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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of ß-amyloid (Aß) plaques and neurofibrillary tangles composed of tau protein in the brain. These neuropathological hallmarks contribute to cognitive impairment by inducing neuronal loss in the cerebral cortex and hippocampus. Unfortunately, current therapeutic approaches only target symptomatic relief and do not impede disease progression. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising candidate for the treatment of age-related neurodegenerative disorders. NMN supplementation could restore NAD+ levels, thereby alleviating neuronal damage and slowing the progression of AD and other aging-associated diseases. AD is closely associated with autophagic impairment and oxidative stress. Our in vivo experiments demonstrated that NMN could ameliorate pathological and behavioral impairments in AD mice. Specifically, NMN enhanced autophagy and promoted p-tau clearance. Meanwhile, NMN could activate the Nrf2/Keap1/NQO1 pathway, thereby reducing the oxidative stress. Immunofluorescence results demonstrated that NMN could alleviate neuronal damage in AD mice. Furthermore, in vitro results showed that the p-tau clearance and antioxidant stress effects of NMN were suppressed by autophagy inhibitor, chloroquine (CQ) or bafilomycin A1 (BafA1), in Aß-induced PC12 cells. Lastly, when Nrf2 was knocked down, the antioxidant stress, autophagy enhancement, and p-tau clearance effects of NMN were all inhibited. In conclusion, our research indicates that NMN exerts therapeutic effect against AD by activating autophagy and the Nrf2/Keap1/NQO1 pathway through a mutual regulating mechanism of autophagy and antioxidative stress. These findings highlight the promising potential of NMN for the treatment of AD.
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Conventional methods for identifying soil heavy metal (HM) pollution sources are limited to area scale, failing to accurately pinpoint sources at specific sites due to the spatial heterogeneity of HMs in mining areas. Furthermore, these methods primarily focus on existing solid waste polluted dumps, defined as "direct pollution sources", while neglecting existing HM pollution hotspots generated by historical anthropogenic activities (e.g., mineral development, industrial discharges), defined as "potential pollution sources". Addressing this gap, a novel remote sensing analysis method is proposed to identify both direct and potential pollution sources at site scale, considering source-sink relationships. Direct pollution sources are extracted using a supervised classification algorithm on high-resolution multispectral imagery. Potential pollution sources depend on the spatial distribution of HM pollution, mapped using a machine learning model with hyperspectral imagery. Additionally, a source identification algorithm is developed for gridded pollution source analysis. Validated through a case study in a cadmium (Cd)-polluted mine area, the proposed method successfully extracted 21 solid waste polluted dumps with an overall accuracy approaching 90 % and a Kappa coefficient of 0.80. Simultaneously, 4167 HM pollution hotspots were identified, achieving optimal inversion accuracy for Cd (Rv2 = 0.91, RMSEv = 4.27, and RPDv = 3.02). Notably, the spatial distribution patterns of these identified sources exhibited a high degree of similarity. Further analysis employing the identification algorithm indicated that 3 polluted dumps and 258 pollution hotspots were pollution sources for a selected high-value point of Cd content. This innovative method provides a valuable methodological reference for precise prevention and control of soil HM pollution.
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The uncontrollable growth of lithium dendrites and the flammability of electrolytes are the direct impediments to the commercial application of high-energy-density lithium metal batteries (LMBs). Herein, this study presents a novel approach that combines microencapsulation and electrospinning technologies to develop a multifunctional composite separator (P@AS) for improving the electrochemical performance and safety performance of LMBs. The P@AS separator forms a dense charcoal layer through the condensed-phase flame retardant mechanism causing the internal separator to suffocate from lack of oxygen. Furthermore, it incorporates a triple strategy promoting the uniform flow of lithium ions, facilitating the formation of a highly ion-conducting solid electrolyte interface (SEI), and encouraging flattened lithium deposition with active SiO2 seed points, considerably suppressing lithium dendrites growth. The high Coulombic efficiency of 95.27% is achieved in Li-Cu cells with additive-free carbonate electrolyte. Additionally, stable cycling performance is also maintained with a capacity retention rate of 93.56% after 300 cycles in LFP//Li cells. Importantly, utilizing P@AS separator delays the ignition of pouch batteries under continuous external heating by 138 s, causing a remarkable reduction in peak heat release rate and total heat release by 23.85% and 27.61%, respectively, substantially improving the fire safety of LMBs.
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BACKGROUND: Catechol (CC), a prevalent phenolic compound, is a byproduct in various agricultural, chemical, and industrial processes. CC detection is crucial for safeguarding water quality and plays a pivotal role in enhancing the overall quality of life of individuals. Electrochemical biosensors exhibit rapid responses, have small sizes, and can be used for real-time monitoring. Therefore, the development of a fast and sensitive electrochemical biosensor for CC detection is crucial. RESULT: In this study, a laccase-based electrochemical biosensor for detection of CC is successfully developed using Fe3O4 nanoparticles as medium and optimized by applying a magnetic field. This research proposes a unique strategy for biosensor enhancement by actively controlling the distribution of magnetic materials on the electrode surface through the application of a magnetic field, resulting in a visibly alternating stripe pattern. This approach effectively disperses magnetic particles, preventing their aggregation and reducing the boundary layer thickness, enhancing the electrochemical response of the biosensor. After fabrication condition optimization, CC is successfully detected using this biosensor. The fabricated sensor exhibits excellent performance with a wide linear detection range of 10-1000 µM, a low detection limit of 1.25 µM, and a sensitivity of 7.9 µA/mM. The fabricated sensor exhibits good selectivity and reliable detection in real water samples. In addition, the laccase-based sensor has the potential for the fast and accurate monitoring of CC in olive oil. SIGNIFICANCE: The magnetic field optimization in this study significantly improved the performance of the electrochemical biosensor for detecting CC in environmental samples. Overall, the sensor developed in this study has the potential for fast and accurate monitoring of CC in environmental samples, highlighting the potential importance of a magnetic field environment in improving the performance of catechol electrochemical biosensors.
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Técnicas Biosensibles , Catecoles , Técnicas Electroquímicas , Lacasa , Catecoles/análisis , Catecoles/química , Lacasa/química , Lacasa/metabolismo , Campos Magnéticos , Nanopartículas de Magnetita/química , Electrodos , Propiedades de Superficie , Límite de Detección , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Contaminantes Químicos del Agua/análisisRESUMEN
PM2.5 remote sensing data was applied in this study, and Theil-Sen Median trend analysis and the Mann-Kendall significance test were utilized to analyze the temporal and spatial variation in PM2.5 in the Shandong Province from 2000 to 2021. The influencing power of the influencing factors on the spatial differentiation of PM2.5 concentration in the Shandong Province was detected at the provincial-city-county levels based on Geo-detector data. The results showed that:â on the temporal scale, the mean ρ(PM2.5)in the Shandong Province ranged from 38.15 to 88.63 µg·m-3 from 2000 to 2021, which was slightly higher than the secondary limit of inhalable particulate matter (35 µg·m-3) in the Ambient Air Quality Standards. On the interannual scale, 2013 was the peak year for the variation in ρ(PM2.5) with a value of 83.36 µg·m-3, according to which the trend of PM2.5 concentrations in the Shandong Province was divided into two phases:a continuous increase and a rapid decrease. On the seasonal scale, PM2.5 concentration presented the distribution characteristics of "low in summer and high in winter and moderate in spring and autumn" and the U-shaped change rule of first decreasing and then increasing. â¡ On the spatial scale, the PM2.5 concentration in the Shandong Province presented a spatial distribution pattern of "high in the west and low in the east." The areas with high PM2.5 concentration were distributed in the western area of the Shandong Province, whereas the areas with low PM2.5 concentration were distributed in the eastern peninsula region. The spatial variation in the changing trend of PM2.5 concentration showed significant spatial heterogeneity, and the extremely significant decrease was mainly distributed in the eastern peninsula region. ⢠The results of factor detection showed that climate factor was an important factor affecting the spatial differentiation of PM2.5 concentration in the Shandong Province. Mean temperature had the highest influence on the spatial differentiation of PM2.5 concentration in the Shandong Province, with a q value of 0.512. Provincial-city-county multi-scale detection results showed that the influencing factors affecting the spatial differentiation of PM2.5 concentration and their influencing power differed at different spatial scales. At the provincial scale, mean temperature, sunshine duration, and slope were the main factors affecting the spatial differentiation of PM2.5 concentration. At the city level, precipitation, elevation, and relative humidity were the main factors affecting the spatial differentiation of PM2.5. At the county level, precipitation, mean temperature, and sunshine duration were the main factors affecting the spatial variation in PM2.5 concentration.
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Developing a gradient porous scaffold similar to bone structure is gaining increasing attention in bone tissue engineering. The GelMA/HAP hydrogel has demonstrated potential in bone repair. Although 3D printing can build GelMA/HAP with porous structure, fabricating porous GelMA/HAP with gradient porosity and pore size in one step remains challenging. In this paper, a gradient porous structure with controllable pore size, based on gelatin methacryloyl (GelMA) and hydxroxyapatite (HAP), was engineered and printed using stereolithography. Firstly, the GelMA and HAP were mixed to prepare a hydrogel with a solid content ranging from 10 wt% to 50 wt% for stereolithography. Taking advantage of the sol-gel characteristics of GelMA/HAP hydrogel, GelMA/HAP was fed on the workbench through a combination of extrusion and paving to form a thin layer. During the curing of each layer, the hydrogel exposed to the curing of a single UV beam immediately solidified, forming a highly interconnected porous structure. Additionally, the hydrogel outside the scanning range could be further polymerized to form a relatively dense structure due to the residual laser energy. Finally, without gradient structural design or changing printing parameters, the gradient porous structure of bone-like could be printed in a single-step process. By adjusting the curing parameters of the single UV beam and the concentration and size of ceramic in the hydrogel, the printed pore diameter of the spongy structure could be controlled within the range of 50-260 µm, while the thickness of the compact area could be adjusted within 130-670 µm.
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Materiales Biocompatibles , Durapatita , Gelatina , Metacrilatos , Impresión Tridimensional , Porosidad , Gelatina/química , Materiales Biocompatibles/química , Durapatita/química , Metacrilatos/química , Andamios del Tejido/química , Hidrogeles/química , Ingeniería de TejidosRESUMEN
Quantitatively determining the direct, indirect, and comprehensive effects of climatic factors on the growing season of the vegetation GPP (GPPGS) in the middle and lower reaches of the Yangtze River at the regional and vegetation type scales can provide a scientific basis for the management and restoration of regional vegetation resources under the background of global climate change. Using MODIS GPP data, meteorological data, and vegetation type data, combined with Theil-Sen Median trend analysis and the Mann-Kendall significance test, the spatiotemporal characteristics of the GPPGS in the middle and lower reaches of the Yangtze River were investigated at different temporal and spatial scales. Path analysis was used to further reveal the direct, indirect, and comprehensive effects of climate factors on GPPGS variation in different vegetation types. The results showed that:â from 2000 to 2021, the vegetation GPPGS in the middle and lower reaches of the Yangtze River showed a fluctuating upward trend, with a rising rate (in terms of C, same below) of 2.70 g·(m2·a)-1 (P<0.01). The GPPGS of different vegetation types all showed a significant upward trend (P<0.01), with shrubs having the highest upward rate of 3.31 g·(m2·a)-1 and cultivated vegetation having the lowest upward rate of 2.54 g·(m2·a)-1. â¡ The proportion of the area with an upward trend in GPPGS in the middle and lower reaches of the Yangtze River was 88.11%. The proportion of the area with an upward trend in GPPGS was greater than 84% for all different vegetation types, with shrubs (49.76%) and cultivated vegetation (44.36%) having significantly higher proportions of the area with an upward trend than that in other vegetation types. ⢠The path analysis results showed that precipitation and the maximum temperature had a significant positive direct effect on vegetation GPPGS (P<0.05), whereas solar radiation had a non-significant positive effect (P ≥ 0.05). The indirect effects of maximum temperature, precipitation, and solar radiation on vegetation GPPGS were all non-significantly negative (P ≥ 0.05). Under the combined effects of direct and indirect influences, precipitation and maximum temperature had a non-significant positive effect on vegetation GPPGS (P ≥ 0.05), whereas solar radiation had a non-significant negative effect on vegetation GPPGS (P ≥ 0.05). Among different vegetation types, precipitation was the main climate factor affecting the changes in GPPGS of cultivated vegetation, whereas the maximum temperature was the main climate factor affecting the changes in GPPGS of coniferous forests, broad-leaved forests, shrubs, and grasslands. ⣠The changes in vegetation GPPGS in the middle and lower reaches of the Yangtze River were mainly influenced by the direct effects of maximum temperature, precipitation, and solar radiation, with the direct effect of precipitation dominating 56.72% of the changes in GPPGS. The research results can provide a reference for quantifying the carbon sequestration potential of vegetation in the middle and lower reaches of the Yangtze River and formulating ecological restoration governance policies tailored to local conditions under the background of global climate change.
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Cambio Climático , Ecosistema , Ríos , Estaciones del Año , Bosques , Temperatura , ChinaRESUMEN
In this study, the critical importance of designing an appropriate immobilized carrier and method for free lipase to ensure exceptional biological catalytic activity and stability was emphasized. Covalent organic frameworks (COF-1) were synthesized as a novel porous carrier with an azine structure (-CN-NC-) through the condensation of hydrazine hydrate and benzene-1,3,5-tricarbaldehyde at room temperature. Simultaneously, Rhizomucor miehei lipase (RML) was immobilized within the COF-1 carrier using an in-situ aqueous phase method. Characterization of the carrier and RML@COF-1 and evaluation of the lipase properties of RML and RML@COF-1 through p-Nitrophenyl palmitate hydrolysis were conducted. Additionally, application in the synthesis of 1, 3-dioleoyl-2-palmitoylglycerol (OPO) was explored. The results showed that RML@COF-1 exhibited a high enzymatic loading of 285.4â¯mg/g. Under 60â conditions, the activity of RML@COF-1 was 2.31 times higher than that of free RML, and RML@COF-1 retained 77.25% of its original activity after 10 cycles of repeated use, indicating its excellent thermal stability and repeatability. Under the optimal conditions (10%, 1:8 PPP/OA, 45â, 5â¯h), the yield of OPO reached 47.35%, showcasing the promising application prospects of the novel immobilized enzyme synthesized via in-situ aqueous phase synthesis for OPO preparation.
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Enzimas Inmovilizadas , Lipasa , Rhizomucor , Lipasa/metabolismo , Lipasa/química , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Rhizomucor/enzimología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/síntesis química , Hidrólisis , Porosidad , Propiedades de Superficie , Triglicéridos/química , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Observational studies have indicated that psychiatric disorders are the most common comorbidities in pediatric epilepsy. However, the existence and direction of a causal relationship between the two remains controversial. This study aims to investigate the association between common childhood psychiatric disorders and epilepsy using a two-sample, bidirectional Mendelian randomization (MR) approach. METHODS: Genetic instruments were obtained from the most recent and largest genome-wide association studies (GWAS), including datasets for epilepsy (N_case = 29,994, N_control = 52,538), attention deficit hyperactivity disorder (ADHD) (N_case = 38,691, N_control = 186,843), autism spectrum disorder (ASD) (N_case = 18,381, N_control = 27,969), and Tourette syndrome (TS) (N_case = 4,819, N_control = 9488). MR analyses were conducted using the inverse variance weighted (IVW) method, weighted median method, and MR-Egger regression. RESULTS: No reliable evidence was found to suggest a causal effect of ADHD, ASD, or TS on epilepsy, nor was there any reliable evidence indicating that epilepsy increases the risk of these three psychiatric disorders. These findings remained consistent across various sensitivity analyses. CONCLUSION: Although observational studies have highlighted a high comorbidity rate between pediatric epilepsy and psychiatric disorders like ADHD and ASD, the MR analysis did not confirm a causal relationship between them. This suggests that previous studies might have been influenced by confounding biases or other biases, potentially overestimating the true relationship. A deeper understanding of the mechanisms underlying these comorbidities is crucial for refining the treatment of pediatric epilepsy.
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Trastorno por Déficit de Atención con Hiperactividad , Epilepsia , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Epilepsia/genética , Epilepsia/epidemiología , Niño , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Comorbilidad , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , Síndrome de Tourette/genética , Síndrome de Tourette/epidemiología , Trastornos Mentales/genética , Trastornos Mentales/epidemiologíaRESUMEN
PURPOSE: More literature studies have reported that alfentanil is safe and effective for labor analgesia. However, there is no unified consensus on the optimal dosage of alfentanil used for epidural analgesia. This study explored the concentration at 90% of minimum effective concentration (EC90) of alfentanil combined with 0.075% ropivacaine in patients undergoing epidural labor analgesia to infer reasonable drug compatibility and provide guidance for clinical practice. METHODS: In this prospective, single-center, double-blind study, a total of 45 singleton term primiparas with vaginal delivery who volunteered for epidural labor analgesia were recruited. The first maternal was administered with 3 µg/mL alfentanil combined with 0.075% ropivacaine with the infusion of 10 mL of the mixture every 50 min at a background dose of 3 mL/h. In the absence of PCEA, a total of 15 mL of the mixture is injected per hour. The subsequent alfentanil concentration was determined on the block efficacy of the previous case, using an up-down sequential allocation with a bias-coin design. 30 min after epidural labor analgesia, the block of patient failed with visual analog score (VAS) > 3, the alfentanil concentration was increased in a 0.5 µg/mL gradient for the next patient, while the block was successful with VAS ≤ 3, the alfentanil concentration was remained or decreased in a gradient according to a randomized response list for the next patient. EC90 and 95% confidence interval were calculated by linear interpolation and prediction model with R statistical software. RESULTS: In this study, the estimated EC90 of alfentanil was 3.85 µg/mL (95% confidence interval, 3.64-4.28 µg/mL). CONCLUSION: When combined with ropivacaine 0.075%, the EC90 of alfentanil for epidural labor analgesia is 3.85 µg/mL in patients undergoing labor analgesia.
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Alfentanilo , Analgesia Epidural , Analgesia Obstétrica , Analgésicos Opioides , Anestésicos Locales , Ropivacaína , Humanos , Ropivacaína/administración & dosificación , Femenino , Método Doble Ciego , Alfentanilo/administración & dosificación , Embarazo , Analgesia Epidural/métodos , Estudios Prospectivos , Adulto , Anestésicos Locales/administración & dosificación , Analgesia Obstétrica/métodos , Analgésicos Opioides/administración & dosificación , Relación Dosis-Respuesta a Droga , Dimensión del Dolor/métodos , Dimensión del Dolor/efectos de los fármacosRESUMEN
Tetramethylpyrazine (TMP) is one of the active ingredients of Chuan Xiong that has been reported to have effects on numerous diseases, including diabetic nephropathy (DN). Whereas, related molecular mechanisms are not fully elucidated. We aimed to explore circACTR2's role in TMP-mediated protective effects on DN. In vitro DN condition was established in human kidney cells (HK-2) by treating high glucose (HG). CCK-8 assay and flow cytometry assay were used to observe cell viability and survival. Oxidative stress was determined by the associated markers using kits. The release of inflammatory factors was detected using ELISA kits. Quantitative real-time PCR (qPCR) and western blot were utilized for expression analysis of cricACTR2, miR-140-5p, and GLI pathogenesis-related 2 (GLIPR2). The binding between miR-140-5p and circACTR2 or GLIPR2 was confirmed by dual-luciferase, RIP, and pull-down studies. HG largely induced HK-2 cell apoptosis, oxidative stress, and inflammation, which were alleviated by TMP. CircACTR2's expression was enhanced in HG-treated HK-2 cells but attenuated in HG + TMP-treated HK-2 cells. CircACTR2 overexpression attenuated the functional effects of TMP and thus restored HG-induced cell apoptosis, oxidative stress, and inflammation. CircACTR2 bound to miR-140-5p to enhance the expression of GLIPR2. MiR-140-5p restoration or GLIPR2 inhibition reversed the role of circACTR2 overexpression. CircACTR2 attenuated the protective effects of TMP on HG-induced HK-2 cell damages by regulating the miR-140-5p/GLIPR2 network, indicating that circACTR2 was involved in the functional network of TMP in DN.
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Pirazinas , Humanos , Pirazinas/farmacología , MicroARNs/metabolismo , Estrés Oxidativo/efectos de los fármacos , ARN Circular/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Línea Celular , Apoptosis/efectos de los fármacos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patologíaRESUMEN
Intraventricular hemorrhage results in posthemorrhagic hydrocephalus (PHH). Neonatal hydrocephalus remains a challenging disease due to the high failure rate of all management strategies. We evaluated long noncoding RNA growth arrest-specific 5 (GAS5)-mediated network in neonatal hydrocephalus, providing a new direction for the treatment of hydrocephalus. The PHH model was constructed in neonatal rats after intracerebroventricular injection with GAS5, miR-325-3p, and chaperonin containing T-complex protein 1, subunit 8 (CCT8) plasmids, or oligonucleotides. Next, behavioral tests, measurement of serum inflammation, observation of brain tissue pathology, and calculation of hemoglobin and brain water contents were implemented. GAS5, miR-325-3p, and CCT8 expression, in combination with their interactions, was checked. As the results reported, collagenase infusion induced hydrocephalus, impairing neurological function, enhancing inflammation and neuronal apoptosis, and increasing hemoglobin and brain water contents. GAS5 and CCT8 were up-regulated, while miR-325-3p was down-regulated in hydrocephalic rats. Downregulating GAS5/CCT8 or upregulating miR-325-3p could inhibit inflammatory response and improve neurological function in young hydrocephalic rats. GAS5 promotes CCT8 expression through sponge adsorption of miR-325-3p. GAS5 silencing-mediated protections against hydrocephalus were counteracted by CCT8 overexpression. In summary, GAS5 aggravates neonatal hydrocephalus and inflammatory responses in a way of leasing miR-325-3p-involved regulation of CCT8.
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Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P-glycoprotein (P-gp) in Caco-2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 µM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P-gp was 11.26 µM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug-drug interaction (DDI) model of PBPK predicted that co-administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P-gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co-medication of Fuzi and Gancao.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Aconitina , Citocromo P-450 CYP3A , Ácido Glicirrínico , Microsomas Hepáticos , Animales , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/genética , Aconitina/farmacocinética , Aconitina/análogos & derivados , Aconitina/toxicidad , Ácido Glicirrínico/farmacocinética , Ácido Glicirrínico/farmacología , Humanos , Células CACO-2 , Masculino , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Ratas , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Ratas Sprague-Dawley , Modelos Biológicos , Inactivación MetabólicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Gancao Decoction (GCD) is widely used to treat cholestatic liver injury. However, it is unclear whether is related to prevent hepatocellular necroptosis. AIM OF THE STUDY: The purpose of this study is to clarify the therapeutic effects of GCD against hepatocellular necroptosis induced by cholestasis and its active components. MATERIALS AND METHODS: We induced cholestasis model in wild type mice by ligating the bile ducts or in Nlrp3-/- mice by intragastrical administering Alpha-naphthylisothiocyanate (ANIT). Serum biochemical indices, liver pathological changes and hepatic bile acids (BAs) were measured to evaluate GCD's hepatoprotective effects. Necroptosis was assessed by expression of hallmarkers in mice liver. Moreover, the potential anti-necroptotic effect of components from GCD were investigated and confirmed in ANIT-induced cholestasis mice and in primary hepatocytes from WT mouse stimulated with Tumor Necrosis Factor alpha (TNF-α) and cycloheximide (CHX). RESULTS: GCD dose-dependently alleviated hepatic necrosis, reduced serum aminotranferase activity in both BDL and ANIT-induced cholestasis models. More importantly, the expression of hallmarkers of necroptosis, including MLKL, RIPK1 and RIPK3 phosphorylation (p- MLKL, p-RIPK1, p-RIPK3) were reduced upon GCD treatment. Glycyrrhetinic acid (GA), the main bioactive metabolite of GCD, effectively protected against ANIT-induced cholestasis, with decreased expression of p-MLKL, p-RIPK1 and p-RIPK3. Meanwhile, the expression of Fas-associated death domain protein (FADD), long isoform of cellular FLICE-like inhibitory protein (cFLIPL) and cleaved caspase 8 were upregulated upon GA treatment. Moreover, GA significantly increased the expression of active caspase 8, and reduced that of p-MLKL in TNF-α/CHX induced hepatocytes necroptosis. CONCLUSIONS: GCD substantially inhibits necroptosis in cholestatic liver injury. GA is the main bioactive component responsible for the anti-necroptotic effects, which correlates with upregulation of c-FLIPL and active caspase 8.
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Colestasis , Medicamentos Herbarios Chinos , Ácido Glicirretínico , Glycyrrhiza , Ratones , Animales , Factor de Necrosis Tumoral alfa/farmacología , Caspasa 8 , Necroptosis , Hígado , Colestasis/inducido químicamente , Colestasis/tratamiento farmacológico , Colestasis/patología , Ácido Glicirretínico/farmacología , 1-Naftilisotiocianato/toxicidadRESUMEN
The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
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Proteínas del Tejido Nervioso , Degeneración Retiniana , Animales , Ratones , Traslocación Bacteriana , Proteínas del Ojo/genética , Amaurosis Congénita de Leber/genética , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Retina/metabolismo , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patologíaRESUMEN
Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.
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Ameloblastoma , Humanos , Ameloblastoma/genética , Ameloblastoma/patología , Recurrencia Local de Neoplasia , Fenotipo , Transformación Celular Neoplásica , Perfilación de la Expresión GénicaRESUMEN
The augmented prevalence of Se (Se) pollution can be attributed to various human activities, such as mining, coal combustion, oil extraction and refining, and agricultural irrigation. Although Se is vital for animals, humans, and microorganisms, excessive concentrations of this element can give rise to potential hazards. Consequently, numerous approaches have been devised to mitigate Se pollution, encompassing physicochemical techniques and bioremediation. The recognition of Se volatilization as a potential strategy for mitigating Se pollution in contaminated environments is underscored in this review. This study delves into the volatilization mechanisms in various organisms, including plants, microalgae, and microorganisms. By assessing the efficacy of Se removal and identifying the rate-limiting steps associated with volatilization, this paper provides insightful recommendations for Se mitigation. Constructed wetlands are a cost-effective and environmentally friendly alternative in the treatment of Se volatilization. The fate, behavior, bioavailability, and toxicity of Se within complex environmental systems are comprehensively reviewed. This knowledge forms the basis for developing management plans that aimed at mitigating Se contamination in wetlands and protecting the associated ecosystems.