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With excessive Mn(â ¡) and Cu(â ¡) pollution in aquatic environments posing potential health risks to inhabitants, the emergence of carbon capture, utilization and storage (CCUS) technology has promoted the improvement of heavy metal remediation technologies. Using hydrothermal sediment as a crystal seed, rhamnolipid was used to mediate biomimetic mineralization to prepare hydrated magnesium carbonate (HMC) composites to enhance the Mn(â ¡)/Cu(â ¡) adsorption performance of alginate hydrogels. Hydrothermal sediment is beneficial for accelerating biomimetic mineralization, while rhamnolipid can induce a crystalline phase transformation from dypingite to nesquehonite. The addition of sediment significantly enhanced the compressive mechanical properties and thermal stability of the hydrogels. The adsorption performances of the nesquehonite and dypingite hydrogels were better for Mn(II) and Cu(II), respectively. An increase in the amount of sediment improved the adsorption of Cu(II) by the hydrogels appropriately, resulting in stronger selectivity for Cu(II). The adsorption of Mn(II) and Cu(II) on the hydrogel beads was thermodynamically spontaneous. The inhibitory effects of sodium dodecyl benzene sulfonate (SDBS), fulvic acid (FA) and alginate on Cu(II) adsorption were more obvious than those of bovine serum albumin (BSA). Both the complexation of functional groups on alginate and mineralization by HMC participated in the adsorption of Mn(II) and Cu(II).
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Multiple sclerosis (MS) is a common autoimmune illness that is difficult to treat. The upregulation of Th17 cells is critical in the pathological process of MS. Hederagenol (Hed) has been shown to lower IL-17 levels, although its role in MS pathophysiology is uncertain. In this study, we explore whether Hed could ameliorate MS by modulating Th17 cell differentiation, with the goal of identifying new treatment targets for MS. The experimental autoimmune encephalomyelitis (EAE) mouse model was conducted and Hed was intraperitoneally injected into mice. The weight was recorded and the clinical symptom grade was assessed. Hematoxylin-eosin staining was carried out to determine the extent of inflammation in the spinal cord and liver. The luxol Fast Blue staining was performed to detect the pathological changes in the myelin sheath. Nerve damage was detected using NeuN immunofluorescence staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. Immunohistology approaches were used to study alterations in immune cells in the spinal cord. The proportions of T cell subsets in the spleens were analyzed by flow cytometry. RORγt levels were measured using quantitative real-time PCR or Western blot. The activity of the RORγt promoter was analyzed by Chromatin immunoprecipitation. Hed administration reduced the clinical symptom grade of EAE mice, as well as the inflammatory infiltration, demyelination, and cell disorder of the spinal cord, while having no discernible effect on the mouse weight. In addition, Hed treatment significantly reduced the number of T cells, particularly Th17 cells in the spinal cord and spleen-isolated CD4+ T cells. Hed lowered the RORγt levels in spleens and CD4+ T cells and overexpression of RORγt reversed the inhibitory effect of Hed on Th17 differentiation. Hed decreased nerve injury by modulating Th17 differentiation through the RORγt promoter. Hed regulates Th17 differentiation by reducing RORγt promoter activity, which reduces nerve injury and alleviates EAE.
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Diverse quinazolinone-[2,3]-fused polycyclic skeletons occupy a prominent position in drug discovery. Even with currently available methods there still remain unmet needs for flexible access to such structures. Herein, we have explored a mild "one pot" procedure for the construction of various quinazolinone-[2,3]-fused polycycles. The procedure involves Pd-catalyzed carbonylation of N-(2-iodophenyl)acetamides, release of the masked terminal amine, and two sequential and spontaneous cyclizations. This generally applicable approach features easy assembly of precursors from readily available starting materials, mild reaction conditions, non-cumbersome operation, and polycyclic diversity.
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Intervertebral disc degeneration (IDD) is a well-established cause of disability, and extensive evidence has identified the important role played by regulatory noncoding RNAs, specifically circular RNAs (circRNAs) and microRNAs (miRNAs), in the progression of IDD. To elucidate the molecular mechanism underlying IDD, we established a circRNA/miRNA/mRNA network in IDD through standardized analyses of all expression matrices. Our studies confirmed the differential expression of the transcription factors early B-cell factor 1 (EBF1), circEYA3, and miR-196a-5p in the nucleus pulposus (NP) tissues of controls and IDD patients. Cell proliferation, apoptosis, and extracellular mechanisms of degradation in NP cells (NPC) are mediated by circEYA3. MiR-196a-5p is a direct target of circEYA3 and EBF1. Functional analysis showed that miR-196a-5p reversed the effects of circEYA3 and EBF1 on ECM degradation, apoptosis, and proliferation in NPCs. EBF1 regulates the nuclear factor kappa beta (NF-кB) signalling pathway by activating the IKKß promoter region. This study demonstrates that circEYA3 plays an important role in exacerbating the progression of IDD by modulating the NF-κB signalling pathway through regulation of the miR196a-5p/EBF1 axis. Consequently, a novel molecular mechanism underlying IDD development was elucidated, thereby identifying a potential therapeutic target for future exploration.
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Degeneración del Disco Intervertebral , MicroARNs , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Transducción de Señal , ARN Circular/genética , Transactivadores/metabolismoRESUMEN
The common use of peroxides in the remediation of malodorous black water may lead to the activation of heavy metals in sediment when eliminating black and odorous substances. The mechanisms of heavy metal interactions with dissolved organic matter (DOM) in response to in situ capping have not been elucidated, but this information could guide the optimization of capping materials. We developed a capping material consisting of hydrothermally carbonized sediment (HCS), hydrated magnesium carbonate (HMC) and sodium percarbonate (SPC) and used microcosm experiments to investigate the dynamics of Mn and Cu at the sediment-water interface in malodorous black water. The results showed that HCS, HMC and SPC contributed multiple functions of mechanical protection, chemical isolation and oxygen provision to the new caps. HMC promoted the conversion of Mn/Cu into carbonate minerals. The optimal mass proportions were 25 % HCS, 60 % HMC and 15 % SPC based on the mixture design. In situ capping altered the fate and transformation of metals in the sediment-overlying water profile in the short term through Mn immobilization and Cu activation. The complexation of Cu(II) ions was significantly stronger than that of Mn(II) ions. In situ capping had a significant effect on the order of complexation of different fluorescent DOM molecules with Mn(II)/Cu(II) ions: microbial byproducts and fulvic acid-like components were preferentially complexed with Cu(II) ions after capping, while phenolic and humic acid-like components preferentially interacted with Mn(II) ions. Humic-like components bound to Cu were affected the most by capping treatment, whereas protein-like components were relatively weakly affected. Our study provides valuable knowledge on the impact of in situ capping on DOM-metal complexes.
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Materia Orgánica Disuelta , Metales Pesados , Metales Pesados/química , Sustancias Húmicas/análisis , Iones , Espectrometría de Fluorescencia/métodosRESUMEN
Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Proteína de Unión a CREB/química , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Dominios Proteicos , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Objectives: The COVID-19 pandemic imposed an enormous disease and economic burden worldwide. SARS-CoV-2 vaccination is essential to containing the pandemic. People living with HIV (PLWH) may be more vulnerable to severe COVID-19 outcomes; thus, understanding their vaccination willingness and influencing factors is helpful in developing targeted vaccination strategies. Methods: A cross-sectional study was conducted between 15 June and 30 August 2022 in Shijiazhuang, China. Variables included socio-demographic characteristics, health status characteristics, HIV-related characteristics, knowledge, and attitudes toward COVID-19 vaccination and COVID-19 vaccination status. Multivariable logistic regression was used to confirm factors associated with COVID-19 vaccination willingness among PLWH. Results: A total of 1,428 PLWH were included, with a 90.48% willingness to receive the COVID-19 vaccination. PLWH were more unwilling to receive COVID-19 vaccination for those who were female or had a fair/poor health status, had an allergic history and comorbidities, were unconvinced and unsure about the effectiveness of vaccines, were unconvinced and unsure about the safety of vaccines, were convinced and unsure about whether COVID-19 vaccination would affect ART efficacy, or did not know at least a type of domestic COVID-19 vaccine. Approximately 93.00% of PLWH have received at least one dose of the COVID-19 vaccine among PLWH, and 213 PLWH (14.92%) reported at least one adverse reaction within 7 days. Conclusion: In conclusion, our study reported a relatively high willingness to receive the COVID-19 vaccination among PLWH in Shijiazhuang. However, a small number of PLWH still held hesitancy; thus, more tailored policies or guidelines from the government should be performed to enhance the COVID-19 vaccination rate among PLWH.
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Flaxseed oil is an important source of vegetable oil with a polyunsaturated fatty acid. It is significant to establish a method to quickly identify adulterated flaxseed oil. In the present study, the qualitative and quantitative analysis of phytosterol of flaxseed oil from different varieties and different production areas in the Qinghai area was first performed by gas chromatography-mass spectrometry (GC-MS) and the phytosterol standard profile of flaxseed oil was established. Then, a combination of similarity evaluation and cluster analysis was used to distinguish pure flaxseed oil from flaxseed oil adulterated with concentrations of 10-50% rapeseed oil, peanut oil, sunflower oil, and sesame oil, and discriminant analysis was used to identify the types of adulterated flaxseed oil. The results showed that similarity evaluation combined with cluster analysis can distinguish pure and adulterated flaxseed oil when the concentration of the adulterant was greater than 10%. Discriminant analysis models accurately identified the types of adulterating oil in flaxseed oil when the concentration of rapeseed, peanut, or sunflower oil was greater than 20%, and that of sesame oil was greater than 30%. This study shows that the determination of the phytosterol composition and chemometrics is a valuable tool to evaluate the purity of flaxseed oil.
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Aceite de Linaza , Fitosteroles , Cromatografía de Gases y Espectrometría de Masas , Aceite de Sésamo/análisis , Aceite de Sésamo/química , Quimiometría , Aceites de Plantas , Aceite de GirasolRESUMEN
The use of the Storm Water Management Model (SWMM) to simulate flows in urban river watersheds necessitates the proper calibration of the various parameters involved in the process. Back Propagation Neural Network (BPNN) is often used to establish relationship between two sets of multivariate variables, such as parameters and simulation results of SWMM. The aim of this study is to establish an improved BPNN to calibrate SWMM. It was found that when using gauged flow data obtained from the urban river management system as calibration data, only using BPNN was not sufficient. An improved BPNN framework was proposed with integrating Principal Component Analysis (PCA) and Genetic Algorithm (GA) process, abbreviated as PCA-GA-BPNN. It was proved to be effective for calibration. The BPNN combined with GA process made 90 % of the predicted parameters within reasonable range, which was only 8 % using BPNN alone. The PCA process reduced the training time up to 64 %. Using a hydrograph of 196 h, compared with the nondominated sorting genetic algorithm (NSGA), PCA-GA-BPNN training time can be reduced from 18,142 s down to 4.5 s. Nash efficiency coefficients (NSE) of hydrographs fitting was 0.75. Including more rainfall events data in calibration achieved better fitting than including more gauging station data.
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Three new formyl phloroglucinol meroterpenoids, eumaidials A-C (1-3), were isolated from the leaves of Eucalyptus globulus subsp. maidenii, along with ten known analogues (4-13). Their chemical structures were determined by various spectral data and electronic circular dichroism calculations. Eumaidial A (1) is the first ß-caryophyllene-based formyl phloroglucinol meroterpenoids from the genus Eucalyptus. Compounds 1-4 and 10 exhibited ATP-citrate lyase inhibitory activities, and compounds 2 and 3 suppressed the hepatocyte lipogenesis.
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Eucalyptus , Complejos Multienzimáticos , Oxo-Ácido-Liasas , Estructura Molecular , Eucalyptus/química , Floroglucinol/farmacología , Floroglucinol/química , Hojas de la Planta/química , Adenosina TrifosfatoRESUMEN
Natural product cantharidin can inhibit multiple myeloma cell growth in vitro, while serious adverse effects limited its clinical application. Therefore, the structural modification of cantharidin is needed. Herein, inspired by the structural similarity of the aliphatic endocyclic moiety in cantharidin and TRIP13 inhibitor DCZ0415, we designed and synthesized DCZ5418 and its nineteen derivatives. The molecular docking study indicated that DCZ5418 had a similar binding mode to TRIP13 protein as DCZ0415 while with a stronger docking score. Moreover, the bioassay studies of the MM-cells viability inhibition, TRIP13 protein binding affinity and enzyme inhibiting activity showed that DCZ5418 had good anti-MM activity in vitro and definite interaction with TRIP13 protein. The acute toxicity test of DCZ5418 showed less toxicity in vivo than cantharidin. Furthermore, DCZ5418 showed good anti-MM effects in vivo with a lower dose administration than DCZ0415 (15 mg/kg vs 25 mg/kg) on the tumor xenograft models. Thus, we obtained a new TRIP13 inhibitor DCZ5418 with improved safety and good activity in vivo, which provides a new example of lead optimization by using the structural fragments of natural products.
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Cantaridina , Mieloma Múltiple , Humanos , ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , Cantaridina/farmacología , Cantaridina/uso terapéutico , Cantaridina/química , Proteínas de Ciclo Celular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Simulación del Acoplamiento Molecular , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patologíaRESUMEN
Auristatins-glucuronide conjugates designed targeting the ß-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against ß-glucuronidase pretreated and untreated cancer cells (IC50 = 5.7 nM â¼ 9.7 nM, IC50 (-Enz) > 1 µM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects.
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Glucuronidasa , Glucurónidos , Ratones , Humanos , Animales , Glucurónidos/farmacología , Microambiente Tumoral , Oligopéptidos/farmacologíaRESUMEN
TLR2 agonists typified by the S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (Pam2CS) motif have exhibited powerful immunostimulatory activities. Based on simplified monoacyl lipopeptide (Carbamate-linked N-Ac PamCS), we describe interesting SAR investigations where modifications are done to alter the size of substituents on the cysteine amine, introduce ionizable groups to the terminal and insert aromatic substitutions to the aliphatic chain. Our structural modifications have led to a highly specific human TLR2/6 agonist 14a (EC50 = 0.424 nM), which behaves like Pam2CSK4 by inducing NF-κB activation to trigger downstream signaling pathways, such as subsequent phosphorylation of related proteins (p65, p38) and production of key inflammatory cytokines (IL-6, IL-1ß, TNF-α). Importantly, the ability to stimulate enhanced T cell response compared to Carbamate-linked N-Ac PamCS makes compound 14a a further potential candidate immunostimulant.
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Adyuvantes Inmunológicos , Receptor Toll-Like 2 , Humanos , Receptor Toll-Like 2/agonistas , Simulación de Dinámica Molecular , Lipopéptidos/química , CarbamatosRESUMEN
Exposure of human tissues to Dechlorane Plus (DP) has raised public concern because of the multiple health threats it may pose to humans. Therefore, it is important to summarize the main findings of previous studies on DP in human tissues and to provide potential guidance for future studies. In this paper, DP levels in different populations and human tissues worldwide since 2009 were systematically reviewed. DP levels in human tissues of workers in e-waste dismantling sites in Guangdong Province, China (median 190 ng·g-1 lw in serum) and DP manufacturing plants in Jiangsu Province, China (mean 857 ng·g-1 lw in whole-blood) are the highest reported worldwide. DP levels in tissues of the general population in recent studies are close to those of residents near e-waste dismantling sites, which should be of concern. DP levels in different human tissues were found to be positively correlated with a pattern of blood > breast milk > adipose tissue. The distribution of DP in different human tissues is mainly lipid-driven and may also be influenced by the interaction of DP with proteins such as human serum albumin. Most of the past studies determined the isomer stereoselectivity of DP in human tissues only by comparing the composition of DP in commercial DP products and human tissues, which lacks evidence of mechanism. Recently, a significantly different affinity of DP isomers for proteins was found, which seems to confirm the isomer selectivity of DP in human tissues. We simulated the binding of DP to human serum albumin and DP to thyroid hormone receptor ß by molecular docking and found differences in the binding behavior of syn-DP and anti-DP to the selected proteins. Molecular docking seems to be a feasible approach for future studies to predict and reveal the mechanisms of DP behavior and health effects in human tissues.
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Aerobic glycolysis has been considered as a hallmark of colorectal cancer (CRC). However, the potential functional regulators of glycolysis in CRC remains to be elucidated. In the current study, we found that Regenerating islet-derived protein 1-alpha (REG1α) was significantly increased in both CRC tissues and serum, and positively associated with CRC patients' lymph node metastasis, advanced tumor stage, and unfavorable prognosis. Ectopic expression of REG1α contributed to various tumorigenic properties, including cell proliferation, cell cycle, migration, invasion, and glycolysis. In contrast, REG1α deficiency in CRC cells attenuated malignant properties and glucose metabolism. Mechanically, REG1α promoted CRC proliferation and metastasis via ß-catenin/MYC axis-mediated glycolysis upregulation. Moreover, the malignant behaviors governed by REG1α could be effectively abolished by silencing of Wnt/ß-catenin/MYC axis or glycolysis process using specific inhibitors. Besides, REG1α expression was mediated by METTL3 in an m6A-dependent manner. Overall, our work defines a novel regulatory model of the METTL3/REG1α/ß-catenin/MYC axis in CRC, which indicates that REG1α could function as a novel biomarker and a potential therapeutic target for patients with CRC.
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Neoplasias Colorrectales , beta Catenina , Humanos , beta Catenina/genética , Glucólisis/genética , Metástasis Linfática , Neoplasias Colorrectales/genética , MetiltransferasasRESUMEN
The neuroprotective role of 5-hydroxymethyl-2-furfural (5-HMF) has been demonstrated in a variety of neurological diseases. The aim of this study is to investigate the effect of 5-HMF on multiple sclerosis (MS). IFN-γ-stimulated murine microglia (BV2 cells) are considered a cell model of MS. With 5-HMF treatment, microglial M1/2 polarization and cytokine levels are detected. The interaction of 5-HMF with migration inhibitory factor (MIF) is predicted using online databases. The experimental autoimmune encephalomyelitis (EAE) mouse model is established, followed by a 5-HMF injection. The results show that 5-HMF facilitates IFN-γ-stimulated microglial M2 polarization and attenuates the inflammatory response. According to the network pharmacology and molecular docking results, 5-HMF has a binding site for MIF. Further results show that blocking MIF activity or silencing CD74 enhances microglial M2 polarization, reduces inflammatory activity, and prevents ERK1/2 phosphorylation. 5-HMF inhibits the MIF-CD74 interaction by binding to MIF, thereby inhibiting microglial M1 polarization and enhancing the anti-inflammatory response. 5-HMF ameliorates EAE, inflammation, and demyelination in vivo. In conclusion, our research indicates that 5-HMF promotes microglial M2 polarization by inhibiting the MIF-CD74 interaction, thereby attenuating inflammation and demyelination in EAE mice.
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Encefalomielitis Autoinmune Experimental , Factores Inhibidores de la Migración de Macrófagos , Animales , Ratones , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
A better understanding of the relationships between non-point source (NPS) pollution-related processes and their drivers will help to develop scientific watershed management measures. Although various studies have explored the drivers' impact on NPS pollution-related processes, quantitative knowledge of the properties within these relationships is still needed. This study uses the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model to produce three related processes of NPS pollution, quick flow (QF), nitrogen export (NE), and sediment export (SE), in the upstream watershed of Chaohu Lake, China. The spatial distributions of QF, NE, and SE and their responses to multiple natural-socioeconomic drivers at nine spatial scales (1 km2, 10 km2, 20 km2, 30 km2, 50 km2, 75 km2, 100 km2, 200 km2, and town) were compared. The results showed that the spatial scale has little impact on the spatial distributions of NPS pollution-related processes. Across the nine scales, the socioeconomic drivers related to agricultural activities, area proportions of cultivated land (cultivated) and paddy field (paddy), have dominant impacts on NE, while the topographical drivers, the connectivity index (IC) and slope, have dominant impacts on both SE and QF. The magnitudes of single and paired natural-socioeconomic drivers' impacts on NPS pollution-related processes increase logarithmically or linearly with increasing spatial scale, but they tend to reach a stable threshold at a certain coarse scale. Our results emphasized the necessity and importance of embracing spatial scale effects in watershed water environmental management.
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Contaminación Difusa , Contaminantes Químicos del Agua , Ecosistema , Lagos , Monitoreo del Ambiente/métodos , Contaminación Difusa/análisis , Fósforo/análisis , China , Contaminantes Químicos del Agua/análisis , Nitrógeno/análisisRESUMEN
As the main pathological basis for the development of cardiovascular and cerebrovascular diseases, atherosclerosis (AS) seriously affects human health. The key targets of biological information analysis of AS can help exploit therapeutic targets. The expression data of early and progressive atherosclerotic tissues were downloaded from the Gene Expression Omnibus (GEO) database. Based on GSE28829 and GSE120521, 74 key genes were obtained through differential expression analysis and weighted correlation network analysis (WGCNA) analysis, which were mainly enriched in the regulating of inflammatory response, chemokine signalling pathway, apoptosis, lipid and AS, Toll-like receptor signalling pathway and so on according to the results of the enrichment analysis. Cytoscape software was applied to screen four pivotal genes (TYROBP, ITGB2, ITGAM and TLR2) based on PPI. The results of the correlation analysis showed that the expression level of pivotal genes was positively related to macrophages M0, and was negatively related to T cells follicular helper. In addition, the expression of ITGB2 was positively related to Tregs. In this study, bioinformatics was applied to screen pivotal genes affecting the progress of AS, which were significantly related to immune-related biological functions and signal pathways of atherosclerotic tissues and the infiltration level of immune cells. Therefore, pivotal genes were expected to become therapeutic targets for AS.
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Aterosclerosis , Humanos , Aterosclerosis/genética , Apoptosis , Biología Computacional , Bases de Datos Factuales , Macrófagos , Perfilación de la Expresión GénicaRESUMEN
The mechanism by which parameters influence the source apportionment results of receptor models is not well understood. Three mature receptor models, namely, principal component analysis-multiple linear regression (PCA-MLR), positive matrix factorization (PMF) and factor analysis with nonnegative constraints (FA-NNC), were comparatively employed for source apportionment of 16 polycyclic aromatic hydrocarbons in 30 street dust samples. The results indicated that the FA-NNC and PMF models produced results with a higher degree of similarity than the results obtained with the PCA-MLR model. Moreover, when the sample size was gradually decreased, similar source profiles were extracted that were consistent with results obtained from all samples. However, the overall contribution rates were not as stable as the source profiles. The PCA-MLR results remained the most stable in both aspects. FA-NNC and PMF performed better in regards to the stability of contribution rates and source profiles, respectively. Improvements in the goodness of fit of overall and individual pollutants were always accompanied by a decrease in the relevance among the variables, indicating that while the model simulation effect was improved, the credibility of the results decreased. Thus, finding an appropriate number of sample size is more appropriate than simply involving too many samples in source apportionment models.
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Monitoreo del Ambiente , Modelos Teóricos , Modelos Lineales , Monitoreo del Ambiente/métodos , Análisis de Componente Principal , Tamaño de la Muestra , Análisis Factorial , ChinaRESUMEN
Fatty-acid binding protein 4 (FABP4) is an essential driver for the progression of metabolic-related inflammatory diseases including obesity, diabetes, atherosclerosis, and various lipid metabolism-related tumors. However, FABP4 inhibitors are not yet available for clinical use, which may be associated with their poor selectivity of FABP3, unsatisfactory efficacy and physicochemical properties. Herein, we reported a systematic optimization of a class of biphenyl scaffold molecules as potent FABP4 inhibitors. Further in vitro and in vivo pharmacokinetic studies identified a selective and orally bioavailable compound 10g, with Ki of 0.51 µM against FABP4, Ki of 33.01 µM against FABP3 and bioavailability F% value of 89.4%. In vivo anti-inflammatory efficacy and multi-organ protection study in LPS-induced inflammatory mice model highlighted the potential of compound 10g as a therapeutic candidate in inflammation-related diseases.