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1.
BMC Musculoskelet Disord ; 25(1): 517, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38970068

RESUMEN

BACKGROUND: Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. OBJECTIVES: This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). METHODS: Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS: In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. CONCLUSIONS: The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.


Asunto(s)
Densidad Ósea , Estudio de Asociación del Genoma Completo , Degeneración del Disco Intervertebral , Análisis de la Aleatorización Mendeliana , Humanos , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/epidemiología , Factores de Riesgo , Masculino , Femenino , Análisis Multivariante
2.
ACS Omega ; 9(29): 31353-31358, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39072120

RESUMEN

Drug-eluting microspheres are commonly used as a local drug delivery system for interventional therapy. However, current drug-eluting microspheres have poor X-ray visibility, which can hinder tracking and postembolization evaluation. In the current study, X-ray-visible poly(acrylic acid) drug-eluting beads loaded with iodized oil (IO-PAA-DEBs) ranging from 100-300 µm were prepared and evaluated both in vitro and in vivo. Iodized oil served as the radiopaque agent, and X-ray and computed tomography scanning confirmed that the microspheres exhibited excellent X-ray-visible properties. The drug-loading capacities of bleomycin hydrochloride, doxorubicin hydrochloride, and oxaliplatin were also investigated. IO-PAA-DEBs exhibited sustained drug release properties, accompanied by a cumulative drug release rate that reached approximately 60% after 120 h. In vitro and in vivo experiments revealed that IO-PAA-DEBs had good biocompatibility. Collectively, these results demonstrated that IO-PAA-DEBs could facilitate transarterial embolization and sustained drug delivery.

3.
ACS Nano ; 18(28): 18650-18662, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-38959157

RESUMEN

Peptide design and drug development offer a promising solution for combating serious diseases or infections. In this study, using an AI-human negotiation approach, we have designed a class of minimal model peptides against tuberculosis (TB), among which K7W6 exhibits potent efficacy attributed to its assembly-induced function. Comprising lysine and tryptophan with an amphiphilic α-helical structure, the K7W6 sequence exhibits robust activity against various infectious bacteria causing TB (including clinically isolated and drug-resistant strains) both in vitro and in vivo. Moreover, it synergistically enhances the effectiveness of the first-line antibiotic rifampicin while displaying low potential for inducing drug resistance and minimal toxicity toward mammalian cells. Biophysical experiments and simulations elucidate that K7W6's exceptional performance can be ascribed to its highly selective and efficient membrane permeabilization activity induced by its distinctive self-assembly behavior. Additionally, these assemblies regulate the interplay between enthalpy and entropy during K7W6-membrane interaction, leading to the peptide's two-step mechanism of membrane interaction. These findings provide valuable insights into rational design principles for developing advanced peptide-based drugs while uncovering the functional role played by assembly.


Asunto(s)
Entropía , Humanos , Péptidos/química , Péptidos/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Antituberculosos/química , Rifampin/química , Rifampin/farmacología , Animales
4.
Org Lett ; 26(27): 5635-5639, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38958212

RESUMEN

The chemical modification of the achiral carbon nanohoops to break the symmetry will result in inherently chiral structures with interesting optical properties. Herein, we report two novel π-extended chiral macrocycles, cyclo[10]paraphenylene-pyrene ([10]CPP-2Pyrene) and cyclo[10]paraphenylene-hexa-peri-hexabenzocoronene ([10]CPP-2HBC). The large substituents on the nanohoop peripheries effectively prevented free rotation and the racemization process. The conformation of each enantiomer is stable enough to be resolved by recycling HPLC.

5.
J Med Chem ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39045829

RESUMEN

Aberrant FGF2/FGFR signaling is implicated in lung squamous cell carcinoma (LSCC), posing treatment challenges due to the lack of targeted therapeutic options. Designing drugs that block FGF2 signaling presents a promising strategy different from traditional kinase inhibitors. We previously reported a ColVα1-derived fragment, HEPV (127AA), that inhibits FGF2-induced angiogenesis. However, its large size may limit therapeutic application. This study combines rational peptide design, molecular dynamics simulations, knowledge-based prediction, and GUV and FRET assays to identify smaller peptides with FGF2-blocking properties. We synthesized two novel peptides, HBS-P1 (45AA) and HBS-P2 (66AA), that retained the heparin-binding site. Both peptides demonstrated anti-LSCC and antiangiogenesis properties in cell viability and microvessel network induction assays. In two LSCC subcutaneous models, HBS-P1, with its affinity for FGF2 and enhanced penetration ability, demonstrated substantial therapeutic potential without apparent toxicities. Our study provides the first evidence supporting the development of collagen V-derived natural peptides as FGF2-blocking agents for LSCC treatment.

6.
Sci Total Environ ; 946: 174477, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-38964412

RESUMEN

Soil fungi are pivotal in alpine and arctic ecosystems that are vulnerable to climate changes. Previous studies have shown broad connections between soil fungi in the arctic and alpine regions, but most of these studies are mainly from Europe and North America, with more sporadic studies from East Asia. Currently, little is known about the biogeographic relationships between soil fungi in alpine meadows of southwestern China (AMSC) and other regions of the world. In addition, the regional-scale spatial patterns of fungal communities in the AMSC, as well as their driving factors and ecological processes, are also poorly understood. In this study, we collected roots and surrounding soils of two dominant ectomycorrhizal plants, Bistorta vivipara and B. macrophylla from the AMSC, and performed bioinformatic and statistical analyses based on high-throughput sequencing of ITS2 amplicons. We found that: (1) fungi from the AMSC were closely related with those from boreal forests and tundra, and saprotrophic fungi had higher dispersal potential than ectomycorrhizal fungi; (2) community compositions exhibited clear divergences among geographic regions and between root and soil samples; (3) climate was the predominant factor driving regional-scale spatial patterns but had less explanatory power for saprotrophic and total fungi from roots than those from soils; (4) homogeneous selection and drift were the key ecological processes governing community assembly, but in communities of saprotrophic and total fungi from soil samples, drift contributed less and its role was partially replaced by dispersal limitation. This study highlights the importance of climatic selection and stochastic processes on fungal community assembly in alpine regions, and emphasizes the significance of simultaneously investigating fungi with different trophic modes and from both roots and soils.


Asunto(s)
Hongos , Pradera , Micorrizas , Microbiología del Suelo , China , Cambio Climático , Clima , Suelo/química , Micobioma
7.
Pathogens ; 13(6)2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38921752

RESUMEN

Clostridium perfringens alpha toxin (CPA), which causes yellow lamb disease in sheep and gas gangrene and food poisoning in humans, is produced by all types of C. perfringens and is the major virulence determinant of C. perfringens type A. CPA induces hemolysis in many species, including humans, murines, sheep and rabbits, through its enzymatic activity, which dissolves the cell membrane. Recent studies have shown that some pore-forming toxins cause hemolysis, which is achieved by the activation of purinergic receptors (P2). However, the relationship between P2 receptors and non-pore-forming toxin hemolysis has not been investigated. In the present study, we examined the function of P2 receptors in CPA toxin hemolysis and found that CPA-induced hemolysis was dependent on P2 receptor activation, and this was also true for Staphylococcus aureus ß-Hemolysin, another non-pore-forming toxin. Furthermore, we use selective P2 receptor antagonists to demonstrate that P2X1 and P2X7 play important roles in the hemolysis of human and murine erythrocytes. In addition, we found that redox metabolism was mainly involved in CPA-induced hemolysis using metabolomic analysis. We further demonstrate that CPA activates P2 receptors and then activates NADPH oxidase through the PI3K/Akt and MEK1/ERK1 pathways, followed by the production of active oxygen to induce hemolysis. These findings contribute to our understanding of the pathological effects of CPA, clarify the relationship between P2 activation and non-pore-forming toxin-induced hemolysis, and provide new insights into CPA-induced hemolysis.

8.
J Cell Mol Med ; 28(12): e18492, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38890795

RESUMEN

Intervertebral disc degeneration (IVDD) severely affects the work and the quality of life of people. We previously demonstrated that silencing activation transcription factor 3 (ATF3) blocked the IVDD pathological process by regulating nucleus pulposus cell (NPC) ferroptosis, apoptosis, inflammation, and extracellular matrix (ECM) metabolism. Nevertheless, whether miR-874-3p mediated the IVDD pathological process by targeting ATF3 remains unclear. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis to identify ATF3 as a key ferroptosis gene in IVDD. Then, Western blotting, flow cytometry, ELISA, and animal experiments were performed to validate the roles and regulatory mechanisms of miR-874-3p/ATF3 signalling axis in IVDD. ATF3 was highly expressed in IVDD patients and multiple cell types of IVDD rat, as revealed by scRNA-seq and bioinformatics analysis. GO analysis unveiled the involvement of ATF3 in regulating cell apoptosis and ECM metabolism. Furthermore, we verified that miR-874-3p might protect against IVDD by inhibiting NPC ferroptosis, apoptosis, ECM degradation, and inflammatory response by targeting ATF3. In vivo experiments displayed the protective effect of miR-874-3p/ATF3 axis on IVDD. These findings propose the potential of miR-874-3p and ATF3 as biomarkers of IVDD and suggest that targeting the miR-874-3p/ATF3 axis may be a therapeutic target for IVDD.


Asunto(s)
Factor de Transcripción Activador 3 , Ferroptosis , Degeneración del Disco Intervertebral , MicroARNs , Núcleo Pulposo , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , MicroARNs/genética , MicroARNs/metabolismo , Animales , Humanos , Ratas , Ferroptosis/genética , Masculino , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Análisis de la Célula Individual/métodos , Apoptosis/genética , Transducción de Señal , Femenino , Persona de Mediana Edad , Ratas Sprague-Dawley , Análisis de Secuencia de ARN/métodos , Matriz Extracelular/metabolismo , Adulto , Regulación de la Expresión Génica , Modelos Animales de Enfermedad , Biología Computacional/métodos
9.
Sci Total Environ ; 946: 174190, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-38936731

RESUMEN

Ecological security (ES) is a crucial indicator for assessing the sustainable development of a region. Currently, most studies on ES primarily focus on process analysis, and the integration of environmental variability into the development of tailored control strategies for regions with varying ecological quality is overlooked. Therefore, in this study, we identified regional ES change processes, employed an optimized system to calculate the ecological security index (ESI), and identified ecological corridors (ECs) through the Minimum Constrained Resource (MCR) model to determine zoning strategies for typical arid regions, using the Ningxia region in the Yellow River Basin of China as an example. The findings showed that (1) from 2006 to 2020, the ESI values of most regions were between 0.2 and 0.4, with small but consistent increases in the ESI values over the years. (2) The proportion of regions with high ES ratings increased by 9.08 % across all districts and counties, and the center of gravity of ES shifted in a north-south and east-west direction. (3) The ESI exhibited a strong positive spatial correlation, characterized by spatial diffusion and spillover effects in most regions. (4) The ECs were predominantly distributed in a north-south direction, involving a total of 20 districts and counties. Based on the principles of sustainable development, we developed a model for the dynamic identification and zoning control of regional ES, aiming to provide a practical framework for effective ecological restoration and protection measures. Additionally, the strategies and methodologies presented in this study serve as important references for similar regions worldwide to facilitate the zoning control of ES, highlighting the broader significance and applicability of the study.

10.
J Org Chem ; 89(11): 8255-8261, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38771292

RESUMEN

Herein we report the construction of an inherently chiral carbon nanoring, cyclo[7]paraphenylene-2,9-rubicene ([7]CPPRu2,9), by combining rubicene with a C-shaped synthon through the Suzuki-Miyaura coupling reaction. The structure was fully confirmed by high-resolution mass spectroscopies (HR-MS) and various NMR techniques. The photophysical properties were investigated by UV-vis absorption and fluorescence spectroscopy as well as the time-resolved fluorescence decay. Moreover, two enantiomers (M)/(P)-[7]CPPRu2,9 were successfully resolved by recyclable HPLC and studied by CD and CPL spectra.

11.
Artículo en Inglés | MEDLINE | ID: mdl-38639759

RESUMEN

During investigations of invertebrate-associated fungi in Yunnan Province of China, a new species, Sporodiniella sinensis sp. nov., was collected. Morphologically, S. sinensis is similar to Sporodiniella umbellata; however, it is distinguished from S. umbellata by its greater number of sporangiophore branches, longer sporangiophores, larger sporangiospores, and columellae. The novel species exhibits similarities of 91.62 % for internal transcribed spacer (ITS), 98.66-99.10 % for ribosomal small subunit (nrSSU), and 96.36-98.22 % for ribosomal large subunit (nrLSU) sequences, respectively, compared to S. umbellata. Furthermore, phylogenetic analyses based on combined sequences of ITS, nrLSU and nrSSU show that it forms a separate clade in Sporodiniella, and clusters closely with S. umbellata with high statistical support. The phylogenetic and morphological evidence support S. sinensis as a distinct species. Here, it is formally described and illustrated, and compared with other relatives.


Asunto(s)
Ácidos Grasos , Mucorales , Animales , Filogenia , China , Análisis de Secuencia de ADN , Composición de Base , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Técnicas de Tipificación Bacteriana , Ácidos Grasos/química , Invertebrados
12.
CNS Neurosci Ther ; 30(4): e14723, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38676295

RESUMEN

AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.


Asunto(s)
Ansiedad , Hipocampo , Inflamación , Receptores de Glutamato Metabotrópico , Animales , Masculino , Ratones , Ansiedad/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran , Hipocampo/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genética
13.
Environ Sci Pollut Res Int ; 31(22): 32725-32745, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38662295

RESUMEN

Ecosystem carbon storage (ECS) is a critical consideration in reducing the impact of global warming and tackling environmental challenges, positioning it at the forefront of contemporary research. Due to the significant differences in the influence of land usage patterns on ECS in various policy contexts and China's commitment to attaining a carbon-neutral status, a model simulating different scenarios is needed to analyze the spatiotemporal characteristics and evolutionary process of carbon storage in terrestrial ecosystems accurately. To address this challenge, this study established a coupling model of "Geographical analysis -Evolution analysis -Predicting (GEP)" for assessing ecosystem ECS and analyzing its spatial characteristics and evolutionary patterns and projecting the spatial distribution of ECS under various developmental scenarios, which analyzed variations in ECS across different levels of magnitude and delineated the changing areas across a range of varying scenarios in the future additionally. The outcomes suggested that the ECS decreased by 1.17 × 106 t from 1990 to 2020, which pertaining to the utilization transfer of land in the area, whose change in ECS levels with a positive trend. It is predicted that the ECS will grow by 1.15 × 106 t and 1.44 × 106 t, in 2030 and 2060 compared with 2020 within the framework of natural development scenario (NDS), while within the framework of ecological protection scene (EPS), ECS will increase significantly, increasing by 3.06 × 106 t and 4.44 × 106 t. There will be more areas where ECS increases within the framework of EPS, by comparing with the NDS. This study offers a comprehensive analysis of Hanzhong City's carbon storage trends, demonstrating its significant impact on climate change mitigation and serving as a predictive model for similar regions, which underscores the importance of localized carbon management strategies, offering valuable insights for local governments in formulating effective climate adaptation and mitigation policies.


Asunto(s)
Ecosistema , China , Carbono , Secuestro de Carbono , Modelos Teóricos , Calentamiento Global
14.
MycoKeys ; 103: 1-24, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38495949

RESUMEN

Two new termite-pathogenic species, Ophiocordycepsglobiperitheciata and O.longistipes, are described from Yunnan Province, China. Six-locus (ITS, nrSSU, nrLSU, tef-1α, rpb1 and rpb2) phylogenetic analyses in combination with morphological observations were employed to characterize these two species. Phylogenetically, O.globiperitheciata is most closely related to Hirsutellacryptosclerotium and O.communis, whereas O.longistipes shares a sister relationship with O.fusiformis. However, O.globiperitheciata differs from H.cryptosclerotium by parasitizing Blattodea and producing clavate, unbifurcated stromata. Ophiocordycepsglobiperitheciata is distinguished from O.communis by multiple stromata, shorter asci and ascospores. Ophiocordycepslongistipes differs from O.fusiformis in producing larger stromata, perithecia, asci and ascospores, as well as smaller citriform or oval conidia. Morphological descriptions of the two new species and a dichotomous key to the 19 termite-pathogenic Ophiocordyceps species are presented.

15.
Nat Commun ; 15(1): 2684, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38538576

RESUMEN

It is a long-standing scientific controversy to achieve anti-Kasha-type multiple emissions by tuning the structures at a molecular level. Although it is known that some conjugated structures have excitation-dependent multiple emissions, no all-benzenoid molecules have yet been reported, the emissions of which originate from different excited states. Herein, we report the design of two symmetry-breaking heterogeneous carbon bisnanohoops that in solution become multiple fluorescent emitters with unusual anti-Kasha characteristics. This phenomenon can be spectroscopically and theoretically explained and will find applications in a wide range of sensing and imaging technologies.

16.
Antioxidants (Basel) ; 13(3)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38539794

RESUMEN

The Greatwall-family protein kinase Rim15 is associated with the nutrient starvation response, whereas its role in oxidative stress responses remains unclear. Here, acetic acid and peroxide were used as two oxidative stress elicitors. The antioxidant indicator assay under acetic acid stress revealed the impaired growth in rim15Δ related to the regulation of antioxidant systems. Comparative transcriptome analysis revealed that differentially expressed genes (DEGs) are predicted to be mostly regulated by oxidative stress-responsive transcriptional factor Yap1. Among the DEGs, acetic acid stress-induced genes were found, and YAP1 disruption also inhibited their induction. The deletion of Rim15 or the Rim15 kinase domain in yap1Δ did not further decrease the gene expression, suggesting that Rim15 functions together with Yap1 in regulating acetic acid stress-induced genes, which requires Rim15 kinase activity. Additionally, Rim15 regulated H2O2 stress tolerance through partially similar but special mechanisms in that Rim15 kinase activity impacted acetic acid and H2O2 stress tolerance in different degrees, indicating the different mechanisms underlying Rim15-mediated redox regulation against different stressors. These results benefit the better understanding of stress signaling pathways related to Rim15. Given that Rim15 and some of its target genes are conserved across eukaryotes, these results also provide a basis for studies of oxidative stress-related processes in other organisms.

17.
ACS Omega ; 9(10): 11829-11835, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38497008

RESUMEN

Advances in chemotherapeutic strategies are urgently required to improve antitumor efficiency. Herein, a carboxylated pillar[6]arene (CP6A) was employed to load chemotherapy medication, nitrogen mustard (NM), via forming a direct host-guest complex, as this helps to decrease the cytotoxicity of NM on normal mammary epithelial cells. Attributed to the stronger complexation ability of CP6A for endogenous spermine (SPM) than for NM, the complexed NM could be competitively released from the CP6A cavity via replacement with SPM. This chemotherapy strategy performed well in vitro and in vivo for SPM-overexpressed cancers. In comparison with free NM, antitumor efficiency of NM/CP6A was significantly enhanced, which originated from the synergistic effect of competitive release of NM and simultaneous trapping of SPM. This strategy might guide expansion to other first-line antitumor agents to improve therapeutic efficacy and decrease side effects, thereby replenishing the possibilities of supramolecular chemotherapy.

18.
J Phys Chem B ; 128(11): 2632-2639, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38467492

RESUMEN

The cellular endocytosis of nanoparticles (NPs) is a fundamental biological process with significant potential in biomedical applications. However, a comprehensive understanding of the mechanistic aspects of endocytosis and the impact of particle properties on this process remains elusive. In this study, we investigated the membrane-wrapping behavior of soft NPs (SNPs) with varying rigidities using theoretical calculations. Our findings reveal that the membrane-wrapping process of SNPs involves a complex energy change including the possible existence of an energy barrier; moreover, it is found that the location and height of this barrier strongly depend on the mechanistic properties of the NPs and membranes. Additionally, by considering force balance in the membrane-wrapping process, we calculated the speed at which NP is internalized by the membrane, showing a nonmonotonic dependence on particle rigidity and/or wrapping degree. These phenomena can be attributed to competition between different energy components associated with NP-membrane binding, membrane tension, and deformations occurring during SNP-membrane interaction processes. Our results contribute to a deeper understanding of cellular-level endocytosis mechanisms and offer potential applications for soft NPs in biomedicine.


Asunto(s)
Nanopartículas , Membrana Celular/química , Nanopartículas/química , Membranas , Endocitosis , Fenómenos Físicos
19.
J Proteome Res ; 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38396335

RESUMEN

Acetic acid is a prevalent inhibitor in lignocellulosic hydrolysate, which represses microbial growth and bioproduction. Histone modification and chromatin remodeling have been revealed to be critical for regulating eukaryotic metabolism. However, related studies in chronic acetic acid stress responses remain unclear. Our previous studies revealed that overexpression of the histone H4 methyltransferase Set5p enhanced acetic acid stress tolerance of the budding yeast Saccharomyces cerevisiae. In this study, we examined the role of Set5p in acetic acid stress by analyzing global protein expression. Significant activation of intracellular protein expression under the stress was discovered, and the functions of the differential proteins were mainly involved in chromatin modification, signal transduction, and carbohydrate metabolism. Notably, a substantial increase of Set5p expression was observed in response to acetic acid stress. Functional studies demonstrated that the restriction of the telomere capping protein Rtc3p, as well as Ies3p and Taf14p, which are related to chromatin regulation, was critical for yeast stress response. This study enriches the understanding of the epigenetic regulatory mechanisms underlying yeast stress response mediated by histone-modifying enzymes. The results also benefit the development of robust yeast strains for lignocellulosic bioconversion.

20.
Entropy (Basel) ; 26(2)2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38392363

RESUMEN

Emergence and causality are two fundamental concepts for understanding complex systems. They are interconnected. On one hand, emergence refers to the phenomenon where macroscopic properties cannot be solely attributed to the cause of individual properties. On the other hand, causality can exhibit emergence, meaning that new causal laws may arise as we increase the level of abstraction. Causal emergence (CE) theory aims to bridge these two concepts and even employs measures of causality to quantify emergence. This paper provides a comprehensive review of recent advancements in quantitative theories and applications of CE. It focuses on two primary challenges: quantifying CE and identifying it from data. The latter task requires the integration of machine learning and neural network techniques, establishing a significant link between causal emergence and machine learning. We highlight two problem categories: CE with machine learning and CE for machine learning, both of which emphasize the crucial role of effective information (EI) as a measure of causal emergence. The final section of this review explores potential applications and provides insights into future perspectives.

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