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1.
Mol Med Rep ; 30(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38963030

RESUMO

DNA methylation is one of the earliest and most significant epigenetic mechanisms discovered. DNA methylation refers, in general, to the addition of a methyl group to a specific base in the DNA sequence under the catalysis of DNA methyltransferase, with S­adenosine methionine as the methyl donor, via covalent bonding and chemical modifications. DNA methylation is an important factor in inducing cancer. There are different types of DNA methylation, and methylation at different sites plays different roles. It is well known that the progression of colorectal cancer (CRC) is affected by the methylation of key genes. The present review did not only discuss the potential relationship between DNA methylation and CRC but also discussed how DNA methylation affects the development of CRC by affecting key genes. Furthermore, the clinical significance of DNA methylation in CRC was highlighted, including that of the therapeutic targets and biomarkers of methylation; and the importance of DNA methylation inhibitors was discussed as a novel strategy for treatment of CRC. The present review did not only focus upon the latest research findings, but earlier reviews were also cited as references to older literature.


Assuntos
Neoplasias Colorretais , Metilação de DNA , Epigênese Genética , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Animais
2.
J Pancreatol ; 7(2): 119-130, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38883575

RESUMO

Objective: Pancreatic cancer is one of the most aggressive malignancies, a robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Methods: A list of bioinformatic analysis were applied in public dataset to construct an immune-related signature. Furthermore, the most pivotal gene in the signature was identified. The potential mechanism of the core gene function was revealed through GSEA, CIBERSORT, ESTIMATE, immunophenoscore (IPS) algorithm, single-cell analysis, and functional experiment. Results: An immune-related prognostic signature and associated nomogram were constructed and validated. Among the genes constituting the signature, interleukin 1 receptor type II (IL1R2) was identified as the gene occupying the most paramount position in the risk signature. Meanwhile, knockdown of IL1R2 significantly inhibited the proliferation, invasion, and migration ability of pancreatic cancer cells. Additionally, high IL1R2 expression was associated with reduced CD8+ T cell infiltration in pancreatic cancer microenvironment, which may be due to high programmed cell death-ligand-1 (PD-L1) expression in cancer cells. Finally, the IPS algorithm proved that patients with high IL1R2 expression possessed a higher tumor mutation burden and a higher probability of benefiting from immunotherapy. Conclusion: In conclusion, our study constructed an efficient immune-related prognostic signature and identified the key role of IL1R2 in the development of pancreatic cancer, as well as its potential to serve as a biomarker for immunotherapy efficacy prediction for pancreatic cancer.

3.
Virology ; 596: 110124, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38838475

RESUMO

While mammals can be infected by influenza A virus either sporadically or with well adapted lineages, aquatic birds are the natural reservoir of the pathogen. So far most of the knowledge on influenza virus dynamics was however gained on mammalian models. In this study, we infected turkeys using a low pathogenic avian influenza virus and determined the infection dynamics with a target-cell limited model. Results showed that turkeys had a different set of infection characteristics, compared with humans and ponies. The viral clearance rates were similar between turkeys and ponies but higher than that in humans. The cell death rates and cell to cell transmission rates were similar between turkeys and humans but higher than those in ponies. Overall, this study indicated the variations of within-host dynamics of influenza infection in avian, humans, and other mammalian systems.


Assuntos
Vírus da Influenza A Subtipo H9N2 , Influenza Aviária , Perus , Animais , Perus/virologia , Influenza Aviária/virologia , Influenza Aviária/transmissão , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/fisiologia , Humanos , Cavalos , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/transmissão , Influenza Humana/virologia
4.
J Agric Food Chem ; 72(26): 14498-14520, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38885200

RESUMO

Trimethylamine N-oxide (TMAO), a characteristic nonprotein nitrogen compound, is widely present in seafood, which exhibits osmoregulatory effects for marine organisms in vivo and plays an important role in aquaculture and aquatic product preservation. However, much attention has been focused on the negative effect of TMAO since it has recently emerged as a putative promoter of chronic diseases. To get full knowledge and maximize our ability to balance the positive and negative aspects of TMAO, in this review, we comprehensively discuss the TMAO in aquatic products from the aspects of physiological functions for marine organisms, flavor, quality, the conversion of precursors, the influences on human health, and the seafood ingredients interaction consideration. Though the circulating TMAO level is inevitably enhanced after seafood consumption, dietary seafood still exhibits beneficial health effects and may provide nutraceuticals to balance the possible adverse effects of TMAO.


Assuntos
Metilaminas , Alimentos Marinhos , Metilaminas/análise , Metilaminas/metabolismo , Humanos , Animais , Alimentos Marinhos/análise , Organismos Aquáticos/química , Peixes
5.
Chem Biol Drug Des ; 103(6): e14558, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828741

RESUMO

This study aimed to explore the active components and the effect of Hedyotis diffusa (HD) against Alzheimer's disease (AD) via network pharmacology, molecular docking, and experimental evaluations. We conducted a comprehensive screening process using the TCMSP, Swiss Target Prediction, and PharmMapper databases to identify the active components and their related targets in HD. In addition, we collected potential therapeutic targets of AD from the Gene Cards, Drugbank, and OMIM databases. Afterward, we utilized Cytoscape to establish both protein-protein interaction (PPI) networks and compound-target (C-T) networks. To gain further insights into the functional aspect, we performed GO and KEGG pathway analyses using the David database. Next, we employed Autodock vina to estimate the binding force between the components and the hub genes. To validate our network pharmacology findings, we conducted relevant experiments on Caenorhabditis elegans, further confirming the reliability of our results. Then a total of six active compounds and 149 therapeutic targets were detected. Through the analysis of the association between active compounds, therapeutic targets, and signaling pathways, it was observed that the therapeutic effect of HD primarily encompassed the inhibition of Aß, suppression of AChE activity, and mitigating oxidative stress. Additionally, our investigation revealed that the key active compounds in HD primarily consisted of iridoids, which exhibited resistance against AD by acting on the Alzheimer's disease pathway and the AGE-RAGE signaling pathway in diabetic complications.


Assuntos
Doença de Alzheimer , Caenorhabditis elegans , Hedyotis , Simulação de Acoplamento Molecular , Farmacologia em Rede , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Hedyotis/química , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
6.
Curr Issues Mol Biol ; 46(5): 3906-3918, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38785510

RESUMO

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

7.
J Environ Manage ; 360: 121119, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733849

RESUMO

Soil property data plays a crucial role in watershed hydrology and non-point source (H/NPS) modeling, but how to improve modeling accuracy with affordable soil samplings and the effects of sampling information on H/NPS modeling remains to be further explored. In this study, the number of sampling points and soil properties were optimized by the information entropy and the spatial interpolation method. Then the sampled properties were parameterized and the effects of different parameterization schemes on H/NPS modeling were tested using the Soil and Water Assessment Tool (SWAT). The results indicated that the required sampling points increased successively for soil bulk density (SOL_BD), soil saturated hydraulic conductivity (SOL_K) and soil available water capacity (SOL_AWC). Compared to the traditional database (Harmonized world soil database), the NSE and R2 performance by new scheme increased by 22.8% and 10.5%, respectively. The entropy-based optimization reduced the sampling points by 13.2%, indicating a more cost-effective scheme. Compared to hydrological simulation, sampled properties showed greater effects on NPS modeling, especially for nitrogen. This proposed method/framework can be generalized to other watersheds by upscaling field soil sampling information to the watershed scale, thus improving H/NPS simulation.


Assuntos
Entropia , Hidrologia , Solo , Modelos Teóricos , Água , Monitoramento Ambiental/métodos
8.
Sci Adv ; 10(15): eadk7678, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38598631

RESUMO

The Rpd3S complex plays a pivotal role in facilitating local histone deacetylation in the transcribed regions to suppress intragenic transcription initiation. Here, we present the cryo-electron microscopy structures of the budding yeast Rpd3S complex in both its apo and three nucleosome-bound states at atomic resolutions, revealing the exquisite architecture of Rpd3S to well accommodate a mononucleosome without linker DNA. The Rpd3S core, containing a Sin3 Lobe and two NB modules, is a rigid complex and provides three positive-charged anchors (Sin3_HCR and two Rco1_NIDs) to connect nucleosomal DNA. In three nucleosome-bound states, the Rpd3S core exhibits three distinct orientations relative to the nucleosome, assisting the sector-shaped deacetylase Rpd3 to locate above the SHL5-6, SHL0-1, or SHL2-3, respectively. Our work provides a structural framework that reveals a dynamic working model for the Rpd3S complex to engage diverse deacetylation sites.


Assuntos
Nucleossomos , Proteínas de Saccharomyces cerevisiae , Histonas/metabolismo , Microscopia Crioeletrônica , Metilação , Histona Desacetilases/metabolismo , DNA/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
9.
Heliyon ; 10(8): e29549, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38655339

RESUMO

Background: In the central nervous system, glioma is the most common malignant tumor, and patients have a poor prognosis. Identification of novel marker genes and establishment of prognostic models are important for early diagnosis and prognosis determination. Methods: Download glioma data from the CGGA and TCG databases. Application of bioinformatics to analyze the impact of CYBB on the clinicopathological characteristics, immunological features and prognosis of gliomas. Using single-cell sequencing data from 7 glioblastoma patients in the CGGA database, the role of CYBB in the tumor microenvironment was analyzed. In addition, a prognostic model was constructed based on CYBB high and low differentially expressed genes and mitochondrial genes. Results: The expression of CYBB is closely related to various clinical features, immune cell infiltration level, immune checkpoint and survival time of patients. A 10-gene prediction model was constructed based on the differentially expressed genes of low and high CYBB and mitochondria-related genes. Glioma patients with higher risk scores had significantly lower survival probabilities. Receiver operating characteristic curves and nomograms were plotted over time to show the predictive accuracy and predictive value of the 10-gene prognostic model. Conclusions: Our study shows that CYBB is strongly correlated with clinical characteristics features and prognosis of glioma patients, and can be used as a potential therapeutic target. Prognostic models based on CYBB and mitochondrial genes have good performance in predicting prognosis of glioma patients.

10.
ACS Appl Mater Interfaces ; 16(15): 18959-18970, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38569111

RESUMO

Fe-based Prussian blue (Fe-PB) analogues have emerged as promising cathode materials for sodium-ion batteries, owing to their cost-effectiveness, high theoretical capacity, and environmental friendliness. However, their practical application is hindered by [Fe(CN)6] defects, negatively impacting capacity and cycle stability. This work reports a hollow layered Fe-PB composite material using 1,3,5-benzenetricarboxylic acid (BTA) as a chelating and etching agent by the hydrothermal method. Compared to benzoic acid, our approach significantly reduces defects and enhances the yield of Fe-PB. Notably, the hollow layered structure shortens the diffusion path of sodium ions, enhances the activity of low-spin Fe in the Fe-PB lattice, and mitigates volume changes during Na-ion insertion/extraction into/from Fe-PB. As a sodium-ion battery cathode, this hollow layered Fe-PB exhibits an impressive initial capacity of 95.9 mAh g-1 at a high current density of 1 A g-1. Even after 500 cycles, it still maintains a considerable discharge capacity of 73.1 mAh g-1, showing a significantly lower capacity decay rate (0.048%) compared to the control sample (0.089%). Moreover, the full cell with BTA-PB-1.6 as the cathode and HC as the anode provides a considerable energy density of 312.2 Wh kg-1 at a power density of 291.0 W kg-1. This research not only enhances the Na storage performance of Fe-PB but also increases the yield of products obtained by hydrothermal methods, providing some technical reference for the production of PB materials using the low-yield hydrothermal method.

11.
Nat Commun ; 15(1): 3094, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605035

RESUMO

Microstructure control in metal additive manufacturing is highly desirable for superior and bespoke mechanical performance. Engineering the columnar-to-equiaxed transition during rapid solidification in the additive manufacturing process is crucial for its technological advancement. Here, we report a powder-size driven melt pool engineering approach, demonstrating facile and large-scale control in the grain morphology by triggering a counterintuitive response of powder size to the additively manufactured 316 L stainless steel microstructure. We obtain coarse-grained (>100 µm) or near-monocrystalline microstructure using fine powders and near-equiaxed, fine-grained (<10 µm) microstructure using coarse powders. This approach shows resourceful adaptability to directed energy deposition and powder-bed fusion with no added cost, where the particle-size dependent powder-flow preheating effects and powder-bed thermophysical properties drive the microstructural variations. This work presents a pathway for leveraging feedstock particle size distribution towards more controllable, cost-effective, and sustainable metal additive manufacturing.

12.
Environ Sci Pollut Res Int ; 31(16): 24525-24535, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38443533

RESUMO

At present, microbial dust suppressants based on microbial communities lack necessary systematic analysis of factors affecting dust suppression performance. Therefore, in this study, the response surface curve method was used to optimize the culture conditions for enrichment of urease-producing microorganisms from activated sludge. The results indicated that when urea = 9.67 g L-1, NH4Cl = 5.21 g L-1, and pH = 9.57, the maximum urease activity of urease-producing microbial community (UPMC) was 8.22 mM min-1. The UPMC under optimized culture conditions reached a mineralization rate of 98.8% on the 1st day of mineralization. Ureolysis is one of the biological mechanisms that trigger microbial mineralization with the consequent effect of dust suppression. The analysis of microbial community structure indicated that the urease-producing bacteria Sporosarcina sp. had the highest abundance at the genus level in the microbial-based dust suppressant compound. Jeotgalicoccus sp. plays an important role in improving and maintaining the stability of urease. In addition, the optimal UPMC had low pathogenicity, which is extremely attractive for the safe application of microbial dust suppressants.


Assuntos
Carbonato de Cálcio , Poeira , Urease/química , Bactérias , Ureia
13.
Cell Signal ; 118: 111137, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38467242

RESUMO

BACKGROUND: Glucose is a fundamental substance for numerous cancers, including glioma. However, its influence on tumor cells regulatory mechanisms remains uncertain. SIRT1 is a regulator of deacetylation and a key player in the progression of malignant tumors. The objective of this study was to examine the role of glucose and SIRT1 in glioma. METHODS: This study investigated the association of SIRT1 expression with clinicopathological features and prognosis in glioma patients using the TCGA database. The Western blotting technique was used to identify the expression of SIRT1 protein in glioma cells. The study also examined the impact of differing glucose concentrations on the biological functions of glioma cells. The study investigated the expression of SIRT1 and HMGB1 signaling pathways in glioma. Additionally, resilience experiments were conducted utilizing SRT1720. RESULTS: SIRT1 is a gene that suppresses tumors and is low expressed in gliomas. Low expression of this gene is strongly linked to a poor prognosis in patients with glioma. High concentrations of glucose can promote the proliferation, migration, and invasion of glioma cells, while also inhibiting apoptosis. The findings of this mechanistic study provide evidence that glucose can down-regulate SIRT1 expression, leading to increased levels of acetylated HMGB1. This in turn promotes the ex-nuclear activation of HMGB1 and associated signaling pathways, ultimately driving glioma malignancy. CONCLUSION: Glucose has the ability to regulate the HMGB1 associated signaling pathway through SIRT1, thus promoting glioma progression. This holds significant research value.


Assuntos
Glioma , Proteína HMGB1 , Humanos , Glioma/genética , Glucose/farmacologia , Proteína HMGB1/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo
14.
J Cancer Res Clin Oncol ; 150(3): 168, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546908

RESUMO

OBJECTIVES: The aim of this study was to investigate the anti-tumor effect of resveratrol (RSV) on glioblastoma (GBM) and its specific mechanism in improving the inflammatory response of the tumor microenvironment. The tumor microenvironment of GBM is highly neuroinflammatory, inducing tumor immunosuppression. Therefore, ameliorating the inflammatory response is an important focus for anti-tumor research. METHODS: The anti-tumor effect of RSV on GBM was demonstrated through in vitro cellular assays, including CCK-8, EdU, PI staining, Transwell, wound healing assay, and flow cytometry. Potential mechanisms of RSV's anti-GBM effects were identified through network pharmacological analysis. In addition, the relationship of RSV with the JAK2/STAT3 signaling pathway and the inflammasome NLRP3 was verified using Western blot. RESULTS: RSV significantly inhibited cell viability in GBM cell lines LN-229 and U87-MG. Furthermore, it inhibited the proliferation and invasive migration ability of GBM cells, while promoting apoptosis. Network pharmacological analysis revealed a close association between the anti-GBM effects of RSV and the JAK/STAT signaling pathway, as well as inflammatory responses. Western blot analysis confirmed that RSV inhibited the over-activation of the inflammasome NLRP3 through the JAK2/STAT3 signaling pathway. Partial reversal of RSV's inhibition of inflammasome NLRP3 was observed with the addition of the JAK/STAT agonist RO8191. CONCLUSIONS: In vitro, RSV can exert anti-tumor effects on GBM and improve the inflammatory response in the GBM microenvironment by inhibiting the activation of the JAK2/STAT3 signaling pathway. These findings provide new insights into potential therapeutic targets for GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Encefálicas/patologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Janus Quinase 2/metabolismo , Microambiente Tumoral
15.
Sci Rep ; 14(1): 3214, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332171

RESUMO

In recent decades, rising air temperatures (AT) and apparent temperatures (AP) have posed growing health risks. In the context of China's rapid urbanization and global climate change, it is crucial to understand the impact of urban land use/land cover (LULC) changes on AP. This study investigates the spatial distribution and long-term variation patterns of AT and AP, using data from 834 meteorological stations across China from 1996 to 2020. It also explores the relationship between AT, AP, and LULC in the urban core areas of 30 major cities. Study reveals that AT and AP exhibit overall high spatial similarity, albeit with greater spatial variance in AP. Notably, regions with significant disparities between the two have been identified. Furthermore, it's observed that the spatial range of high AP change rates is wider than that of AT. Moreover, the study suggests a potential bivariate quadratic function relationship between ΔT (the difference between AT and AP) and Wa_ratio and Ar_ratio, indicating the presence of a Least Suitable Curve (LSC), [Formula: see text]. Urban LULC planning should carefully avoid intersecting with this curve. These findings can provide valuable insights for urban LULC planning, ultimately enhancing the thermal comfort of urban residents.

16.
ACS Sens ; 9(2): 736-744, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38346401

RESUMO

The expression of microRNA (miRNA) changes in many diseases plays an important role in the diagnosis, treatment, and prognosis of diseases. Spinal cord injury (SCI) is a serious disease of the central nervous system, accompanied by inflammation, cell apoptosis, neuronal necrosis, axonal rupture, demyelination, and other pathological processes, resulting in impaired sensory and motor functions of patients. Studies have shown that miRNA expression has changed after SCI, and miRNAs participate in the pathophysiological process and treatment of SCI. Therefore, quantitative analysis and monitoring of the expression of miRNA were of great significance for the diagnosis and treatment of SCI. Through the SCI-related miRNA chord plot, we screened out miRNA-21-5p and miRNA-let-7a with a higher correlation. However, for traditional detection strategies, it is still a great challenge to achieve a fast, accurate, and sensitive detection of miRNA in complex biological environments. The most frequently used method for detecting miRNAs is polymerase chain reaction (PCR), but it has disadvantages such as being time-consuming and cumbersome. In this paper, a novel SERS sensor for the quantitative detection of miRNA-21-5p and miRNA-let-7a in serum and cerebrospinal fluid (CSF) was developed. The SERS probe eventually formed a sandwich-like structure of Fe3O4@hpDNA@miRNA@hpDNA@GNCs with target miRNAs, which had high specificity and stability. This SERS sensor achieved a wide range of detection from 1 fM to 1 nM and had a good linear relationship. The limits of detection (LOD) for miRNA-21-5p and miRNA-let-7a were 0.015 and 0.011 fM, respectively. This new strategy realized quantitative detection and long-term monitoring of miRNA-21-5p and miRNA-let-7a in vivo. It is expected to become a powerful biomolecule analysis tool and will provide ideas for the diagnosis and treatment of many diseases.


Assuntos
MicroRNAs , Traumatismos da Medula Espinal , Humanos , Reação em Cadeia da Polimerase , Limite de Detecção , Prognóstico , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/genética
17.
Redox Biol ; 70: 103076, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38340635

RESUMO

Wilson's disease (WD) is a genetic disorder that primarily leads to the pathological accumulation of copper (Cu) in the liver, causing an abnormal increase in reactive oxygen species (ROS). The prevailing clinical therapy for WD involves lifelong use of Cu chelation drugs to facilitate Cu excretion in patients. However, most available drugs exert severely side-effects due to their non-specific excretion of Cu, unsuitable for long-term use. In this study, we construct a prochelator that enables precise and controlled delivery of Cu chelator drugs to the liver in WD model, circumventing toxic side effects on other organs and normal tissues. This innovative prochelator rapidly releases the chelator and the fluorescent molecule methylene blue (MB) upon activation by ROS highly expressed in the liver of WD. The released chelator coordinates with Cu, efficiently aiding in Cu removal from the body and effectively inhibiting the pathological progression of WD.


Assuntos
Degeneração Hepatolenticular , Humanos , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/patologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Espécies Reativas de Oxigênio , Cobre
18.
Eur J Pharmacol ; 967: 176398, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38350591

RESUMO

OBJECTIVES: Inflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI. METHODS: Rats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro. RESULTS: In vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-ß. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1ß). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1ß expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages. CONCLUSION: Gabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.


Assuntos
Infarto do Miocárdio , Fator de Necrose Tumoral alfa , Ratos , Animais , Gabapentina/farmacologia , Gabapentina/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , PPAR gama/metabolismo , Remodelação Ventricular , Fator de Crescimento Neural/metabolismo , Cálcio/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Macrófagos , Anti-Inflamatórios/farmacologia , Inflamação/metabolismo
19.
Mar Drugs ; 22(2)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38393047

RESUMO

Patients with ulcerative colitis (UC) have higher rates of depression. However, the mechanism of depression development remains unclear. The improvements of EPA and DHA on dextran sulfate sodium (DSS)-induced UC have been verified. Therefore, the present study mainly focused on the effects of EPA and DHA on UC-induced depression in C57BL/6 mice and the possible mechanisms involved. A forced swimming test and tail suspension experiment showed that EPA and DHA significantly improved DSS-induced depressive-like behavior. Further analysis demonstrated that EPA and DHA could significantly suppress the inflammation response of the gut and brain by regulating the NLRP3/ASC signal pathway. Moreover, intestine and brain barriers were maintained by enhancing ZO-1 and occludin expression. In addition, EPA and DHA also increased the serotonin (5-HT) concentration and synaptic proteins. Interestingly, EPA and DHA treatments increased the proportion of dominant bacteria, alpha diversity, and beta diversity. In conclusion, oral administration of EPA and DHA alleviated UC-induced depressive-like behavior in mice by modulating the inflammation, maintaining the mucosal and brain barriers, suppressing neuronal damage and reverting microbiota changes.


Assuntos
Colite Ulcerativa , Humanos , Camundongos , Animais , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Colite Ulcerativa/metabolismo , Transdução de Sinais , Inflamação/metabolismo , Modelos Animais de Doenças , Colo/metabolismo
20.
BMC Pulm Med ; 24(1): 65, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38297272

RESUMO

BACKGROUND: Exercise is crucial for pulmonary rehabilitation and improving the prognosis of lung transplantation (LTx) patients. However, many LTx patients in China have low exercise tolerance and compliance, and the reasons behind these challenges have not been fully elucidated. Therefore, this qualitative research aims to identify the barriers to and facilitators of exercise rehabilitation in LTx patients. METHODS: From January to July 2023, 15 stable LTx patients were recruited and participated in in-depth, semi-structured, face-to-face interviews at Henan Provincial People's Hospital. The interview transcripts were analyzed using the COM-B model and the Theoretical Domains Framework (TDF). RESULTS: Six general themes including 19 barriers and 14 facilitators for the exercise rehabilitation of LTx patients were identified based on the COM-B model and TDF. The barriers to exercise included physical limitations, insufficient exercise endurance, lack of knowledge, and lack of motivation. The facilitators of exercise included motivation, self-efficacy, perceived significance of exercise rehabilitation, and social support. CONCLUSION: The study offers detailed insight into the development and implementation of exercise rehabilitation intervention strategies for LTx patients. By combining COM-B model and TDF, the study provides strong evidence that active behavior change strategies are required for LTx patients to promote their participation in exercise rehabilitation. Professional support, pulmonary rehabilitation training, behavior change technology, and digital health tools are essential for strengthening the evidence system for reporting exercise efficacy and effectiveness.


Assuntos
Exercício Físico , Transplante de Pulmão , Adulto , Humanos , Pesquisa Qualitativa , Terapia por Exercício , Apoio Social , Motivação
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