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1.
J Biol Chem ; : 107694, 2024 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-39159816

RESUMEN

The canonical Wnt signaling pathway plays crucial roles in cell fate decisions as well as in pathogenesis of various diseases. Previously, we reported Caprin-2 as a new regulator of canonical Wnt signaling through a mechanism of facilitating LRP5/6 phosphorylation. Here, we resolved the crystal structure of the N-terminal homologous region 1 (HR1) domain of human Caprin-2 (hCap2_HR1). HR1 domain is so far only observed in Caprin-2 and its homologous protein Caprin-1, and the function of this domain remains largely mysterious. Here, the structure showed that hCap2_HR1 forms a homo-dimer and exhibits an overall structure roughly resembling the appearance of a pair of scissors. Moreover, we found that residues R200 and R201, which located at a basic cluster within the N-terminal "blades" region, are critical for Caprin-2's localization to the plasma membrane. In line with this, mutations targeting these two residues decrease Caprin-2's activity in the canonical Wnt signaling. Overall, we characterized a previously unknown "scissors"-like structure of the full-length HR1 domain, and revealed its function in mediating Caprin-2's localization to the plasma membrane.

2.
J Biol Chem ; 300(7): 107453, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38852886

RESUMEN

Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.


Asunto(s)
Virus de la Fiebre Porcina Africana , Antivirales , G-Cuádruplex , Virus de la Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/metabolismo , Animales , Chlorocebus aethiops , Células Vero , Antivirales/farmacología , Antivirales/química , Porcinos , Fiebre Porcina Africana/virología , Fiebre Porcina Africana/metabolismo , Porfirinas/química , Porfirinas/farmacología , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacología , Ácidos Picolínicos/metabolismo , Replicación Viral/efectos de los fármacos , Proteínas Virales/genética , Proteínas Virales/metabolismo , Proteínas Virales/química , Aminoquinolinas
3.
BMC Microbiol ; 24(1): 76, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38454361

RESUMEN

Aeromonas dhakensis (A. dhakensis) is becoming an emerging pathogen worldwide, with an increasingly significant role in animals and human health. It is a ubiquitous bacteria found in terrestrial and aquatic milieus. However, there have been few reports of reptile infections. In this study, a bacterial strain isolated from a dead Aldabra giant tortoise was identified as A. dhakensis HN-1 through clinical observation, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS), and gene sequencing analysis. Subsequently, to evaluate its pathogenicity, the detection of virulence genes and mice infection experiments were performed. A. dhakensis HN-1 was found to contain seven virulence genes, including alt, ela, lip, act, aerA, fla, and hlyA. Mice infected with A. dhakensis HN-1 exhibited hemorrhage of varying degrees in multiple organs. The half-maximal lethal dose (LD50) value of A. dhakensis HN-1 for mice was estimated to be 2.05 × 107 colony forming units (CFU)/mL. The antimicrobial susceptibility test revealed that A. dhakensis HN-1 was resistant to amoxicillin, penicillin, ampicillin and erythromycin. This is the first report of A. dhakensis in Aldabra giant tortoises, expanding the currently known host spectrum. Our findings emphasize the need for One Health surveillance and extensive research to reduce the spread of A. dhakensis across the environment, humans, and animals.


Asunto(s)
Aeromonas , Tortugas , Humanos , Animales , Ratones , Virulencia/genética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
4.
Environ Res ; 251(Pt 2): 118303, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38295978

RESUMEN

A novel intercalated nanocomposite of mercapto-modified cellulose/bentonite (LCS-BE-SH) was synthesized by high-speed shearing method in one step at room temperature, and was applied to remove Cd from solution and remediate Cd-contaminated soil. Results revealed that cellulose long-chain molecules have intercalated into bentonite nanolayers and interlayer spacing was increased to 1.411 nm, and grafting -SH groups improved adsorption selectivity, which enabled LCS-BE-SH to have distinct capability of Cd adsorption (qmax = 147.21 mg/g). Kinetic and thermodynamics showed that Cd adsorption onto LCS-BE-SH was well fitted by pseudo-second-order and Langmuir adsorption isotherm. Characterizations of the adsorbents revealed that synergistic effect of complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH)2, CdCO3) mechanism played a major role in Cd removal. In soil remediation, application of LCS-BE-SH was most effective (67.31 %) in Cd immobilization compared to the control (8.85 %), which reduced exchangeable Cd from 37.03 % to 11.44 %. Meanwhile, soil pH, soil organic matter, available phosphorus, and enzyme activities (catalase, urease, and dehydrogenase) were improved LCS-BE-SH treatment. The main immobilization mechanism in soil included complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH)2, Cd-Fe-hydroxide). Overall, this work applied a promising approach for Cd removal in aqueous and Cd remediation in soil by using an effective eco-friendly LCS-BE-SH nanocomposites.


Asunto(s)
Bentonita , Cadmio , Celulosa , Restauración y Remediación Ambiental , Nanocompuestos , Contaminantes del Suelo , Bentonita/química , Cadmio/química , Nanocompuestos/química , Contaminantes del Suelo/química , Restauración y Remediación Ambiental/métodos , Celulosa/química , Adsorción
5.
Environ Res ; 252(Pt 4): 119076, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38710430

RESUMEN

The large yield of anaerobic digestates and the suboptimal efficacy of nutrient slow-release severely limit its practical application. To address these issues, a new biochar based fertilizer (MAP@BRC) was developed using biogas residue biochar (BRC) to recover nitrogen and phosphorus from biogas slurry. The nutrient release patterns of MAP@BRC and mechanisms for enhancing soil fertility were studied, and it demonstrated excellent performance, with 59% total nitrogen and 50% total phosphorus nutrient release rates within 28 days. This was attributed to the coupling of the mechanism involving the dissolution of struvite skeletons and the release of biochar pores. Pot experiments showed that crop yield and water productivity were doubled in the MAP@BRC group compared with unfertilized planting. The application of MAP@BRC also improved soil nutrient levels, reduced soil acidification, increased microbial populations, and decreased soil heavy metal pollution risk. The key factors that contributed to the improvement in soil fertility by MAP@BRC were an increase in available nitrogen and the optimization of pH levels in the soil. Overall, MAP@BRC is a safe, slow-release fertilizer that exhibits biochar-fertilizer interactions and synergistic effects. This slow-release fertilizer was prepared by treating a phosphorus-rich biogas slurry with a nitrogen-rich biogas slurry, and it simultaneously addresses problems associated with livestock waste treatment and provides a promising strategy to promote zero-waste agriculture.


Asunto(s)
Biocombustibles , Carbón Orgánico , Fertilizantes , Nitrógeno , Fósforo , Suelo , Fertilizantes/análisis , Carbón Orgánico/química , Suelo/química , Fósforo/análisis , Nitrógeno/análisis , Biocombustibles/análisis , Agricultura/métodos
6.
Sensors (Basel) ; 24(7)2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38610324

RESUMEN

The traditional rearview mirror method cannot fully guarantee safety when driving trucks. RGB and infrared images collected by cameras are used for registration and recognition, so as to achieve the perception of surroundings and ensure safe driving. The traditional scale-invariant feature transform (SIFT) algorithm has a mismatching rate, and the YOLO algorithm has an optimization space in feature extraction. To address these issues, this paper proposes a truck surround sensing technique based on multi-features and an improved YOLOv5 algorithm. Firstly, the edge corner points and infrared features of the preset target region are extracted, and then a feature point set containing the improved SIFT algorithm is generated for registration. Finally, the YOLOv5 algorithm is improved by fusing infrared features and introducing a composite prediction mechanism at the prediction end. The simulation results show that, on average, the image stitching accuracy is improved by 17%, the time is reduced by 89%, and the target recognition accuracy is improved by 2.86%. The experimental results show that this method can effectively perceive the surroundings of trucks, accurately identify targets, and reduce the missed alarm rate and false alarm rate.

7.
Toxics ; 12(5)2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38787135

RESUMEN

Chicken feathers represent a viable material for producing biochar adsorbents. Traditional slow pyrolysis methods often result in sulfur element losses from chicken feathers, whereas hydrothermal reactions generate substantial amounts of nutrient-rich hydrothermal liquor. Magnesium-modified high-sulfur hydrochar MWF was synthesized through magnesium modification, achieving a S content of 3.68%. The maximum equilibrium adsorption amounts of MWF for Cd2+ and Pb2+ were 25.12 mg·g-1 and 70.41 mg·g-1, respectively, representing 4.00 times and 2.75 times of WF. Magnesium modification elevated the sulfur content, pH, ash content, and electronegativity of MWF. The primary mechanisms behind MWF's adsorption of Cd2+ and Pb2+ involve magnesium ion exchange and complexation with C=O/O=C-O, quaternary N, and S functional groups. MWF maintains robust stability and antioxidative properties, even with low aromaticity levels. Given the lower energy consumption during hydrochar production, MWF offers notable carbon sequestration benefits. The hydrothermal solution derived from MWF is nutrient-rich. Following supplementation with inorganic fertilizer, the hydrothermal solution of MWF significantly enhanced bok choy growth compared to the control group. In general, adopting magnesium-modified hydrothermal reactions to produce hydrochar and converting the resultant hydrothermal solution into water-soluble fertilizer proves a viable strategy for the eco-friendly utilization of chicken feathers. This approach carries substantial value for heavy metal remediation and agricultural practices.

8.
J Hazard Mater ; 470: 134288, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38626685

RESUMEN

Steroid hormones are highly potent compounds that can disrupt the endocrine systems of aquatic organisms. This study explored the spatiotemporal distribution of 49 steroid hormones in agricultural soils, ditch water, and sediment from suburban areas of Guangzhou City, China. The average concentrations of Σsteroid hormones in the water, soils, and sediment were 97.7 ng/L, 4460 ng/kg, and 9140 ng/kg, respectively. Elevated hormone concentrations were notable in water during the flood season compared to the dry season, whereas an inverse trend was observed in soils and sediment. These observations were attributed to illegal wastewater discharge during the flood season, and sediment partitioning of hormones and manure fertilization during the dry season. Correlation analysis further showed that population, precipitation, and number of slaughtered animals significantly influenced the spatial distribution of steroid hormones across various districts. Moreover, there was substantial mass transfer among the three media, with steroid hormones predominantly distributed in the sediment (60.8 %) and soils (34.4 %). Risk quotients, calculated as the measured concentration and predicted no-effect concentration, exceeded 1 at certain sites for some hormones, indicating high risks. This study reveals that the risk assessment of steroid hormones requires consideration of their spatiotemporal variability and inter-media mass transfer dynamics in agroecosystems.


Asunto(s)
Agricultura , Monitoreo del Ambiente , Sedimentos Geológicos , Contaminantes del Suelo , Contaminantes Químicos del Agua , China , Sedimentos Geológicos/química , Sedimentos Geológicos/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes del Suelo/análisis , Esteroides/análisis , Suelo/química , Hormonas/análisis , Disruptores Endocrinos/análisis , Ciudades , Medición de Riesgo
9.
Front Immunol ; 15: 1363664, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38476231

RESUMEN

The balance of the microbiome, which is sensitive to temperature changes, plays a crucial role in maintaining overall health and reducing the risk of diseases. However, the specific mechanisms by which immunity and microbiota interact to adapt to cold stress have yet to be addressed. In this study, Nanjiang Yellow goats were chosen as a model and sampled during the cold (winter, cold stress) and warm (spring) seasons, respectively. Analyses of serum immune factors, as well as the composition of rumen and fecal microbial communities, were conducted to explore the crosstalk between microbiota and innate immunity under cold stress. Significantly increased levels of IgA (P < 0.01) were observed in the cold season compared to the warm season. Conversely, the levels of IL-2 (P = 0.02) and IL-6 (P < 0.01) diminished under cold stress. However, no significant differences were observed in IgG (P = 0.89), IgM (P = 0.42), and IL-4 (P = 0.56). While there were no significant changes in the diversity of bacterial communities between the warm and cold seasons, positive correlations between serum IgA, IL-2, IL-6 concentrations and several genera were observed. Furthermore, the weighted gene co-expression network analysis indicated that the microbiota enriched in the MEbrown module positively correlated with IgA, while the microbiota enriched in the MEblue module positively correlated with IL-2 and IL-6. The strong correlation between certain probiotics, including Alistipes, Bacteroides, Blautia, and Prevotellaceae_UCG.004, and the concentration of IL-2, and IL-6 suggests their potential role in immunomodulatory properties. This study provides valuable insights into the crosstalk between microbial communities and immune responses under the challenge of cold stress. Further studies on the immunomodulatory properties of these probiotics would contribute to the development of strategies to enhance the stress resistance of animals for improved overall health and survival.


Asunto(s)
Respuesta al Choque por Frío , Microbiota , Animales , Rumen , Cabras , Interleucina-2 , Interleucina-6 , Inmunidad Innata , Bacteroidetes , Inmunoglobulina A
10.
J Colloid Interface Sci ; 674: 345-352, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-38941928

RESUMEN

Aqueous zinc batteries (AZBs) with the advantages of safety, low cost, and sustainability are promising candidates for large-scale energy storage devices. However, the issues of interface side reactions and dendrite growth at the zinc metal anode (ZMA) significantly harm the cycling lifespan of AZBs. In this study, we designed a nano-molecular sieve additive, fullerenol (C60(OH)n), which possesses a surface rich in hydroxyl groups that can be uniformly dispersed in the aqueous solution, and captures free water in the electrolyte, thereby suppressing the occurrence of interfacial corrosion. Besides, fullerenol can be further reduced to fullerene (C60) on the surface of ZMA, holding a unique self-smoothing effect that can inhibit the growth of dendritic Zn. With the synergistic action of these two effects, the fullerenol-contained electrolyte (FE) enables dendrite-free ZMAs. The Zn-Ti half-cell using FE exhibits stable cycling over 2500 times at 5 mA cm-2 with an average Coulombic efficiency as high as 99.8 %. Additionally, the Zn-NaV3O8 cell using this electrolyte displays a capacity retention rate of 100 % after 1000 cycles at -20 °C. This work provides important insights into the molecular design of multifunctional electrolyte additives.

11.
Toxics ; 12(1)2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38251027

RESUMEN

Argillaceous limestone (AL) is comprised of carbonate minerals and clay minerals and is widely distributed throughout the Earth's crust. However, owing to its low surface area and poorly active sites, AL has been largely neglected. Herein, manganic manganous oxide (Mn3O4) was used to modify AL by an in-situ deposition strategy through manganese chloride and alkali stepwise treatment to improve the surface area of AL and enable its utilization as an efficient adsorbent for heavy metals removal. The surface area and cation exchange capacity (CEC) were enhanced from 3.49 to 24.5 m2/g and 5.87 to 31.5 cmoL(+)/kg with modification, respectively. The maximum adsorption capacities of lead (Pb2+), copper (Cu2+), and nickel (Ni2+) ions on Mn3O4-modified argillaceous limestone (Mn3O4-AL) in mono-metal systems were 148.73, 41.30, and 60.87 mg/g, respectively. In addition, the adsorption selectivity in multi-metal systems was Pb2+ > Cu2+ > Ni2+ in order. The adsorption process conforms to the pseudo-second-order model. In the multi-metal system, the adsorption reaches equilibrium at about 360 min. The adsorption mechanisms may involve ion exchange, precipitation, electrostatic interaction, and complexation by hydroxyl groups. These results demonstrate that Mn3O4 modification realized argillaceous limestone resourcization as an ideal adsorbent. Mn3O4-modified argillaceous limestone was promising for heavy metal-polluted water and soil treatment.

12.
Chem Commun (Camb) ; 60(64): 8435-8438, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39036930

RESUMEN

Introducing a methyl group into 1,3-dioxolane (DOL) to obtain a stable cyclic ether, 4-methyl-1,3-dioxolane (4-Me DOL), allows it to be used as an additive in LiPF6-based carbonate electrolytes. The addition of 4-Me DOL can form a stable SEI with good Li+ transport ability, which can simultaneously improve the rate capability and cycling performance of lithium metal batteries.

13.
J Hazard Mater ; 469: 133965, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38471381

RESUMEN

Cadmium (Cd) contamination in agricultural soil has been an elevated concern due to the high health risks associated with the transfer through the soil-food chain, particularly in the case of rice. Recently, there has numerous researches on the use of nanoparticle-loaded materials for heavy metal-polluted soil remediation, resulting in favorable outcomes. However, there has been limited research focus on the field-scale application and recovery. This study was aimed to validate the Cd reduction effect of the nano-FeS loaded lignin hydrogel composites (FHC) in mildly polluted paddies, and to propose a field-scale application method. Hence, a multi-site field experiment was conducted in southern China. After the application for 94-103 days, the FHC exhibited a high integrity and elasticity, with a recovery rate of 91.90%. The single-round remediation led to decreases of 0.42-31.72% in soil Cd content and 1.52-49.11% in grain Cd content. Additionally, this remediation technique did not adversely impact rice production. Consequently, applying FHC in the field was demonstrated to be an innovative, efficient, and promising remediation technology. Simultaneously, a strategy was proposed for reducing Cd levels while cultivating rice in mildly polluted fields using the FHC.


Asunto(s)
Oryza , Contaminantes del Suelo , Cadmio/análisis , Lignina , Hidrogeles , Contaminantes del Suelo/análisis , Suelo
14.
Front Plant Sci ; 15: 1340336, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38590742

RESUMEN

China consumes 35% of the world's fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria, Nitrospirae, and Bacteroidetes. Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

15.
J Hazard Mater ; 469: 134080, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38522204

RESUMEN

Humus substances (HSs) participate in extracellular electron transfer (EET), which is unclear in heterogeneous soil. Here, a microbial electrochemical system (MES) was constructed to determine the effect of HSs, including humic acid, humin and fulvic acid, on soil electron transfer. The results showed that fulvic acid led to the optimal electron transfer efficiency in soil, as evidenced by the highest accumulated charges and removal of total petroleum hydrocarbons after 140 days, with increases of 161% and 30%, respectively, compared with those of the control. However, the performance of MES with the addition of humic acid and humin was comparable to that of the control. Fulvic acid amendment enhanced the carboxyl content and oxidative state of dissolved organic matter, endowing a better electron transfer capacity. Additionally, the presence of fulvic acid induced an increase in the abundance of electroactive bacteria and organic degraders, extracellular polymeric substances and functional enzymes such as cytochrome c and NADH synthesis, and the expression of m tr C gene, which is responsible for EET enhancement in soil. Overall, this study reveals the mechanism by which HSs stimulate soil electron transfer at the physicochemical and biological levels and provides basic support for the application of bioelectrochemical technology in soil.


Asunto(s)
Benzopiranos , Sustancias Húmicas , Suelo , Sustancias Húmicas/análisis , Suelo/química , Electrones
16.
J Hazard Mater ; 475: 134857, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38876017

RESUMEN

Interactions between positively charged amino-modified (APS) and negatively charged bare (BPS) polystyrene nanoplastics may cause heteroaggregation in aquatic environments. This study investigated the effects of particle concentration ratio, solution chemistry [electrolytes, pH, and natural organic matter (NOM)], and interaction sequence on their heteroaggregation kinetics. In the absence of electrolytes and NOM, the APS/BPS ratio for attaining maximum heteroaggregation rate (khetero) increased from APS/BPS= 3/7 to APS/BPS= 1/1 as pH increased from 4 to 10, indicating that electrostatic interactions dominated heteroaggregation. In the absence of NOM, khetero ranked APS/BPS= 2/3 > APS/BPS= 1/1 > APS/BPS= 3/2. Colloidal stability decreased linearly as pH increased from 4 to 8 at APS/BPS= 1/1, while diffusion-limited heteroaggregation persisted at pH 10. In NaCl solution, humic acid (HA) retarded heteroaggregation more effectively than sodium alginate (SA) via steric hindrance and weakening electrostatic interactions, following the modified Derjaguin-Landau-Verwey-Overbeek (MDLVO) theory. Compared with simultaneous interactions among APS, BPS, NaCl, and NOM, the NOM retardation effects on heteroaggregation weakened if delaying its interaction with others. In CaCl2 solution, the effects of NOM on heteroaggregation depended on counterbalance among charge screening, steric hindrance, and calcium bridging. These findings highlight the important role of heteroaggregation between oppositely charged nanoplastics on their fate and transport in aquatic environments.

17.
Nat Commun ; 15(1): 4054, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38744881

RESUMEN

Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.


Asunto(s)
Receptor X de Pregnano , Receptor X de Pregnano/metabolismo , Receptor X de Pregnano/antagonistas & inhibidores , Humanos , Ligandos , Cristalografía por Rayos X , Células Hep G2 , Modelos Moleculares , Unión Proteica
18.
Environ Sci Pollut Res Int ; 31(23): 33385-33397, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38678533

RESUMEN

In this study, Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) were assessed for their ability to enhance the activity of persulfate (PS). Various controlling factors including PS dosages, initial pH, water-soil ratio, ratio of Fe2+, and Fe3O4 MNPs to PS were considered in both the Fe2+/PS system and the Fe3O4 MNPs/PS system. Results showed that the Fe3O4 MNP-activated PS system exhibited high processing efficiency owing to the gradual release of Fe2+. This process occurred in a wide pH range (5-11), attributed to the synergistic action of sulfate radicals (SO4-·) and hydroxyl radicals (OH·) under alkaline conditions, effectively mitigating soil acidification. The ratio of Fe3O4 MNPs to PS and water-soil ratio significantly influenced the degradation rate with the highest petroleum hydrocarbon degradation rate exceeding 80% (82.31%). This rate was 3.1% higher than that achieved by the Fe2+/PS system under specific conditions: PS dosage of 0.05 mol/L, Fe3O4 MNPs to PS ratio of 1:10, water-soil ratio of 2:1, and initial pH of 11. Meanwhile, oxidant consumption in the Fe3O4 MNPs/PS system was halved compared to the Fe2+/PS system due to the slow release of Fe2+ and less ineffective consumption of SO4-·. Mechanistically, the possible degradation process was divided into three parts: the initial chain reaction, the proliferating chain reaction, and the terminating chain reaction. The introduction of Fe3O4 MNPs accelerated the degradation rate of pentadecane, heneicosane, eicosane, tritetracontane, and 9-methylnonadecane.


Asunto(s)
Restauración y Remediación Ambiental , Contaminantes del Suelo , Suelo , Contaminantes del Suelo/química , Suelo/química , Restauración y Remediación Ambiental/métodos , Sulfatos/química , Nanopartículas de Magnetita/química
19.
Stem Cell Res Ther ; 15(1): 149, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38783393

RESUMEN

BACKGROUND: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. METHODS: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. RESULTS: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. CONCLUSION: Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.


Asunto(s)
5'-Nucleotidasa , Enfermedades Autoinmunes , Vesículas Extracelulares , Células Madre Mesenquimatosas , Uveítis , Animales , Uveítis/patología , Uveítis/terapia , Uveítis/metabolismo , Uveítis/inmunología , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/genética , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/inmunología , Ratones , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/inmunología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino , Proteínas de Unión al Retinol , Humanos
20.
Virus Res ; 340: 199303, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38145807

RESUMEN

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that mainly causes acute diarrhea/vomiting, dehydration, and mortality in piglets, possessing economic losses and public health concerns. However, there are currently no proven effective antiviral agents against PDCoV. Cepharanthine (CEP) is a naturally occurring alkaloid used as a traditional remedy for radiation-induced symptoms, but its underlying mechanism of CEP against PDCoV has remained elusive. The aim of this study was to investigate the anti-PDCoV effects and mechanisms of CEP in LLC-PK1 cells. The results showed that the antiviral activity of CEP was based on direct action on cells, preventing the virus from attaching to host cells and virus replication. Importantly, Surface Plasmon Resonance (SPR) results showed that CEP has a moderate affinity to PDCoV receptor, porcine aminopeptidase N (pAPN) protein. AutoDock predicted that CEP can form hydrogen bonds with amino acid residues (R740, N783, and R790) in the binding regions of PDCoV and pAPN. In addition, RT-PCR results showed that CEP treatment could significantly reduce the transcription of ZBP1, cytokine (IL-1ß and IFN-α) and chemokine genes (CCL-2, CCL-4, CCL-5, CXCL-2, CXCL-8, and CXCL-10) induced by PDCoV. Western blot analysis revealed that CEP could inhibit viral replication by inducing autophagy. In conclusion, our results suggest that the anti-PDCoV activity of CEP is not only relies on competing the virus binding with pAPN, but also affects the proliferation of the virus in vitro by downregulating the excessive immune response caused by the virus and inducing autophagy. CEP emerges as a promising candidate for potential anti-PDCoV therapeutic development.


Asunto(s)
Benzodioxoles , Bencilisoquinolinas , Infecciones por Coronavirus , Coronavirus , Deltacoronavirus , Enfermedades de los Porcinos , Animales , Porcinos , Coronavirus/genética , Antígenos CD13/metabolismo
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