotrófico Ciliar , Quinasas Janus , Leucemia , MicroARNs , Humanos , Regiones no Traducidas 3'/genética , Quinasas Janus/genética , MicroARNs/genética , Transducción de Señal , Factores de Transcripción STAT , Células Jurkat , Subunidad alfa del Receptor del Factor Neurotrófico Ciliar/genética , Leucemia/genética
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