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The development of oligomeric glucagon-like peptide-1 (GLP-1) and GLP-1-containing coagonists holds promise for enhancing the therapeutic potential of the GLP-1-based drugs for treating type 2 diabetes mellitus (T2DM). Here, we report a facile, efficient, and customizable strategy based on genetically encoded SpyCatcher-SpyTag chemistry and an inducible, cleavable self-aggregating tag (icSAT) scheme. icSAT-tagged SpyTag-fused GLP-1 and the dimeric or trimeric SpyCatcher scaffold were designed for dimeric or trimeric GLP-1, while icSAT-tagged SpyCatcher-fused GLP-1 and the icSAT-tagged SpyTag-fused GIP were designed for dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. These SpyCatcher- and SpyTag-fused protein pairs were spontaneously ligated directly from the cell lysates. The subsequent icSAT scheme, coupled with a two-step standard column purification, resulted in target proteins with authentic N-termini, with yields ranging from 35 to 65 mg/L and purities exceeding 99%. In vitro assays revealed 3.0- to 4.1-fold increased activities for dimeric and trimeric GLP-1 compared to mono-GLP-1. The dual GLP-1/GIP receptor agonist exhibited balanced activity toward the GLP-1 receptor or the GIP receptor. All the proteins exhibited 1.8- to 3.0-fold prolonged half-lives in human serum compared to mono-GLP-1 or GIP. This study provides a generally applicable click biochemistry strategy for developing oligomeric or dual peptide/protein-based drug candidates.
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Química Clic , Péptido 1 Similar al Glucagón , Péptido 1 Similar al Glucagón/química , Humanos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/metabolismo , Diseño de Fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/química , Polipéptido Inhibidor Gástrico/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistasRESUMEN
OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.
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Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Quimioterapia de Inducción , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Masculino , Femenino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Quimioradioterapia/métodos , Quimioterapia de Inducción/métodos , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Estudios Retrospectivos , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Adulto , Anciano , Estadificación de Neoplasias , Resultado del Tratamiento , Estimación de Kaplan-Meier , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Adulto JovenRESUMEN
AIM: To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1 R) agonist with Fc fusion protein structure. METHODS: We designed and constructed an Fc fusion protein that is a dual agonist (HEC-CG115) with an empirically optimized potency ratio for GLP-1R and GIPR. The long-term effects of HEC-CG115 on body weight and glycaemic control were evaluated in diet-induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC-CG115 in Sprague-Dawley rats. RESULTS: HEC-CG115 displayed high potency for GIPR and relatively low potency for GLP-1R, and we labelled it 'imbalanced'. In animal models, HEC-CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet-induced obese model mice. HEC-CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4-week subcutaneous toxicity study conducted to assess the biosafety of HEC-CG115, the no observed adverse effect level was determined to be 3 mg/kg. CONCLUSION: HEC-CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat-dose toxicity study. Therefore, the use of HEC-CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Animales , Ratones , Ratas , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G , Pérdida de PesoRESUMEN
The application of X-ray imaging in military, industrial flaw detection, and medical examination is inseparable from the wide application of scintillator materials. In order to substitute for lead, lower costs, and reduce self-absorption, organic-inorganic hybrid lead-free perovskite scintillators are emerging as a new option. In this work, novel (TEA)2Zr1-xTexCl6 perovskite microcrystals (MCs) were successfully synthesized by a hydrothermal method, with Te4+ doping, which leads to yellow triplet-state self-trapped excitons emission. The emission peak of (TEA)2Zr1-xTexCl6 located at 605 nm under X-ray excitation, which was applied to X-ray imaging, shows a clear wiring structure inside the USB connector. The detection limit (DL) of 820 nGyair/s for (TEA)2Zr0.9Te0.1Cl6 is well below the dose rate corresponding to a standard medical X-ray diagnosis is 5.5 µGyair/s. This work opens up a new path for organic-inorganic hybrid lead-free scintillators.
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The pericarps of Trichosanthes kirilowii are often used to treat cough in traditional Chinese medicine, and its ethanol extract exhibited effective therapeutic effects on acute lung injury (ALI) in vivo caused by H1N1. An anticomplement activity-guided fractionation on the extract resulted in the isolation of ten new terpenoids, including seven monoterpenoids, trichosanates A-G (1-7), and three cucurbitane-type triterpenoids, cucurbitacins W-Y (8-10), as well as eleven known terpenoids (11-21). The new terpenoids' structures were determined by spectroscopic analysis, X-ray crystallographic analysis (1), electronic circular dichroism (ECD) analysis and calculations (2-10). Twelve monoterpenoids (1-7 and 11-15) and five cucurbitane-type triterpenoids (8-10, 18, and 20) exhibited anticomplement activity in vitro. For the monoterpenoids, the long aliphatic chain substituents might enhance their anticomplement activity. Additionally, two representative anticomplement terpenoids, 8 and 11, obviously attenuated H1N1-induced ALI in vivo by inhibiting complement overactivation and reducing inflammatory responses.
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Subtipo H1N1 del Virus de la Influenza A , Trichosanthes , Triterpenos , Cucurbitacinas , Trichosanthes/química , Monoterpenos/farmacología , Triterpenos/farmacología , Triterpenos/química , Extractos Vegetales/farmacologíaRESUMEN
Bisphenol A (BPA) is one of the most widely used chemical products, which is discharged into rivers and oceans, posing great hazards to organisms such as reproductive toxicity, hormone imbalance and cardiopathy induction. With the expansion harm of BPA, people have paid more attention to the environmental effects. In this paper, the degradation of BPA from the synthetic wastewater using the immobilization of horseradish peroxidase membrane reactor (HPR) was investigated. The immobilized HRP microporous membrane was prepared by the porous calcium alginate method. In addition, the reuse of the immobilized HPR membrane and the measurement of membrane flux showed that the membrane has good activity and stability. Finally, the experimental parameters including reaction time, pH, the concentration of BPA and the dosage of H2O2 were optimized to remove the BPA, and about 78% degradation efficiency of BPA was achieved at the optimal condition as follows: H2O2 to BPA molar ratio of 1.50 with an initial BPA concentration of 0.1 mol/L, the HPR dosage of 3.84 u/mL, the initial solution pH of 7.0, a temperature of 20 °C and a contact time of 10 min.
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Alginatos , Peróxido de Hidrógeno , Humanos , Polimerizacion , Peroxidasa de Rábano SilvestreRESUMEN
As an important physical quantity to describe the resistance of fluid to flow, viscosity is an essential property of fluids in fluid mechanics, chemistry, medicine, as well as hydraulic engineering. While traditional measurement methods, including the rotating-cylinder method, capillary tube method and falling sphere method, have significant drawbacks especially in terms of accuracy, response time and the sample must be made to move. In this work, a novel Beer-Lambert law-based method was proposed for the viscosity measurement. Specifically, this work demonstrates that viscosity can be quantitatively reflected by spectral line intensity, and castor oil was selected due to its viscous temperature properties (viscosity has been accurately measured under different temperature), and its transmission spectrum at different temperatures ranging from 10 to 50°C was detected firstly. Then, the principal component analysis (PCA) was employed to obtain the intrinsic features of the transmission spectrum. Finally, the processed data was utilized to train and verify the radial basis function (RBF) neural network. As a result, the accuracy of the predictions conducted by means of the RBF reached 98.45%, which indicates the complicated and non-linear relationships between spectra formation and viscosity can be depicted well by RBF. The results show that the real-time in-situ optical detection method adopted in this work represents a great leap forward in the viscosity measurement, which fundamentally reforms the traditional viscosity measurement methods.
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The measured distance error caused by double peaks in the BOTDRs (Brillouin optical time domain reflectometers) system is a kind of Brillouin scattering spectrum (BSS) deformation, discussed and simulated for the first time in the paper, to the best of the authors' knowledge. Double peak, as a kind of Brillouin spectrum deformation, is important in the enhancement of spatial resolution, measurement accuracy, and crack detection. Due to the variances of the peak powers of the BSS along the fiber, the measured starting point of a step-shape frequency transition region is shifted and results in distance errors. Zero-padded short-time-Fourier-transform (STFT) can restore the transition-induced double peaks in the asymmetric and deformed BSS, thus offering more accurate and quicker measurements than the conventional Lorentz-fitting method. The recovering method based on the double-peak detection and corresponding BSS deformation can be applied to calculate the real starting point, which can improve the distance accuracy of the STFT-based BOTDR system.
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Protein modification has been found to affect the estimation of protein concentration in some of the traditional dye-based absorbance measurements. In this work, a distinct reduction in A595 was observed during the quantitation of a PEGylated exendin-4 analogue (Ex4C) by the Bradford method and the PEGylation process was found to interfere with the measurement. Lys(12), Arg(20), and Lys(27) were further proved to be the major amino acids that functioned as dye-binding sites. The shielding effect produced by the large polymer was demonstrated to depend on the length of PEG that was used for modification.
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Péptidos/análisis , Péptidos/química , Polietilenglicoles/química , Ponzoñas/análisis , Ponzoñas/química , Exenatida , HumanosRESUMEN
In order to deal with the global energy crisis and environmental problems, reducing carbon dioxide through artificial photosynthesis has become a hot topic. Lead halide perovskite is attracted people's attention because of its excellent photoelectric properties, but the toxicity and long-term instability prompt people to search for new photocatalysts. Herein, a series of <111> inorganic double perovskites Cs4 Mn1-x Cux Sb2 Cl12 microcrystals (x = 0, 0.1, 0.2, 0.3, 0.4, and 0.5) are synthesized and characterized. Among them, Cs4 Mn0.7 Cu0.3 Sb2 Cl12 microcrystals have the best photocatalytic performance, and the yields of CO and CH4 are 503.86 and 68.35 µmol g-1 , respectively, after 3 h irradiation, which are the highest among pure phase perovskites reported so far. In addition, in situ Fourier transform infrared (FT-IR) spectroscopy and electron spin resonance (ESR) spectroscopy are used to explore the mechanism of the photocatalytic reaction. The results highlight the potential of this class of materials for photocatalytic reduction reactions.
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This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.
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Biosimilares Farmacéuticos , Péptidos Similares al Glucagón , Voluntarios Sanos , Fragmentos Fc de Inmunoglobulinas , Proteínas Recombinantes de Fusión , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Área Bajo la Curva , Pueblo Asiatico , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , China , Pueblos del Este de Asia , Péptidos Similares al Glucagón/farmacocinética , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/efectos adversos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/inmunología , Inyecciones Subcutáneas , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Glucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear. EXPERIMENTAL APPROACH: We designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats. KEY RESULTS: The high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study. CONCLUSION: We compared the potential of the Fc fusion protein GLP-1/GCG dual receptor agonists with different receptor selectivity to provide the setting for future GLP-1/GCG dual receptor agonists to treat obesity and MASLD.
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Dieta Alta en Grasa , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Fragmentos Fc de Inmunoglobulinas , Obesidad , Receptores de Glucagón , Proteínas Recombinantes de Fusión , Animales , Humanos , Ratones , Ratas , Dieta Alta en Grasa/efectos adversos , Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptidos Similares al Glucagón/farmacología , Fragmentos Fc de Inmunoglobulinas/farmacología , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas Sprague-Dawley , Receptores de Glucagón/agonistas , Receptores de Glucagón/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Pérdida de Peso/efectos de los fármacosRESUMEN
Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs + Laser treatment was superior to that of high-dose CPT, and PCRHNs + Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs + Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella, which may be attributed to diarrhea caused by CPT, thus leading to a reduction in microbial burden; additionally, Escherichia-Shigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea. PCRHNs + Laser treatment increased the abundance of Lactobacillus (probiotics), possibly due to the photothermal effect of the PCRHNs. This effect increased catalase activity, thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body, which is conducive to the growth of facultative anaerobic bacteria.
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This study delved into the physiological and molecular mechanisms underlying the mitigation of cadmium (Cd) stress in the model medicinal plant Salvia miltiorrhiza through the application of ZnO quantum dots (ZnO QDs, 3.84 nm). A pot experiment was conducted, wherein S. miltiorrhiza was subjected to Cd stress for six weeks with foliar application of 100 mg/L ZnO QDs. Physiological analyses demonstrated that compared to Cd stress alone, ZnO QDs improved biomass, reduced Cd accumulation, increased the content of photosynthetic pigments (chlorophyll and carotenoids), and enhanced the levels of essential nutrient elements (Ca, Mn, and Cu) under Cd stress. Furthermore, ZnO QDs significantly lowered Cd-induced reactive oxygen species (ROS) content, including H2O2, O2-, and MDA, while enhancing the activity of antioxidant enzymes (SOD, POD, APX, and GSH-PX). Additionally, ZnO QDs promoted the biosynthesis of primary and secondary metabolites, such as total protein, soluble sugars, terpenoids, and phenols, thereby mitigating Cd stress in S. miltiorrhiza. At the molecular level, ZnO QDs were found to activate the expression of stress signal transduction-related genes, subsequently regulating the expression of downstream target genes associated with metal transport, cell wall synthesis, and secondary metabolite synthesis via transcription factors. This activation mechanism contributed to enhancing Cd tolerance in S. miltiorrhiza. In summary, these findings shed light on the mechanisms underlying the mitigation of Cd stress by ZnO QDs, offering a potential nanomaterial-based strategy for enhancing Cd tolerance in medicinal plants.
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Cadmio , Puntos Cuánticos , Especies Reactivas de Oxígeno , Salvia miltiorrhiza , Óxido de Zinc , Puntos Cuánticos/química , Óxido de Zinc/química , Óxido de Zinc/toxicidad , Salvia miltiorrhiza/efectos de los fármacos , Salvia miltiorrhiza/metabolismo , Cadmio/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Estrés Fisiológico/efectos de los fármacos , Antioxidantes/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacosRESUMEN
Matrine is one of the main active components extracted from Sophora flavescens, S. subprostrata and S. alopecuroides. In recent years, its anti-tumor activity has attracted wide attention. According to studies, matrine shows the anti-tumor effect through multiple channels such as inducing apoptosis and autophagy of cancer cells, arresting cell cycle, inhibiting tumor cell migration, angiogenesis and NF-kappaB, as well as the synergistic effect with chemotherapeutics. Along with the further studies on matrine's anti-tumor mechanism, it has a broad prospect for development and application in tumor clinical treatment.
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Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Neoplasias/tratamiento farmacológico , Quinolizinas/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , MatrinasRESUMEN
The pathogenesis of rheumatoid arthritis (RA) is heavily impacted by the inflammation and activation of fibroblast-like synoviocytes (FLS). The objective of this investigation is to clarify the involvement of exosomes derived from FLS stimulated by tumour necrosis factor α (TNF-α) in angiogenesis and the underlying mechanisms. FLS cells were obtained from synovial fluid of RA patients and exosomes were obtained from FLS cell supernatant with TNF-α stimulation by ultracentrifugation. Exosomes were subsequently analysed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. The functional effects of exosomes with TNF-α stimulation on human umbilical vein endothelial cells (HUVEC) migration, invasion, and angiogenesis was evaluated using wound scratch healing test, transwell invasion assay, and tube formation assay. DNA nanoball-seq (DNBSEQ) sequencing platform was utilised to analysis different expression miRNA from exosomes, miRNA and mRNA from HUVEC. The expression level of miR-200a-3p was determined through quantitative real-time polymerase chain reaction (qRT-PCR). The quantification of KLF6 and VEGFA expression levels were performed by qRT-PCR and western blot analysis. The validation of the association between miR-200a-3p and KLF6 was established through a fluorescence enzyme reporting assay. In comparison to exosome induced by PBS, exosome induced by TNF-α exhibited a substantial exacerbation of invasion, migration, and angiogenesis in HUVEC. 4 miRNAs in exosomes and HUVEC cells, namely miR-1246, miR-200a-3p, miR-30a-3p, and miR-99b-3p was obtained. MiR-200a-3p maintained high consistency with the sequencing results. We obtained 5 gene symbols, and KLF6 was chose for further investigation. The expression of miR-200a-3p in exosomes induced by TNF-α and in HUVEC treated with these exosomes demonstrated a significantly increase. Additionally, HUVEC cells displayed a notable decrease in KLF6 expression and a significant elevation in VEGFA expression. This was further confirmed by the fluorescence enzyme report assay, which provided evidence of the direct targeting of KLF6 by miR-200a-3p. Exosomes induced by TNF-α have the ability to enhance the migration, invasion, and angiogenesis of HUVEC cells via the miR-200a-3p/KLF6/VEGFA axis.
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Artritis Reumatoide , Exosomas , MicroARNs , Sinoviocitos , Humanos , Artritis Reumatoide/metabolismo , Proliferación Celular , Exosomas/genética , Exosomas/metabolismo , Exosomas/patología , Fibroblastos/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Factor 6 Similar a Kruppel/metabolismo , Factor 6 Similar a Kruppel/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Sinoviocitos/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Frailty is a major health issue associated with aging. Diet affects frailty status; however, studies on the associations between the low-carbohydrate diet (LCD) score, low-fat diet (LFD) score and frailty in older Chinese adults are scarce. This study aimed to examine the associations between the LCD score, LFD score and risk of frailty in older Chinese adults. We analyzed data from 6414 participants aged ≥ 60 years from the China Northwest Natural Population Cohort: Ningxia Project. Frailty was measured using the frailty index (FI), calculated from 28 items comprising diseases, behavioral disorders and blood biochemistry and classified as robust, pre-frail and frail. LCD and LFD scores were calculated using a validated food frequency questionnaire (FFQ). Multiple logistic regression models were used to evaluate associations between LCD, LFD scores and frail or pre-frail status after adjusting for confounders. Participants' mean age was 66.60 ± 4.15 years, and 47.8% were male. After adjusting for age, sex, educational level, drinking, smoking, BMI, physical activity and total energy, compared to the lowest quartile (Q1: reference), the odds ratios (ORs) for pre-frail and frail status in the highest quartile (Q4) of LCD score were 0.73 (95% confidence intervals: 0.61-0.88; p for trend = 0.017) and 0.73 (95%CI: 0.55-0.95; p for trend = 0.035), respectively. No significant associations were observed between LFD score and either pre-frail or frail status. Our data support that lower-carbohydrate diets were associated with lower pre-frail or frail status, particularly in females, while diets lower in fat were not significantly associated with the risk of either pre-frail or frail status in older Chinese adults. Further intervention studies are needed to confirm these results.
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Dieta Baja en Carbohidratos , Dieta con Restricción de Grasas , Fragilidad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Envejecimiento , Pueblos del Este de Asia , Anciano Frágil , Evaluación Geriátrica , Vida IndependienteRESUMEN
This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar (RD12014) compared to reference liraglutide (Victoza) in healthy Chinese male subjects, so as to provide the basis for the similarity evaluation of the two drugs. Eligible subjects were randomized 1:1 to two sequences (RD12014-Victoza or Victoza-RD12014). Subjects received a single 0.6 mg dose of Victoza or RD12014 by abdominal subcutaneous injection during the first period. After a 7-day washout period, subjects received the alternative drug during the second period. Blood samples were collected at predefined timepoints for PKs and immunogenicity assessment. The primary PK end points were maximum plasma concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last ). PK bioequivalence was achieved, if the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax and AUC0-last were within the range of 80.00-125.00%. Safety was assessed throughout the study. The 90% CIs of the GMR of RD12014 to Victoza for Cmax and AUC0-last were completely within the range of 80.00-125.00%. Thirteen treatment-related adverse events (TRAEs) were reported in 11 subjects (22.4%) in the RD12014 group, compared to 12 TRAEs reported in 12 subjects (24.5%) in the Victoza group. The blood samples of 49 subjects were negative for anti-drug antibody and the neutralizing antibody was not further detected. This study demonstrated PK similarity of RD12014 to Victoza in healthy Chinese male subjects. Safety and immunogenicity profiles were comparable between the two groups.
Asunto(s)
Biosimilares Farmacéuticos , Liraglutida , Humanos , Masculino , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/farmacocinética , China , Voluntarios Sanos , Liraglutida/efectos adversos , Liraglutida/farmacocinética , Equivalencia TerapéuticaRESUMEN
Objectives. Hyperuricemia (HUA) is a disease caused by increased production of uric acid (UA) or reduced excretion of UA in the body. Results of an epidemiological survey show that 60% of patients with HUA have hyperlipidemia (HPA). Dendrobium officinalis (DOF) six nostrum (DOS) is based on the theory of traditional Chinese medicine for the transformation of the traditional Chinese nostrum Si Miao Wan. In this article, we aim to discuss the efficacy and mechanism of DOS in reducing UA and regulating lipid metabolism. The rat model of HUA with HPA was induced by potassium oxonate (PO) combined with high-fat sorghum feed. We monitored the serum UA and blood lipids. Liver xanthine oxidase (XOD), adenosine deaminase (ADA), lipoprotein lipase (LPL), and fatty acid-binding protein (FABP1) activities were measured by enzyme-linked immunosorbent assay (ELISA) after the last administration of DOS. We performed a histopathological examination of rat kidney and intestine. Immunohistochemistry (IHC) was used to detect the expression of renal inflammatory proteins NLRP3 / Caspase-1 and intestinal inflammatory proteins TLR4 / NLRP3. We used western blot for measurement of liver hypoxanthine-guanine phosphoribosyl transferase (HPRT1) protein expression and renal PDZ domain protein kidney 1 (PDZK1) protein expression. DOS administration significantly reduced serum UA, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) level, and improved liver steatosis in the model rat. At the same time, DOS treatment effectively inhibited liver XOD and ADA, increased the level of liver HPRT1, and reduced the production of UA. Additional studies had shown that DOS can restore normal UA excretion function in the intestine and kidney and regulated liver lipids metabolism. IHC and histopathological sections showed that DOS reduced the level of kidney, intestinal inflammatory body (NLRP3, Caspase-1, and TLR4), improved inflammation of the kidney and intestinal tract in rats. DOS is a promising drug that can effectively reduce serum UA and lipid level in the model rat. The mechanism of action may be related to inhibition of UA production, promotion of UA excretion, regulation of lipids metabolism, and anti-inflammatory response.
RESUMEN
In the present paper the fluorescence spectra of the blood serum excited with different wavelength were measured with the fluorescence photometer RF5301 (SHIMADZU) made in Japan. The relationship between the fluorescence spectra of the serum and the wavelength of the excitation light was studied during the experiment. The experimental results show that the linetype and peak wavelength of the fluorescence spectra of serum excited by ultraviolet radiation with different wavelength are almost the same, and they do not depend on the excitation wavelength. But the fluorescence peak value changes with the excitation wavelength. There are two high intensity emission intervals in the fluorescence spectra. One of these is from about 300 nm to 410 nm, and the other is below 310 nmr The fluorescence spectra are mostly centralized in the first interval, and the wavelengths of fluorescence peaks were found around two locations: one is near 330 nm and the other is near 370 nm. At this time the strife phenomena occur. When the excitation wavelength is about 250 nm or higher, the fluorescence peak only occurs at 330 nm, and the optimal excitation wavelength is 300 nm. While the wavelength is greater than 320 nm, the fluorescence intensity of the first interval begins to fall, while that of the other augments. And at this time the peak of wavelength of fluorescence is 452 nm. This study provides the experimental foundations for advanced study and applications of the characteristics of fluorescence spectrum of blood serum, and also offers the references to the wavelength selection of excitation light in the application of the photo-induced fluorescence spectra diagnostic technology.