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Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) ~400 Mya. Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no chromosome-level assembly has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged ~350 Mya, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications, and the resulting intragenomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape but also highlight a potentially meaningful genomic contrast between homosporous and heterosporous species.
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Genoma de Planta , Genómica , Genoma de Planta/genética , Tamaño del Genoma , Filogenia , Evolución MolecularRESUMEN
Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.
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Toxinas Bacterianas , Neoplasias de la Mama , Clostridioides difficile , Neoplasias Mamarias Animales , Humanos , Animales , Ratones , Femenino , Vía de Señalización Wnt , Neoplasias de la Mama/metabolismo , Toxinas Bacterianas/metabolismo , Clostridioides difficile/metabolismo , CisplatinoRESUMEN
Acacetin, a flavonoid compound, possesses a wide range of pharmacological effects, including antimicrobial, immune regulation, and anticancer effects. Some key steps in its biosynthetic pathway were largely unknown in flowering plants. Here, we present the first haplotype-resolved genome of Chrysanthemum indicum, whose dried flowers contain abundant flavonoids and have been utilized as traditional Chinese medicine. Various phylogenetic analyses revealed almost equal proportion of three tree topologies among three Chrysanthemum species (C. indicum, C. nankingense, and C. lavandulifolium), indicating that frequent gene flow among Chrysanthemum species or incomplete lineage sorting due to rapid speciation might contribute to conflict topologies. The expanded gene families in C. indicum were associated with oxidative functions. Through comprehensive candidate gene screening, we identified five flavonoid O-methyltransferase (FOMT) candidates, which were highly expressed in flowers and whose expressional levels were significantly correlated with the content of acacetin. Further experiments validated two FOMTs (CI02A009970 and CI03A006662) were capable of catalyzing the conversion of apigenin into acacetin, and these two genes are possibly responsible acacetin accumulation in disc florets and young leaves, respectively. Furthermore, combined analyses of ancestral chromosome reconstruction and phylogenetic trees revealed the distinct evolutionary fates of the two validated FOMT genes. Our study provides new insights into the biosynthetic pathway of flavonoid compounds in the Asteraceae family and offers a model for tracing the origin and evolutionary routes of single genes. These findings will facilitate in vitro biosynthetic production of flavonoid compounds through cellular and metabolic engineering and expedite molecular breeding of C. indicum cultivars.
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Chrysanthemum , Evolución Molecular , Flavonas , Genoma de Planta , Filogenia , Proteínas de Plantas , Chrysanthemum/genética , Chrysanthemum/metabolismo , Chrysanthemum/enzimología , Flavonas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genoma de Planta/genética , Haplotipos , Diploidia , Flavonoides/metabolismo , Flavonoides/biosíntesis , Flores/genética , Flores/enzimología , Flores/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismoRESUMEN
Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.
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Cobre , Ferroptosis , Hipoxia , Ratones Endogámicos C57BL , Animales , Cobre/metabolismo , Cobre/deficiencia , Masculino , Ratones , Hipoxia/metabolismo , Humanos , Células Hep G2 , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo , Metabolismo de los Lípidos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/etiología , Hierro/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , PPAR alfa/metabolismo , PPAR alfa/genéticaRESUMEN
Two-dimensional (2D) carbon nitride materials have emerged as a versatile platform for the design of high-performance nanoelectronics, but strong anisotropy in 2D carbon nitrides has rarely been reported. In this work, a 2D carbon nitride with strong anisotropy composed of tetra-, penta-, and hexa-rings (named as TPH-C5N3) is proposed. This TPH-C5N3 exhibits both dynamical and mechanical stability. Furthermore, it also showcases remarkable thermal stability, reaching up to 2300 K, as evidenced by AIMD simulations conducted in an NVT environment utilizing the Nosé-Hoover thermostat. Significantly, TPH-C5N3 demonstrates high anisotropic ratios in its mechanical properties, positioning it as the frontrunner in the current carbon nitride systems. In addition, a Dirac cone with an anisotropic ratio of 55.8% and Fermi velocity of 7.26 × 105 m s-1 is revealed in TPH-C5N3. The nontrivial topological properties of TPH-C5N3 are demonstrated by a non-zero Z2 invariant and topologically protected edge states. Our study offers theoretical insights into an anisotropic 2D carbon nitride material, laying the groundwork for its design and synthesis.
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pyWitness is a python toolkit for recognition memory experiments, with a focus on eyewitness identification (ID) data analysis and model fitting. The current practice is for researchers to use different statistical packages to analyze a single dataset. pyWitness streamlines the process. In addition to conducting key data analyses (e.g., receiver operating characteristic analysis, confidence accuracy characteristic analysis), statistical comparisons, signal-detection-based model fits, simulated data generation, and power analyses are also possible. We describe the package implementation and provide detailed instructions and tutorials with datasets so that users can follow. There is also an online manual that is regularly updated. We developed pyWitness to be user-friendly, reduce human interaction with pre-processing and processing of data and model fits, and produce publication-ready plots. All pyWitness features align with open science practices, such that the algorithms, fits, and methods are reproducible and documented. While pyWitness is a python toolkit, it can also be used from R for users more accustomed to this environment.
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Procesos Mentales , Reconocimiento en Psicología , Humanos , Curva ROC , Algoritmos , Análisis de DatosRESUMEN
BACKGROUND: Insulin has been reported to exhibit anti-inflammatory activities in the context of bowel inflammation. However, the role of the interaction between insulin and the microbiota in gut health is unclear. Our goal was to investigate the mechanism of action of insulin in bowel inflammation and the relationship between insulin and the gut microbiota. METHODS: We used acute and chronic murine models of inflammatory bowel disease (IBD) to evaluate whether insulin influences the progression of colitis. Colonic tissues, the host metabolome and the gut microbiome were analyzed to investigate the relationship among insulin treatment, the microbiome, and disease. Experiments involving antibiotic (Abx) treatment and fecal microbiota transplantation (FMT) confirmed the association among the gut microbiota, insulin and IBD. In a series of experiments, we further defined the mechanisms underlying the anti-inflammatory effects of insulin. RESULTS: We found that low-dose insulin treatment alleviated intestinal inflammation but did not cause death. These effects were dependent on the gut microbiota, as confirmed by experiments involving Abx treatment and FMT. Using untargeted metabolomic profiling and 16S rRNA sequencing, we discovered that the level of the secondary bile acid lithocholic acid (LCA) was notably increased and the LCA levels were significantly associated with the abundance of Blautia, Enterorhadus and Rumi-NK4A214_group. Furthermore, LCA exerted anti-inflammatory effects by activating a G-protein-coupled bile acid receptor (TGR5), which inhibited the polarization of classically activated (M1) macrophages. CONCLUSION: Together, these data suggest that insulin alters the gut microbiota and affects LCA production, ultimately delaying the progression of IBD.
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Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Ratones , Humanos , Animales , Insulina , ARN Ribosómico 16S/genética , Colitis/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inflamación , Microbioma Gastrointestinal/genética , Ácidos y Sales Biliares , Receptores Acoplados a Proteínas G , Antiinflamatorios , Ratones Endogámicos C57BLRESUMEN
Advancement of endogenous biomarkers for drug transporters as a tool for assessing drug-drug interactions (DDIs) depends on initial identification of biomarker candidates and relies heavily on biomarker validation and its response to reference inhibitors in vivo. To identify endogenous biomarkers of breast cancer resistance protein (BCRP), we applied metabolomic approaches to profile plasma from Bcrp-/-, multidrug resistance protein (Mdr)1a/1b-/-, and Bcrp/Mdr1a/1b-/- mice. Approximately 130 metabolites were significantly altered in Bcrp and P-glycoprotein (P-gp) knockout mice, indicating numerous metabolite-transporter interactions. We focused on BCRP-specific substrates and identified riboflavin, which was significantly elevated in the plasma of Bcrp single- and Bcrp/P-gp double- but not P-gp single-knockout mice. Dual BCRP/P-gp inhibitor elacridar caused a dose-dependent increase of the area under the plasma concentration-time curve (AUC) of riboflavin in mice (1.51- and 1.93-fold increases by 30 and 150 mg/kg elacridar, respectively). In three cynomolgus monkeys, we observed approximately 1.7-fold increases in the riboflavin concentrations caused by ML753286 (10 mg/kg), which correlated well with the increase of sulfasalazine, a known BCRP probe in monkeys. However, the BCRP inhibitor had no effect on isobutyryl carnitine, arginine, or 2-arachidonoyl glycerol levels. Additionally, clinical studies on healthy volunteers indicated low intrasubject and intermeal variability of plasma riboflavin concentrations. In vitro experiments using membrane vesicles demonstrated riboflavin as a select substrate of monkey and human BCRP over P-gp. Collectively, this proof-of-principle study indicates that riboflavin is a suitable endogenous probe for BCRP activity in mice and monkeys and that future investigation of riboflavin as a blood-based biomarker of human BCRP is warranted. SIGNIFICANCE STATEMENT: Our results identified riboflavin as an endogenous biomarker candidate of BCRP. Its selectivity, sensitivity, and predictivity regarding BCRP inhibition have been explored. The findings of this study highlight riboflavin as an informative BCRP plasma biomarker in animal models. The utility of this biomarker requires further validation by evaluating the effects of BCRP inhibitors of different potencies on riboflavin plasma concentrations in humans. Ultimately, riboflavin may shed light on the risk assessment of BCRP DDIs in early clinical trials.
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Encéfalo , Neoplasias de la Mama , Humanos , Ratones , Animales , Femenino , Encéfalo/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Ratones Noqueados , Biomarcadores/metabolismo , Interacciones Farmacológicas , Neoplasias de la Mama/metabolismoRESUMEN
PURPOSE: The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition. METHODS: We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP. RESULTS: ECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (IC50s of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC50 ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold). CONCLUSIONS: ECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions.
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Transportadoras de Casetes de Unión a ATP , Proteínas de Neoplasias , Humanos , Ratas , Animales , Transportadoras de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Macaca fascicularis/metabolismo , Proteínas de Neoplasias/metabolismo , Paclitaxel , Interacciones FarmacológicasRESUMEN
BACKGROUND: Invasive candidiasis is the most common hospital-acquired fungal infection in intensive care units (ICU). The Geriatric Nutritional Risk Index (GNRI) score was developed to evaluate the nutritional status of elderly adults. We aimed to assess the association between the GNRI score and the risk of invasive candidiasis in elderly patients admitted to ICU. METHODS: Hospitalization information of elderly patients with invasive candidiasis was collected retrospectively from Medical Information Mart for Intensive Care (MIMIC) IV and MIMIC-III Clinical Database CareVue subset from 2001 to 2019. The main outcome of this study was the diagnosis of invasive candidiasis in patients. We employed a multivariable Cox regression and propensity score matching to balance the influence of confounding factors on the outcome. Furthermore, we conducted sensitivity analyses by categorizing the GNRI into classes based on thresholds of 98, 92, and 81. RESULTS: A total of 6739 patients were included in the study, among whom 134 individuals (2%) were diagnosed with invasive candidiasis. The GNRI scores of patients with invasive candidiasis upon admission to the ICU were significantly lower, measuring 88.67 [79.26-98.27], compared to the control group with a score of 99.36 [87.98-110.45] (P < 0.001). The results of the multivariable Cox regression analysis demonstrated a strong association between higher GNRI scores and a decreased risk of invasive candidiasis infection (HR: 0.98, 95% CI: 0.97-0.99, P = 0.002). Consistently, similar results were obtained when analyzing the propensity score-matched cohort (HR: 0.99, 95% CI: 0.98-1, P = 0.028). Sensitivity analyses further confirmed a significantly increased risk of invasive candidiasis infection with lower GNRI scores. Specifically, the following associations were observed: GNRI ≤ 98 (HR: 1.83, 95% CI: 1.23-2.72, P = 0.003), GNRI ≤ 92 (HR: 1.68, 95% CI: 1.17-2.4, P = 0.005), 82 ≤ GNRI ≤ 92 (HR: 1.63, 95% CI: 1.01-2.64, P = 0.046), GNRI ≤ 81 (HR: 2.31, 95% CI: 1.44-3.69, P < 0.001). CONCLUSIONS: Lower GNRI score was significantly associated with an increased risk of invasive candidiasis in elderly patients in ICU. Further research is needed to validate whether improving nutrition can prevent invasive candidiasis.
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Candidiasis Invasiva , Desnutrición , Humanos , Anciano , Desnutrición/complicaciones , Evaluación Nutricional , Estudios Retrospectivos , Enfermedad Crítica , Estado Nutricional , Candidiasis Invasiva/epidemiología , Factores de RiesgoRESUMEN
Butylphthalide, a prescription medicine recognized for its efficacy in treating ischemic strokes approved by the State Food and Drug Administration of China in 2005, is sourced from the traditional botanical remedy Ligusticum chuanxiong. While chemical synthesis offers a viable route, limitations in the production of isomeric variants with compromised bioactivity necessitate alternative strategies. Addressing this issue, biosynthesis offers a promising solution. However, the intricate in vivo pathway for butylphthalide biosynthesis remains elusive. In this study, we examined the distribution of butylphthalide across various tissues of L. chuanxiong and found a significant accumulation in the rhizome. By searching transcriptome data from different tissues of L. chuanxiong, we identified four rhizome-specific genes annotated as 2-oxoglutarate-dependent dioxygenase (2-OGDs) that emerged as promising candidates involved in butylphthalide biosynthesis. Among them, LcSAO1 demonstrates the ability to catalyze the desaturation of senkyunolide A at the C-4 and C-5 positions, yielding the production of butylphthalide. Experimental validation through transient expression assays in Nicotiana benthamiana corroborates this transformative enzymatic activity. Notably, phylogenetic analysis of LcSAO1 revealed that it belongs to the DOXB clade, which typically encompasses genes with hydroxylation activity, rather than desaturation. Further structure modelling and site-directed mutagenesis highlighted the critical roles of three amino acid residues, T98, S176, and T178, in substrate binding and enzyme activity. By unraveling the intricacies of the senkyunolide A desaturase, the penultimate step in the butylphthalide biosynthesis cascade, our findings illuminate novel avenues for advancing synthetic biology research in the realm of medicinal natural products.
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Medicamentos Herbarios Chinos , Ligusticum , Ligusticum/química , Filogenia , Medicamentos Herbarios Chinos/química , Rizoma/químicaRESUMEN
Liver-stage Plasmodium in humans is an early stage of malarial infection. Decoquinate (DQ) has a potent multistage antimalarial activity. However, it is practically water insoluble. In this study, the hot-melt extrusion (HME) approach was employed to prepare solid dispersions of DQ to improve oral bioavailability. The DQ dispersions were homogeneous in an aqueous suspension that contained most DQ (>90%) in the aqueous phase. Soluplus, a solubilizer, was found compatible with DQ in forming nanoparticle formulations during the HME process. Another excipient HPMC AS-126 was also proven to be suitable for making DQ nanoparticles through HME. Particle size and antimalarial activity of HME DQ suspensions remained almost unchanged after storage at 4°C for over a year. HME DQ was highly effective at inhibiting Plasmodium infection in vitro at both the liver stage and blood stage. HME DQ at 3 mg/kg by oral administration effectively prevented Plasmodium infection in mice inoculated with Plasmodium berghei sporozoites. Orally administered HME DQ at 2,000 mg/kg to mice showed no obvious adverse effects. HME DQ at 20 mg/kg orally administered to rats displayed characteristic distributions of DQ in the blood with most DQ in the blood cells, revealing the permeability of HME DQ into the cells in relation to its antimalarial activity. The DQ dispersions may be further developed as an oral formulation targeting Plasmodium infection at the liver stage.
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Antimaláricos , Decoquinato , Malaria , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Decoquinato/farmacología , Composición de Medicamentos , Calor , Hígado , Malaria/tratamiento farmacológico , Ratones , Plasmodium berghei , Ratas , SolubilidadRESUMEN
Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administrations of 50 and 100 mg/kg of CDCA were first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/ß-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor agonist, had no effect on hepatic OATP1B protein, although it induced the intestinal P-glycoprotein and MR2 proteins by â¼2-fold. Moreover, multiple doses of CDCA resulted in a steady â¼2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII areas under the curve were observed after multiple administrations compared with the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B downregulation by FXR in humans is warranted, as such downregulation effects may be involved in bile acid homeostasis and potential drug interactions in man. SIGNIFICANCE STATEMENT: Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day of chenodeoxycholic acid (CDCA), a Farnesoid X receptor agonist, for 8 days. These results lead to a better understanding of OATP1B downregulation by CDCA and its role on bile acid and drug disposition.
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Ácido Quenodesoxicólico , Coproporfirinas , Transportador 1 de Anión Orgánico Específico del Hígado , Animales , Ácidos y Sales Biliares , Biomarcadores/metabolismo , Ácido Quenodesoxicólico/metabolismo , Ácido Quenodesoxicólico/farmacología , Coproporfirinas/sangre , Coproporfirinas/metabolismo , Regulación hacia Abajo , Interacciones Farmacológicas , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Macaca fascicularis/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , ARN MensajeroRESUMEN
OBJECTIVE: This study aimed to establish Chinese norms for the Chinese version of the Parent's Evaluation of Aural/Oral of Children (PEACH) rating scale. DESIGN AND STUDY SAMPLE: The PEACH scores were collected from 198 parents whose children have normal hearing. The test-retest reliability of the PEACH scale was evaluated in a subgroup of 34 parents. Another 27 parents also filled out a Putonghua Communicative Development Inventory which was used to explore the relationship between the PEACH ratings and language scores. RESULTS: The normative curve was established using a logit regression function. The total scores increase rapidly with increasing age. A plateau starts from 22 months with the PEACH score reaching 90% and achieves the maximum score of 95% by 47 months of age. The test-retest analyses showed high reliability for all subscales, with all the correlation coefficients values exceeding 0.9 (p < 0.01). The 90% and 95% confidence intervals were provided to facilitate evaluation of differences between scores obtained under different conditions. A significant correlation was found between the PEACH total score and language performance (p < 0.05). CONCLUSIONS: Normative data from the Chinese population was provided to enable performance of an individual child to be related to their normally hearing peers.
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Lenguaje , Padres , Niño , China , Audición , Humanos , Lactante , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Various functional components in tea have been well developed, but less research has been explored on glycoproteins in tea. In this paper, three types of glycoprotein fractions, namely tea selenium-binding glycoprotein1-1 (TSBGP1-1), TSBGP2-1, and TSBGP3-1, respectively, were extracted and purified from selenium-enriched coarse green tea. Chemical analysis revealed that three fractions were glycoproteins, but their selenium content, molecular weight, and monosaccharide composition were significantly different. Fourier transforms infrared (FT-IR) analysis indicated that three fractions contained characteristic absorption peaks of glycoproteins but differed in secondary structural composition. Thermogravimetric (TG) analysis showed that the thermal stability of the three fractions was dramatically distinct. The in vitro hypoglycemic activity showed that TSBGPs significantly activated the insulin receptor substrate 2 (IRS2)/protein kinase B (Akt) pathway in LO2 cells, then enhanced glucose metabolism and inhibited gluconeogenesis, and finally ameliorated insulin resistance (IR) and glucose metabolism disorders. Furthermore, Pearson correlation analysis reveals that the hypoglycemic activity was significantly correlated with Se, protein, monosaccharide composition (especially glucose), molecular weight, and secondary structure. Our results show that Se-enriched tea glycoprotein is a desirable candidate for developing anti-diabetic food, and TSBGP-2 and TSBGP-3 had a better regulation effect. Our results can provide a research reference for the extraction, physicochemical property, and function of selenium-enriched plant glycoproteins.
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Selenio , Glicoproteínas , Hipoglucemiantes/análisis , Hipoglucemiantes/farmacología , Monosacáridos/análisis , Selenio/análisis , Espectroscopía Infrarroja por Transformada de Fourier , Té/químicaRESUMEN
Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4ß-hydroxycholesterol (4ßHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4ßHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.
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Coproporfirinas/sangre , Expresión Génica/efectos de los fármacos , Rifampin/farmacología , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/biosíntesis , Animales , Biomarcadores/sangre , Femenino , Hidroxicolesteroles/sangre , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Macaca fascicularis , Masculino , Rifampin/administración & dosificación , Rifampin/sangre , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genéticaRESUMEN
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.
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Amidas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
PURPOSE: The main purpose of the current study was to assess the development of auditory and speech perception and the effects of the age at implantation in CI children after long-period follow up. MATERIALS AND METHODS: Five hundred and forty-four young children participated in this study (339 males and 205 females). The age at implantation ranged from 6 months to 36 months. All subjects were prelingually bilateral profound sensorineural hearing loss. They were divided into 3 groups according to the implant ages: group 1 (age at implantation < 12 months, n = 109); group 2 (12 months < age at implantation < 24 months, n = 284); and group 3 (24 months < age at implantation < 36 months, n = 151). The categorical auditory performance (CAP) was used to assess auditory abilities and the speech intelligibility rating (SIR) was used to assess the speech intelligibility of these CI children. The tests were administered at pre-surgery and 1, 3, 6, 12, 24, 36, 48- and 60-months post-surgery. RESULTS: All the subjects demonstrated improvements of auditory abilities and speech intelligibility after CI surgery. The auditory ability developed quickly in 12 months after implantation. However, the speech intelligibility scores show rapid improvement within 24 months post implantation. Significant difference was found between group 1 and group 3, group 2 and group 3 before 12 months post-implantation for CAP and SIR. The three groups of children showed similar development pattern for their auditory abilities and speech intelligibility. CONCLUSION: The results of this study suggested dramatic and continuous improvement of the auditory and speech abilities post implantation in these CI children. Furthermore, the age at implantation played a considerably smaller role in the improvement of hearing and speech abilities. However, earlier implantation still benefits the language development.
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Percepción Auditiva , Implantación Coclear , Implantes Cocleares , Pérdida Auditiva Sensorineural/psicología , Pérdida Auditiva Sensorineural/cirugía , Percepción del Habla , Factores de Edad , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Desarrollo del Lenguaje , Masculino , Factores de Tiempo , Resultado del TratamientoRESUMEN
Objective: The purpose of the present study was to examine the effects of NLFC fitting in hearing aids and auditory acclimatisation on speech perception and sound-quality rating in hearing-impaired, native Mandarin-speaking adult listeners.Design: Mandarin consonant, vowel and tone recognition were tested in quiet and sentence recognition in noise (speech-shaped noise at a +5 dB signal-to-noise ratio) with NLFC-on and NLFC-off. Sound-quality ratings were collected on a 0-10 scale at each test session. A generalised linear model and correlational analyses were performed.Study sample: Thirty native Mandarin-speaking adults with moderate-to-severe sensorineural hearing loss were recruited.Results: The hearing-impaired listeners showed significantly higher accuracy with NLFC-on than with NLFC-off for consonant and sentence recognition and the recognition performance improved with both NLFC-on and off as a function of increased length of use. The satisfaction score of sound-quality ratings for different types of sounds significantly increased with NLFC-on than with NLFC-off. The speech recognition results showed moderate to strong correlation with the unaided hearing thresholds.Conclusion: For native Mandarin-speaking listeners with hearing loss, the NLFC technology provided modest but significant improvement in Mandarin fricative and sentence recognition. Subjectively, the naturalness and overall preference of sound-quality satisfaction judgement also improved with NLFC.
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Umbral Auditivo , Corrección de Deficiencia Auditiva/instrumentación , Audífonos/psicología , Pérdida Auditiva Sensorineural/rehabilitación , Percepción del Habla , Adulto , Anciano , Anciano de 80 o más Años , China , Corrección de Deficiencia Auditiva/psicología , Correlación de Datos , Femenino , Humanos , Lenguaje , Modelos Lineales , Masculino , Persona de Mediana Edad , Ruido , Prueba del Umbral de Recepción del HablaRESUMEN
Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.