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(20 S)-Ginsenoside Rh2 is a natural saponin derived from Panax ginseng Meyer (P. ginseng), which showed significantly potent anticancer properties. However, its low water solubility and bioavailability strongly restrict its pharmaceutical applications. The aim of current research is to develop a modified (20 S)-Ginsenoside Rh2 formulation with high solubility, dissolution rate and bioavailability by combined computational and experimental methodology. The "PharmSD" model was employed to predict the optimal polymer for (20 S)-Ginsenoside Rh2 solid dispersion formulations. The solubility of (20 S)-Ginsenoside Rh2 in various polymers was assessed, and the optimal ternary solid dispersion was evaluated across different dissolution mediums. Characterization techniques included the Powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). Molecular dynamics simulations were employed to elucidate the formation mechanism of the solid dispersion and the interactions among active pharmaceutical ingredient (API) and excipient molecules. Cell and animal experiments were conducted to evaluate the in vivo performance of the modified formulation. The "PharmSD" solid dispersion model identified Gelucire 44/14 as the most effective polymer for enhancing the dissolution rate of Rh2. Subsequent experiment also confirmed that Gelucire 44/14 outperformed the other selected polymers. Moreover, the addition of the third component, sodium dodecyl sulfate (SDS), in the ternary solid dispersion formulation significantly amplified dissolution rates than the binary systems. Characterization experiments revealed that the API existed in an amorphous state and interacted via hydrogen bonding with SDS and Gelucire. Moreover, molecular modeling results provided additional evidence of hydrogen bonding interactions between the API and excipient molecules within the optimal ternary solid dispersion. Cell experiments demonstrated efflux ratio (EfR) of Rh2 ternary solid dispersion was lower than that of pure Rh2. In vivo experiments revealed that the modified formulation substantially improved the absorption of Rh2 in rats. Our research successfully developed an optimal ternary solid dispersion for Rh2 with high solubility, dissolution rate and bioavailability by integrated computational and experimental tools. The combination of Artificial Intelligence (AI) technology and molecular dynamics simulation is a wise way to support the future formulation development.
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Probiotic intervention is an effective strategy to alleviate oxidative stress-related diseases. Our previous studies found that Lactiplantibacillus plantarum NJAU-01 (NJAU-01) exhibited antioxidant effects in a D-galactose (D-gal)-induced aging mouse model. However, the underlying mechanism remains to be unveiled. This study was aimed to investigate the ameliorative effect and mechanism of NJAU-01 against oxidative stress induced by D-gal. The results showed that NJAU-01 could reverse the tendency of a slow body weight gain induced by D-gal. NJAU-01 relieved hepatic oxidative stress via increasing the hepatic total antioxidant capacity and antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). Moreover, the malondialdehyde (MDA) level was reversed after NJAU-01 supplementation. The proteomic results showed that there were 201 differentially expressed proteins (DEPs) between NJAU-01 and D-gal groups. NJAU-01 regulated the expressions of glutathione S-transferase Mu 5 (Gstm5), glutathione S-transferase P2 (Gstp2) and NADH dehydrogenase 1α subcomplex subunit 7 (Ndufa7) related to oxidative stress, and autophagy protein 5 (Atg5) and plasma alpha-L-fucosidase (Fuca2) involved in autophagy, etc. 16S rDNA sequencing results showed that NJAU-01 supplementation could regulate the gut microbiota dysbiosis induced by D-gal via increasing the relative abundances of the phylum Firmicutes and the genus Lactobacillus and reducing the relative abundances of the phylum Bacteroidetes and the genera Lachnospiraceae_NK4A136_group as well as Prevotellaceae_UCG-001, etc.. Spearman correlation analysis results showed that the altered gut microbiota composition had a significant correlation with antioxidant enzyme activities and the DEPs related to oxidative stress. Overall, NJAU-01 alleviated hepatic oxidative stress induced by D-gal via manipulating the gut microbiota composition and hepatic protein expression profile.
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Galactosa , Microbioma Gastrointestinal , Hígado , Estrés Oxidativo , Probióticos , Proteómica , Estrés Oxidativo/efectos de los fármacos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Probióticos/farmacología , Probióticos/administración & dosificación , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Lactobacillus plantarum , Antioxidantes/farmacología , Malondialdehído/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Domoic acid (DA)-producing algal blooms are a global marine environmental issue. However, there has been no previous research addressing the question regarding the fate of DA in marine benthic environments. In this work, we investigated the DA fate in the water-sediment microcosm via the integrative analysis of a top-down metabolic model, metagenome, and metabolome. Results demonstrated that biodegradation is the leading mechanism for the nonconservative attenuation of DA. Specifically, DA degradation was prominently completed by the sediment aerobic community, with a degradation rate of 0.0681 ± 0.00954 d-1. The DA degradation pathway included hydration, dehydrogenation, hydrolysis, decarboxylation, automatic ring opening of hydration, and ß oxidation reactions. Moreover, the reverse ecological analysis demonstrated that the microbial community transitioned from nutrient competition to metabolic cross-feeding during DA degradation, further enhancing the cooperation between DA degraders and other taxa. Finally, we reconstructed the metabolic process of microbial communities during DA degradation and confirmed that the metabolism of amino acid and organic acid drove the degradation of DA. Overall, our work not only elucidated the fate of DA in marine environments but also provided crucial insights for applying metabolic models and multi-omics to investigate the biotransformation of other contaminants.
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Biotransformación , Sedimentos Geológicos , Ácido Kaínico , Toxinas Marinas , Ácido Kaínico/análogos & derivados , Ácido Kaínico/metabolismo , Sedimentos Geológicos/microbiología , Toxinas Marinas/metabolismo , Microbiota , Metaboloma , Biodegradación Ambiental , Metagenoma , Contaminantes Químicos del Agua/metabolismo , MultiómicaRESUMEN
The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.
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Antibacterianos , Linezolid , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Humanos , Animales , Linezolid/farmacología , Relación Estructura-Actividad , Células CACO-2 , Ratones , Estructura Molecular , Relación Dosis-Respuesta a Droga , Staphylococcus aureus/efectos de los fármacos , Ratas , Farmacorresistencia Bacteriana/efectos de los fármacos , Masculino , Enterococcus faecalis/efectos de los fármacos , Oxazolidinonas/farmacología , Oxazolidinonas/química , Oxazolidinonas/síntesis química , Ratas Sprague-DawleyRESUMEN
Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.
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Anfotericina B , Antifúngicos , Fungemia , Profármacos , Animales , Anfotericina B/administración & dosificación , Anfotericina B/farmacología , Anfotericina B/química , Anfotericina B/farmacocinética , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/uso terapéutico , Humanos , Fungemia/tratamiento farmacológico , Nanopartículas/química , Liberación de Fármacos , Micelas , Ratones , Femenino , Química Clic , Candida albicans/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/administración & dosificaciónRESUMEN
HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Pirimidinas , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Humanos , Relación Estructura-Actividad , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Estructura Molecular , Ratas , Relación Dosis-Respuesta a Droga , Masculino , Simulación del Acoplamiento Molecular , Ratas Sprague-DawleyRESUMEN
Plant viral diseases compromise the growth and yield of the crop globally, and they tend to be more serious under extreme temperatures and drought climate changes. Currently, regulatory dynamics during plant development and in response to virus infection at the plant cell level remain largely unknown. In this study, single-cell RNA sequencing on 23 226 individual cells from healthy and tomato chlorosis virus-infected leaves was established. The specific expression and epigenetic landscape of each cell type during the viral infection stage were depicted. Notably, the mesophyll cells showed a rapid function transition in virus-infected leaves, which is consistent with the pathological changes such as thinner leaves and decreased chloroplast lamella in virus-infected samples. Interestingly, the F-box protein SKIP2 was identified to play a pivotal role in chlorophyll maintenance during virus infection in tomato plants. Knockout of the SlSKIP2 showed a greener leaf state before and after virus infection. Moreover, we further demonstrated that SlSKIP2 was located in the cytomembrane and nucleus and directly regulated by ERF4. In conclusion, with detailed insights into the plant responses to viral infections at the cellular level, our study provides a genetic framework and gene reference in plant-virus interaction and breeding in the future research.
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Hojas de la Planta , Solanum lycopersicum , Transcriptoma , Solanum lycopersicum/virología , Solanum lycopersicum/genética , Solanum lycopersicum/crecimiento & desarrollo , Hojas de la Planta/virología , Hojas de la Planta/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Análisis de la Célula Individual , Enfermedades de las Plantas/virología , Enfermedades de las Plantas/genética , Regulación de la Expresión Génica de las Plantas , Crinivirus/genética , Crinivirus/fisiologíaRESUMEN
Cellular senescence is an irreversible cell-cycle arrest in response to a variety of cellular stresses, which contribute to the pathogenesis of a variety of age-related degenerative diseases. However, effective antisenescence strategies are still lacking. Drugs that selectively target senescent cells represent an intriguing therapeutic strategy to delay aging and age-related diseases. Thus, we thought to investigate the effects of dihydroartemisinin (DHA) on senescent cells and elucidated its mechanisms underlying aging. Stress-induced premature senescence (SIPS) model was built in NIH3T3 cells using H2O2 and evaluated by ß-galactosidase staining. Cells were exposed to DHA and subjected to cellular activity assays including viability, ferroptosis, and autophagy. The number of microtubule-associated protein light-chain 3 puncta was detected by immunofluorescence staining. The iron content was assessed by spectrophotometer and intracellular reactive oxygen species (ROS) was measured by fluorescent probe dichlorodihydrofluorescein diacetate. We found that DHA triggered senescent cell death via ferroptosis. DHA accelerated ferritin degradation via promoting autophagy, increasing the iron contents, promoting ROS accumulation, thus leading to ferroptotic cell death in SIPS cells. In addition, autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. Moreover, Atg5 silencing and autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. We also revealed that the expression of p-AMP-activated protein kinase (AMPK) and p-mammalian target of rapamycin (mTOR) in senescent cells was downregulated. These results suggested that DHA may be a promising drug candidate for clearing senescent cells by inducing autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.
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Proteínas Quinasas Activadas por AMP , Artemisininas , Ferroptosis , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Senescencia Celular , Peróxido de Hidrógeno/farmacología , Hierro , Células 3T3 NIH , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Background: Malnutrition is the most common nutritional issue in Alzheimer's disease (AD) patients, but there is still a lack of a comprehensive evaluation of the nutritional status in AD patients. This study aimed to determine the potential association of various nutritional indices with AD at different stages. Methods: Subjects, including individuals with normal cognition (NC) and patients diagnosed with AD, were consecutively enrolled in this cross-sectional study. Demographics, body composition, dietary patterns, nutritional assessment scales and nutrition-related laboratory variables were collected. Binary logistics regression analyses and receiver operating characteristic (ROC) curves were used to indicate the association between nutrition-related variables and AD at different stages. Results: Totals of 266 subjects, including 73 subjects with NC, 72 subjects with mild cognitive impairment due to AD (AD-MCI) and 121 subjects with dementia due to AD (AD-D) were included. There was no significant difference in dietary patterns, including Mediterranean diet and Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet between the three groups. Lower BMI value, smaller hip and calf circumferences, lower Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) scores, and lower levels of total protein, albumin, globulin, and apolipoprotein A1 were associated with AD (all p < 0.05). Total protein and albumin levels had the greatest ability to distinguish AD from non-AD (AUC 0.80, 95% CI 0.74-0.84, p < 0.001), increased by combining calf circumference, MNA score and albumin level (AUC 0.83, 95% CI 0.77-0.88, p < 0.001). Albumin level had the greatest ability to distinguish NC from AD-MCI (AUC 0.75, 95% CI 0.67-0.82, p < 0.001), and MNA score greatest ability to distinguish AD-MCI from AD-D (AUC 0.72, 95% CI 0.65-0.78, p < 0.001). Conclusion: Nutritional status of AD patients is significantly compromised compared with normal controls, and tends to be worsened with AD progresses. Early identification and intervention of individuals with nutritional risk or malnutrition may be significantly beneficial for reducing the risk, development, and progression of AD.
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BACKGROUND: Ginsenosides have received increased amounts of attention due to their ability to modulate the intestinal flora, which may subsequently alleviate alcoholic liver disease (ALD). The effects of ginseng fermentation solution (GFS) on the gut microbiota and metabolism in ALD patients have not been explored. PURPOSE: This research aimed to explore the regulatory effect of GFS on ALD both in vitro and in vivo. METHOD: This study assessed the anti-ALD efficacy of GFS using an LO2 cell model and a zebrafish model. Untargeted metabolomics was used for differentially abundant metabolite analysis, and high-throughput 16S rRNA sequencing was used to examine the effect of GFS on ALD. RESULTS: The LO2 cell line experiments demonstrated that GFS effectively mitigated alcohol-induced oxidative stress and reduced apoptosis by upregulating PI3K and Bcl-2 expression and decreasing the levels of malondialdehyde, total cholesterol, and triglycerides. In zebrafish, GFS improved morphological and physiological parameters and diminished oxidative stress-induced ALD. Meanwhile, the results from Western blotting indicated that GFS enhanced the expression of PI3K, Akt, and Bcl-2 proteins while reducing Bax protein expression, thereby ameliorating the ALD model in zebrafish. Metabolomics data revealed significant changes in a total of 46 potential biomarkers. Among them, metabolites such as prostaglandin F2 alpha belong to arachidonic acid metabolism. In addition, GFS also partly reversed the imbalance of gut microbiota composition caused by alcohol. At the genus level, alcohol consumption elevated the presence of Flectobacillus, Curvibacter, among others, and diminished Elizabethkingia within the intestinal microbes of zebrafish. Conversely, GFS reversed these effects, notably enhancing the abundance of Proteobacteria and Archaea. Correlation analyses further indicated a significant negative correlation between prostaglandin F2 alpha, 11,14,15-THETA, Taurocholic acid and Curvibacter. CONCLUSION: This study highlights a novel mechanism by which GFS modulates anti-ALD activity through the PI3K/Akt signalling pathway by influencing the intestinal flora-metabolite axis. These results indicate the potential of GFS as a functional food for ALD treatment via modulation of the gut flora.
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Microbioma Gastrointestinal , Hepatopatías Alcohólicas , Panax , Animales , Humanos , Apoptosis/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Fermentación , Microbioma Gastrointestinal/efectos de los fármacos , Ginsenósidos/farmacología , Hepatopatías Alcohólicas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Panax/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Pez CebraRESUMEN
BACKGROUND: Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. AIM: To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. METHODS: The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. RESULTS: Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. CONCLUSION: TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Pronóstico , Estudios Retrospectivos , Estadificación de Neoplasias , Neoplasias Colorrectales/patología , Neoplasias del Colon/patologíaRESUMEN
Sea cucumber intestines are considered a valuable resource in the sea cucumber processing industry due to their balanced amino acid composition. Studies have reported that peptides rich in glutamate and branched-chain amino acids have anti-fatigue properties. However, the function of the sea cucumber intestine in reducing exercise-induced fatigue remains unclear. In this study, we enzymatically hydrolyzed low molecular weight peptides from sea cucumber intestines (SCIP) and administered SCIP orally to mice to examine its effects on exercise-induced fatigue using swimming and pole-climbing exhaustion experiments. The results revealed that supplementation with SCIP significantly prolonged the exhaustion time of swimming in mice, decreased blood lactate and urea nitrogen levels, and increased liver and muscle glycogen levels following a weight-loaded swimming test. Immunofluorescence analysis indicated a notable increase the proportion of slow-twitch muscle fiber and a significant decrease the proportion of fast-twitch muscle fiber following SCIP supplementation. Furthermore, SCIP upregulated mRNA expression levels of Ca2+ /Calcineurin upstream and downstream regulators, thereby contributing to the promotion of skeletal muscle fiber type conversion. This study presents the initial evidence establishing SCIP as a potential enhancer of skeletal muscle fatigue resistance, consequently providing a theoretical foundation for the valuable utilization of sea cucumber intestines.
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Calcineurina , Pepinos de Mar , Ratones , Animales , Calcineurina/metabolismo , Calcineurina/farmacología , Pepinos de Mar/metabolismo , Músculo Esquelético/metabolismo , Péptidos/farmacología , Natación/fisiología , Transducción de Señal , Intestinos , Péptido Hidrolasas/metabolismoRESUMEN
Wu-tou decoction (WTD), a traditional Chinese medicine prescription, is used to treat rheumatoid arthritis (RA). It works by controlling intestinal flora and its metabolites, which in turn modulates the inflammatory response and intestinal barrier function. Small molecular compounds (SM) and polysaccharides (PS) were the primary constituents of WTD extract. In this work, a model of adjuvant-induced arthritis (AIA) in rats was established and treated with WTD, SM, and PS, respectively. 16S rRNA gene sequencing was used to examine the regulatory impact of the various groups on the disturbance of the gut flora induced by RA. Further, since PS cannot be absorbed into the blood, the influence of PS on the absorption and metabolism of SM was studied by examining their pharmacokinetic (PK) parameters of 23 active components in SM by UPLC-MS/MS. WTD was found to be more effective than PS and SM in alleviating arthritis in AIA rats, which may be related to changes in gut flora. The PK properties of 13 active compounds were altered after PS intervene. Based on the findings, PS may be able to manage the disruption of intestinal microbiota, enhance the intestinal environment of model animals, and hence influence SM absorption and metabolism.
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The chemical complexity and toxicity of volatile organic compounds (VOCs) are primarily encountered through intensive anthropogenic emissions in suburban areas. Here, pollution characteristics, impacts on secondary pollution formation, and health risks were investigated through continuous in-field measurements from 1-30 June 2020 in suburban Nanjing, adjacent to national petrochemical industrial parks in China. On average, the total VOCs concentration was 34.47 ± 16.08 ppb, which was comprised mostly by alkanes (41.8%) and halogenated hydrocarbons (29.4%). In contrast, aromatics (17.4%) dominated the ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAFP) with 59.6% and 58.3%, respectively. Approximately 63.5% of VOCs were emitted from the petrochemical industry and from solvent usage based on source apportionment results, followed by biogenic emissions of 22.3% and vehicle emissions of 14.2%. Of the observed 46 VOC species, hexachlorobutadiene, dibromoethane, butadiene, tetrachloroethane, and vinyl chloride contributed as high as 98.8% of total carcinogenic risk, a large fraction of which was ascribed to the high-level emissions during ozone pollution episodes and nighttime. Therefore, the mitigation of VOC emissions from petrochemical industries would be an effective way to reduce secondary pollution and potential health risks in conurbation areas.
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AIMS: To investigate the roles of neurotrophic factors on cognition in patients with Alzheimer's disease (AD) carrying Apolipoprotein E (APOE) ε4. METHODS: Totals of 173 patients with AD were divided into APOE ε4 carrier and non-carrier groups, and their demographics, cognition, and neurotrophic factors in cerebrospinal fluid (CSF) were compared. Multiple linear regression analyses were performed to assess correlations among APOE ε4, neurotrophic factors and cognition. Mediation analyses were conducted to assess the sequential associations among APOE ε4, nerve growth factor (NGF), and cognition. RESULTS: Global cognition and multiple domains were impaired in the APOE ε4 carrier group (all p < 0.05). NGF level in the APOE ε4 carrier group was lower than that in the non-carrier group (p = 0.016). NGF level showed significant correlations with both global and multiple domains cognitions. Specifically, NGF mediated the association between APOE ε4 and Animal Fluency Test score (ß, -0.45; 95% CI [-0.96, -0.07]; p < 0.001) and Trail Making Test-A (time) (ß, 0.15; 95% CI [0.01, 0.33]; p < 0.001). CONCLUSION: APOE ε4 is associated with cognitive impairment, and those carrying APOE ε4 have decreased NGF level in CSF. Declined NGF level is correlated with compromised cognition. NGF mediates APOE ε4-associated cognitive impairment.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Disfunción Cognitiva , Factor de Crecimiento Nervioso , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Masculino , Femenino , Apolipoproteína E4/genética , Anciano , Factor de Crecimiento Nervioso/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/psicología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Anciano de 80 o más AñosRESUMEN
RATIONALE: TongFu XieXia Decoction (TFXXD), a formulation rooted in traditional Chinese medicine and optimized through clinical practice, serves as an advanced version of the classic Da Cheng Qi decoction used for treating intestinal obstruction (IO), demonstrating significant therapeutic efficacy. However, due to the intricate nature of herbal compositions, the principal constituents and potential mechanisms of TFXXD have yet to be clarified. Accordingly, this study seeks to identify the active compounds and molecular targets of TFXXD, as well as to elucidate its anti-IO mechanisms. METHODS: Qualitative identification of the principal constituents of TFXXD was accomplished using ultra-high preformance liquid chromatography-quadrupole-orbitrap mass spectrometry (UPLC-Q-Orbitrap-MS/MS) analysis. PharmMapper facilitated the prediction of potential molecular targets, whereas protein-protein interaction analysis was conducted using STRING 11.0. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Metascape database. A "compounds-target-pathway" network was meticulously constructed within Cytoscape 3.8.2. Finally, molecular docking studies were performed to investigate the interactions between the core target and the crucial compound. RESULTS: UPLC-Q-Orbitrap-MS/MS analysis identified 65 components with high precision and sensitivity. Furthermore, 64 potential targets were identified as integral to TFXXD bioactivity in IO treatment. Gene Ontology enrichment analysis revealed 995 distinct biological functions, while the Kyoto Encyclopedia of Genes and Genomes enrichment analysis identified 143 intricate signaling pathways. CONCLUSION: Molecular docking studies substantiated the substantial affinity between the TFXXD bioactive constituents and their corresponding targets in the context of IO. TFXXD exerts its therapeutic efficacy in IO through a multifaceted interplay between multiple compounds, targets, and pathways. The integration of network pharmacology with UPLC-Q-Orbitrap-MS/MS has emerged as a promising strategy to unravel the intricate web of molecular interactions underlying herbal medicine. However, it is imperative to emphasize the necessity for further in vivo and in vitro experiments.
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Medicamentos Herbarios Chinos , Obstrucción Intestinal , Humanos , Farmacología en Red , Cromatografía Líquida de Alta Presión , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Obstrucción Intestinal/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
SCOPE: Hypertrophic chondrocytes have a decisive regulatory role in the process of fracture healing, and the fate of hypertrophic chondrocytes is not only apoptosis. However, the mechanism of sea cucumber (Stichopus japonicus) intestinal peptide (SCIP) on fracture promotion is still unclear. This study aims to investigate the effect of sea cucumber intestinal peptide on the differentiation fate of hypertrophic chondrocytes in a mouse tibial fracture model. METHODS AND RESULTS: Mice are subjected to open fractures of the right tibia to establish a tibial fracture model. The results exhibit that the SCIP intervention significantly promotes the mineralization of cartilage callus, decreases the expression of the hypertrophic chondrocyte marker Col X, and increases the expression of the osteoblast marker Col I. Mechanically, SCIP promotes tibial fracture healing by promoting histone acetylation and inhibiting histone methylation, thereby upregulating pluripotent transcription factors induced the differentiation of hypertrophic chondrocytes to the osteoblast lineage in a manner distinct from classical endochondral ossification. CONCLUSION: This study is the first to report that SCIP can promote tibial fracture healing in mice by inducing the differentiation of hypertrophic chondrocytes to the osteoblast lineage. SCIP may be considered raw material for developing nutraceuticals to promote fracture healing.
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Pepinos de Mar , Fracturas de la Tibia , Ratones , Animales , Condrocitos/metabolismo , Curación de Fractura/fisiología , Tibia , Histonas/metabolismo , Osteoblastos/metabolismo , Osteogénesis/fisiología , Fracturas de la Tibia/metabolismo , Péptidos/farmacología , Péptidos/metabolismo , Diferenciación CelularRESUMEN
OBJECTIVE@#To investigate the imaging effect of a near-infrared fluorescent targeted probe ICG-NP41 on the neurovascular bundles (NVB) around the prostate in rats.@*METHODS@#A near-infrared fluorescent targeted probe ICG-NP41 was synthesized. An animal model for NVB imaging was established using Sprague-Dawley rats (250-400 g). Experiments were conducted using a custom-built near-infrared windowⅡ(NIR-Ⅱ) small animal in vivo imaging system, and images collected were processed using ImageJ and Origin. The fluorescence signal data were statistically analyzed using GraphPad Prism. The signal-to-background ratio (SBR) for NVB was quantitatively calculated to explore the effective dosage and imaging time points. Finally, paraffin pathology sections and HE staining were performed on the imaging structures.@*RESULTS@#Except for rats in the control group (n=2), right-sided NVB of the rats injected with ICG-NP41 (n=2 per group) were all observed in NIR-Ⅱ fluorescence mode 2 h and 4 h after administration. At 2 h and 4 h, average SBR of cavernous nerve in 2 mg/kg group in fluorescence mode was 1.651±0.142 and 1.619±0.110, respectively, both higher than that in white light mode (1.111±0.036), with no significant difference (P>0.05); average SBR of 4 mg/kg group in fluorescence mode were 1.168±0.066 and 1.219±0.118, respectively, both higher than that in white light mode (1.081±0.040), with no significant difference (P>0.05). At 2 h and 4 h, the average SBR of 2 mg/kg and 4 mg/kg groups in fluorescence mode were higher than that of the control group (SBR=1), the average SBR of the 2 mg/kg group was higher than that of the 4 mg/kg group, and all the above with no significant difference (P>0.05). The average diameter of the nerve measured by full width at half maxima method was about (178±15) μm. HE staining of paraffin sections showed the right major pelvic ganglion.@*CONCLUSION@#The near-infrared fluorescent targeted probe ICG-NP41 can be used for real-time imaging of the NVB around the prostate in rats, providing a potential feasible solution for localizing NVB in real time during nerve-sparing radical prostatectomy.
Asunto(s)
Masculino , Ratas , Animales , Próstata/diagnóstico por imagen , Parafina , Verde de Indocianina , Ratas Sprague-Dawley , Colorantes FluorescentesRESUMEN
Objective:To explore the clinical outcomes of intraoperative fluoroscopy on femoral tunnel placement in treating professional snow sports athletes with anterior cruciate ligament (ACL) injury.Methods:A retrospective case series study was used to analyze the clinical data of 13 professional snow sports athletes with ACL injury treated in the National Institute of Sports Medicine, General Administration of Sport of China from January 2016 to January 2019. There were 5 males and 8 females, aged 16-27 years [(18.5±3.0)years]. Intraoperative lateral fluoroscopy combined with quadrant method was performed for the accurate femoral tunnel placement in single-bundle ACL reconstruction by using autologous hamstring tendon in all patients. KT1000 side-to-side difference (KT1000-ssd), pivot shift test, International Knee Documentation Committee (IKDC) subjective score, Lysholm score, Marx activity scale and maximum extension and flexion resistance ratio of the involved and uninvolved knee were compared before operation (or before injury) and at 3, 6, 12 and 24 months after operation. Whether returning to the field, time taken in returning to the field and re-injury were recorded at each follow-up visit. ACL graft signal intensity ratio (SIR) in MRI of the involved knee was evaluated at postoperative 24 months.Results:All patients were followed up for 24-33 months [(25.8±2.7)months]. There were 7 patients with KT1000-ssd degree I, 5 with degree II and 1 with degree III before operation, compared to 12 patients with KT1000-ssd degree 0 and 1 with degree I at 3 and 6 months after operation and 13 patients with KT1000-ssd degree 0 at 12 and 24 months after operation. The pivot shift test was grade I in 8 patients and grade II in 5 before operation, compared to 11 patients with degree 0 and 2 with degree I at 3 months after operation and 12 patients with degree 0 and 1 with degree I at 6, 12 and 24 months after operation. IKDC subjective score was (68.0±4.3)points, (84.7±7.9)points, (94.6±3.3)points and (96.5±1.8)points at postoperative 3, 6, 12 and 24 months, respectively. Six months after operation, IKDC subjective score was significantly improved compared to the preoperative (48.3±25.0)points (all P<0.01). The Lysholm score was (63.4±6.6)points, (80.1±6.5)points, (93.8±4.6)points and (96.5±2.4)points at postoperative 3, 6, 12 and 24 months, respectively. Six months after operation, the Lysholm score was significantly improved compared to the preoperative (47.5±29.4)points (all P<0.01). The Marx activity scale was (7.4±0.5)points, (13.8±0.7)points, (14.6±0.8)points and (15.0±0.7)points at postoperative 3, 6, 12 and 24 months, respectively, significantly lower than (16.0±0.0)points before the injury (all P<0.01). The maximum extension resistance ratio of the involved and uninvolved knee was 0.60±0.10, 0.85±0.08, 0.91±0.06 and 0.97±0.04 at postoperative 3, 6, 12 and 24 months, respectively. Six months after operation, the maximum extension resistance ratio of the involved and uninvolved knee was significantly increased compared to the preoperative 0.57±0.18 (all P<0.01).The maximum flexion resistance ratios of involved and uninvolved knee were 0.64±0.09, 0.82±0.06, 0.89±0.04 and 0.94±0.06 at postoperative 3, 6, 12 and 24 months, respectively. Six months after operation, the maximum flexion resistance ratio of the involved and uninvolved knee was significantly increased compared to the preoperative 0.60±0.12 (all P<0.01). Thirteen athletes returned to the field within 12 months after operation with the time taken in returning to the field ranging from 5-12 months [(8.7±1.9)months]. There was no ACL re-injury at postoperative 24 months. The ACL graft SIR in MRI of the involved knee was 1.80±0.20 at postoperative 24 months. Conclusion:Intraoperative fluoroscopy on femoral tunnel placement in the treatment of professional snow sports athletes with ACL injury can significantly improve the knee joint stability, subjective function, sports performance and muscle strength within 6 months, and can help them return to the field within 12 months, and accelerates graft healing.
RESUMEN
Tumor brings great threat to human public health. In recent years, incidence rate and mortality of tumor were rapidly increased in the world. Anti-tumor therapies have undergone the development of cytotoxic therapy, targeted therapy, and immunotherapy. Among them, tumor immunotherapy is rapidly developed and becomes an important anti-tumor therapy in recent years, although it also brings some related side effects. Tumor microenvironment (TME) is composed of immune cells, vascular vessels, fibroblasts, the extracellular matrix, etc. TME significantly affects the efficacy of immunotherapy. Macrophages in the TME are named as tumor associated macrophages (TAMs). Recently, increasing studies have shown that TAMs play an important role in the regulation of tumor immunity, especially in tumor immune surveillance and immune escape. Currently, more and more anti-tumor immunotherapy strategies targeting TAMs are at the development stage. Based on the important role of TAMs in the TME and their potential as therapeutic targets in tumor immunotherapy, we first reviewed the subtypes and functions of TAMs, as well as the roles of TAMs in tumors. Furthermore, we summarized the research progress on anti-tumor strategies targeting TAMs and the current status of drug targeting TAMs. The current review will provide new ideas and novel insights for tumor immunotherapy.