RESUMEN
Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.
Asunto(s)
Médula Ósea , Carcinogénesis , Interleucina-4 , Mielopoyesis , Transducción de Señal , Animales , Humanos , Ratones , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interleucina-4/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Monocitos/efectos de los fármacos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Recurrencia , Transducción de Señal/efectos de los fármacosRESUMEN
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally. Although CVD events do not typically manifest until older adulthood, CVD develops gradually across the life-course, beginning with the elevation of risk factors observed as early as childhood or adolescence and the emergence of subclinical disease that can occur in young adulthood or midlife. Genomic background, which is determined at zygote formation, is among the earliest risk factors for CVD. With major advances in molecular technology, including the emergence of gene-editing techniques, along with deep whole-genome sequencing and high-throughput array-based genotyping, scientists now have the opportunity to not only discover genomic mechanisms underlying CVD but use this knowledge for the life-course prevention and treatment of these conditions. The current review focuses on innovations in the field of genomics and their applications to monogenic and polygenic CVD prevention and treatment. With respect to monogenic CVD, we discuss how the emergence of whole-genome sequencing technology has accelerated the discovery of disease-causing variants, allowing comprehensive screening and early, aggressive CVD mitigation strategies in patients and their families. We further describe advances in gene editing technology, which might soon make possible cures for CVD conditions once thought untreatable. In relation to polygenic CVD, we focus on recent innovations that leverage findings of genome-wide association studies to identify druggable gene targets and develop predictive genomic models of disease, which are already facilitating breakthroughs in the life-course treatment and prevention of CVD. Gaps in current research and future directions of genomics studies are also discussed. In aggregate, we hope to underline the value of leveraging genomics and broader multiomics information for characterizing CVD conditions, work which promises to expand precision approaches for the life-course prevention and treatment of CVD.
Asunto(s)
Enfermedades Cardiovasculares , Humanos , Anciano , Adulto Joven , Adulto , Niño , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/prevención & control , Estudio de Asociación del Genoma Completo , Genómica , Factores de RiesgoRESUMEN
Epidemiological and experimental research has indicated an association between perfluorooctane sulfonate (PFOS) exposure and liver disease. However, the potential hepatotoxic effects and mechanisms of low-level prenatal PFOS exposure in offspring remain ambiguous. The objective of this research was to examine the alterations in liver transcriptomic and metabolomic profiles in offspring rats at postnatal day (PND) 30 following gestational and lactational exposure to PFOS (from gestational day 1 to 20 and PND 1 to 21). Pregnant Sprague-Dawley rats were separated into a control group (3% starch gel solution, oral gavage) and a PFOS exposure group (0.03 mg/kg body weight per day, oral gavage). Histopathological changes in liver sections were observed by hematoxylin and eosin staining. Biochemical analysis was conducted to evaluate changes in glucose and lipid metabolism. Transcriptomic and metabolomic analyses were utilized to identify significant genes and metabolites associated with alterations of liver glucose and lipid metabolism through an integrated multi-omics analysis. No significant differences were found in the measured biochemical parameters. In total, 167 significant differentially expressed genes (DEGs) related to processes such as steroid biosynthesis, PPAR signaling pathway, and fat digestion and absorption were identified in offspring rats in the PFOS exposure group. Ninety-five altered metabolites were exhibited in the PFOS exposure group, such as heptaethylene glycol, lysoPE (0:0/18:0), lucidenic acid K, and p-Cresol sulfate. DEGs associated with steroid biosynthesis, PPAR signaling pathway, fat digestion and absorption were significantly upregulated in the PFOS exposure group (P < 0.05). The analysis of correlations indicated that there was a significant inverse correlation between all identified differential metabolites and the levels of fasting blood glucose, high-density lipoprotein, and triglycerides in the PFOS exposure group (P < 0.05). Our findings demystify that early-life PFOS exposure can lead to alterations in transcriptomic and metabolomic profiles in the offspring's liver, which provided mechanistic insights into the potential hepatotoxicity and developmental toxicity associated with environmentally relevant levels of PFOS exposure.
Asunto(s)
Ácidos Alcanesulfónicos , Fluorocarburos , Efectos Tardíos de la Exposición Prenatal , Embarazo , Humanos , Femenino , Ratas , Animales , Ratas Sprague-Dawley , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Animales Recién Nacidos , Exposición Materna/efectos adversos , Lactancia , Hígado , Glucosa/metabolismo , Perfilación de la Expresión Génica , Esteroides/metabolismo , Fluorocarburos/toxicidadRESUMEN
In 1997, the discovery of single molecule-surface enhanced Raman spectroscopy (SM-SERS) rekindled broad interests owing to its ultrahigh enhancement factor up to the 1014-1015 level. However, regretfully, the advantage of SM-SERS with an ultralow detection limit has not yet been fully utilized in commercialized applications. Here, we report a strategy, which we name confined-enhanced Raman spectroscopy, in which the overall Raman properties can be remarkably improved with in situ-formed active nanoshell on the surface of silver or gold nanoparticles. The nanoshell can confine and anchor molecules onto the surface of plasmonic nanoparticles and avoid desorption from hot spots so that the "on and off" blinking effect can be eliminated. It is the first time the single-molecule detection of analytes with super sensitivity, high stability, and reproducibility based on gold nanoparticles has been realized. In addition, this strategy is suitable for SERS detection in diverse molecule systems, including biomedical diagnosis, catalytic reaction, etc.
RESUMEN
The construction of two distal stereocenters through a single catalytic process is of great interest in organic synthesis. While there are some successful reports regarding stereodivergent preparation of 1,3- or 1,4-stereocenters, the more challenged 1,5-nonadjacent stereocenters have never been achieved in a stereodivergent fashion. Herein we describe a synergistic palladium/copper catalysis for 1,4-difunctionalization reactions of 1,3-dienes, providing access to 1,5-nonadjacent quaternary stereocenters. Because each of the two catalysts separately controlled one of the newly formed stereocenters, stereodivergent synthesis of all four diastereomers of the products could readily be achieved simply by choosing an appropriate combination of chiral catalysts. Experimental and computational studies supported a mechanism involving a Heck/Tsuji-Trost cascade reaction, and the origins of the stereoselectivity were elucidated.
RESUMEN
The leaves of Morus alba L. (called Sangye in Chinese, ML), which belong to the genus Morus., are highly valuable edible plants in nutrients and nutraceuticals. In Asian countries including China, Japan and Korea, ML are widely used as functional foods including beverages, noodles and herbal tea because of its biological and nutritional value. Meanwhile, ML-derived products in the form of powders, extracts and capsules are widely consumed as dietary supplements for controlling blood glucose and sugar. Clinical studies showed that ML play an important role in the treatment of metabolic diseases including the diabetes, dyslipidemia, obesity, atherosclerosis and hypertension. People broadly use ML due to their nutritiousness, deliciousness, safety, and abundant active benefits. However, the systematic pharmacological mechanisms of ML on metabolic diseases have not been fully revealed. Therefore, in order to fully utilize and scale relevant products about ML, this review summarizes the up-to-date information about the ML and its constituents effecting on metabolic disease.
Asunto(s)
Enfermedades Metabólicas/tratamiento farmacológico , Morus , Preparaciones de Plantas/uso terapéutico , Animales , Etnobotánica , Humanos , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/prevención & control , Fitoterapia , Hojas de la Planta , Preparaciones de Plantas/química , Preparaciones de Plantas/farmacologíaRESUMEN
Metal-hydride-catalyzed hydroalkylation of 1,3-dienes with enolizable carbonyl compounds is an atom- and step-economical method for preparing chiral molecules with allylic stereocenters. Although high diastereo- and enantioselectivities have been achieved for many coupling partners, aldehydes have not yet been used for this purpose because they are less stable than other carbonyl compounds under basic conditions and they have the potential to rapidly epimerize at the α-position. Moreover, stereodivergent hydroalkylation reactions of 1,3-dienes to access complementary diastereomers with vicinal stereocenters is challenging. Herein, we describe a synergistic palladium/amine catalyst system that allowed us to achieve the first stereodivergent hydroalkylation reactions of 1,3-dienes with aldehydes. By choosing an appropriate combination of chiral palladium and amine catalysts, we could obtain either syn or anti coupling products, and this method therefore provides highly diastereo- and enantioselective access to complementary diastereomers of chiral aldehydes with α,ß-vicinal stereocenters. Density functional theory calculations revealed a mechanism involving PdH formation and migratory insertion into the alkene, followed by C-C bond formation. The origin of the stereoselectivities was investigated by means of distortion/interaction analysis.
RESUMEN
To achieve ultrasensitive detection of trace targets through solution-based surface-enhanced Raman spectroscopy (SERS), direct adsorption of the target molecules on a SERS-active surface is vital. In this work, cetyltrimethylammonium bromide (CTAB)-capped gold nano-bipyramids (Au BPs) with different aspect ratios (ARs) are prepared and the surface is successfully modified by a simple ligand exchange method. Cysteamine-capped gold nano-bipyramids (cyst-Au BPs) are obtained by means of replacement of CTAB by cysteamine using Au-S covalent bonding and applied in the solution-based SERS detection of different pigment molecules, which always have weak affinity to the gold surface. The hydrogen bonding between the pigment molecule and cysteamine causes the aggregation of Au BPs to generate local electromagnetic field enhancement. The influence of the AR and concentration of Au BPs on SERS properties is investigated. The SERS detection of weak-affinity molecules to an extremely low limit shows that the cyst-Au BPs are highly sensitive compared to CTAB-capped Au BPs. The limit of detection (LOD) of allura red as low as 0.1 ppb and that of sunset yellow as low as 1 ppb show that the proposed strategy has many advantages due to its simplicity and fast and rapid detection for the sensitivity analysis of weak-affinity molecules.
Asunto(s)
Cisteamina , Nanopartículas del Metal , Oro , Límite de Detección , Espectrometría RamanRESUMEN
Intake of arsenic (As) via drinking water has been a serious threat to global public health. Though there are numerous reports of As neurotoxicity, its pathogenesis mechanisms remain vague especially its chronic effects on metabolic network. Hippocampus is a renowned area in relation to learning and memory, whilst recently, cerebellum is argued to be involved with process of cognition. Therefore, the study aimed to explore metabolomics alternations in these two areas after chronic As exposure, with the purpose of further illustrating details of As neurotoxicity. Twelve 3-week-old male C57BL/6J mice were divided into two groups, receiving deionized drinking water (control group) or 50 mg/L of sodium arsenite (via drinking water) for 24 weeks. Learning and memory abilities were tested by Morris water maze (MWM) test. Pathological and morphological changes of hippocampus and cerebellum were captured via transmission electron microscopy (TEM). Metabolic alterations were analyzed by gas chromatography-mass spectrometry (GC-MS). MWM test confirmed impairments of learning and memory abilities of mice after chronic As exposure. Metabolomics identifications indicated that tyrosine increased and aspartic acid (Asp) decreased simultaneously in both hippocampus and cerebellum. Intermediates (succinic acid) and indirect involved components of tricarboxylic acid cycle (proline, cysteine, and alanine) were found declined in cerebellum, indicating disordered energy metabolism. Our findings suggest that these metabolite alterations are related to As-induced disorders of amino acids and energy metabolism, which might therefore, play an important part in mechanisms of As neurotoxicity.
Asunto(s)
Arsénico/toxicidad , Cerebelo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Redes y Vías Metabólicas/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Arsénico/metabolismo , Cerebelo/metabolismo , Cerebelo/ultraestructura , Cromatografía de Gases y Espectrometría de Masas , Hipocampo/metabolismo , Hipocampo/ultraestructura , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Metabolómica/métodos , Ratones , Ratones Endogámicos C57BL , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Ratas , Contaminantes Químicos del Agua/metabolismoRESUMEN
A method was developed for the determination of mercuric ion Hg(II). It is based on hybridization chain reaction (HCR) and surface-enhanced Raman scattering (SERS). Raman signal DNA and streptavidin were self-assembled on gold nanoparticles as a novel signal nanoprobe (AuNP-sDNA). A thymine-mercury(II)-thymine structure was immobilized on magnetic beads (MBs). The HCR makes use of two hairpin probes that are initiated by the trigger DNA to form a stable nicked dsDNA structure (MB-TS-hDNAs). A large number of the binding sites is provided to connect the signal nanoprobe. The stable sandwich structure (MB-TS-hDNA/AuNP-sDNA) was isolated by applying a magnetic field and used in the amplification step. In this way, Hg(II) can be determined sensitively after multiple signal amplification. The SERS signal, measured at 1499 cm-1, increases linearly in the 0.1 pM to 10 nM Hg(II) concentration range, and the limit of detection is 0.08 pM (at an S/N ratio of 3). The method was applied to the detection of Hg(II) in spiked environment water samples, with recoveries ranging from 96 to 119%. Graphical abstract Schematic of a method based on the use of a stable T-Hg(II)-T structure and a self-assembled nanoprobe. It was applied to the trace Hg(II) detection based on hybridization chain reaction (HCR) and surface-enhanced Raman scattering (SERS).
RESUMEN
OBJECTIVE: To investigate the effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China. METHODS: The main urban area of Chongqing was divided into polluted area and clean area according to the air pollution data shown on the Environmental Protection Agency Website of Chongqing between 2010 and 2015. A cluster sampling method was used to select 695 third- or fourth-grade children from 2 primary schools in the clean or polluted area as study subjects, with 313 children from the clean area and 382 children from the polluted area. Pulmonary function was examined for all children and a standard American epidemiological questionnaire (ATS-DLD-78-C) was used to investigate the prevalence of respiratory diseases and symptoms. RESULTS: Compared with the clean area, the polluted area had significantly higher concentrations of inhalable particles (PM10), fine particulate matter (PM2.5), and nitric oxide (NOX) (P<0.05). The multivariate logistic regression analysis was performed after adjustment for confounding factors, and the results showed that compared with those in the clean area, the children in the polluted area had significantly higher risks of cough (OR=1.644), cough during cold (OR=1.596), expectoration during cold (OR=2.196), persistent expectoration (OR=1.802), and wheezing (OR=2.415). The boys and girls in the clean area had significantly higher forced vital capacity and forced expiratory volume in one second than those in the polluted area (P<0.05). CONCLUSIONS: Air pollution in the main urban area of Chongqing is associated with the increased prevalence of respiratory symptoms in school-aged children and has certain effect on children's pulmonary function.
Asunto(s)
Contaminación del Aire/efectos adversos , Enfermedades Respiratorias/etiología , Niño , Femenino , Volumen Espiratorio Forzado , Humanos , Modelos Logísticos , Masculino , Capacidad VitalRESUMEN
Exosome-based liquid biopsies possess great potential in monitoring cancer development However, current exosome detection biosensors require large exosome volumes, showing the weak detection sensitivity. Besides, these methods pay little attention to in situ analysis of exosomes, hence limiting the provision of more accurate clinically-relevant information. Herein, we develop an innovative label-free biosensor combining the low-cost thermophoretic enrichment method with the surface-enhanced Raman spectroscopy (SERS) detection. Based on the thermophoretic enrichment strategy, exosomes and gold nanoparticles can be enriched together into a small area with a scale of 500 µm within 10 min. The Raman signals of various exosomes derived from normal, cancerous cell lines and human serum are dynamically monitored in situ, with the limit of detection of 102-103 particles per microliter, presenting higher sensitivity compared with the similar label-free SERS detection. The spectral data set of different exosomes is applied to train for multivariate classification of cell types and to estimate how the normal exosome data resemble cancer cell exosome. The reliable classification and identification of different exosomes can be realized. The current biosensor is convenient, low-cost and requires small exosome volumes (â¼3 µL), and if validated in larger cohorts may contribute to the tumor prediction and diagnosis.
Asunto(s)
Técnicas Biosensibles , Exosomas , Nanopartículas del Metal , Humanos , Oro , Espectrometría RamanRESUMEN
The investigation into the impact of gravel on water infiltration process and hydraulic parameters in stony soil could offer a theoretical basis to enhance water availability in rocky mountain area. A one-dimensional vertical infiltration experiment was used in this study. Six groups of gravel content of 0% (CK), 10% (W1), 20% (W2), 30% (W3), 40% (W4) and 50% (W5) were established to explore the changes in the wetting front, cumulative infiltration volume and infiltration rate. Then the accuracy of four infiltration models in simulating soil water infiltration processes was evaluated. Finally, Hydrus-1D was used to perform numerical inversion of the soil water content after infiltration. The findings revealed that: (1) When the infiltration time reached 300 min, the wetting front of the W1, W2, W3, W4 and W5 treatments was 11.00%, 17.00%, 32.25%, 38.75% and 54.50% lower than CK, the cumulative infiltration volume was 29.80%, 38.97%, 45.62%, 54.74% and 73.17% lower than CK, and the stable infiltration rate was 50.98%, 52.94%, 66.67%, 68.63% and 86.27% lower than CK. (2) The soil-water infiltration processes were accurately described by the Horton model, the coefficient of determination (R2) > 0.935. (3) The simulation results of Hydrus-1D showed that with the increase of gravel content, the values of the retention water content (θr), saturated water content (θs), shape coefficient (n) and saturated hydraulic conductivity (Ks) were decreased, the values of the reciprocal of air-entry (α) were increased. The value of R2 was more than 0.894, the root mean square error (RMSE) and mean absolute error (MAE) were less than 2%, which demonstrated that the Hydrus-1D model exhibited superior capability in simulating the changes of water content in stony soil in rocky mountain area. The findings of this study demonstrated that gravel could decrease the water infiltration process and affect the water availability. It could provide data support for the water movement process of stony soil and rational utilization of limited water resources in mountainous area.
RESUMEN
The objective of this study was to explore the effects of different amounts of biochar on the migration process and characteristics of NO3--N in loessial soil. In this study, six groups of mixed soil samples with biochar and loessial soil mass ratios of 0% (T0), 1% (T1), 2% (T2), 3% (T3), 4% (T4), and 5% (T5) were used as research objects. NO3--N was used as the tracer. Through the indoor soil column solute transport simulation tests, the effects of different biochar application amounts on the NO3--N transport process in loessial soil were simulated and studied. The results showed that the breakthrough curve of NO3--N in loessial soil shifted to the right with the increasing of biochar application, and the peak value gradually decreased. The initial penetration time, complete penetration time, and total penetration time increased with the increasing of biochar application amount. The total penetration time of NO3- in the T1, T2, T3, T4, and T5 treatments was 1.26, 2.31, 2.72, 3.22, and 3.57 times that of T0, respectively. The R2 was > 0.997 and RMSE was < 2.083 of the two-zone model (TRM). Compared with the convection-dispersion equation (CDE), the TRM model had higher fitting accuracy and could better simulate the NO3--N migration process in loessial soil after the application of different contents of biochar. The analysis of the fitting parameters of the TRM model showed that the average pore velocity, hydrodynamic dispersion coefficient, and water content ratio in the movable zone gradually decreased with the increasing of biochar application, whereas the dispersion and mass exchange coefficient showed an increasing trend. The results showed that biochar application could effectively enhance the ability of loessial soil to fix NO3--N, reduce the leakage of NO3--N to groundwater, and play an important role in maintaining soil fertility and preventing groundwater pollution.
Asunto(s)
Carbón Orgánico , Suelo , NitrógenoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: It has been widely reported that various anti-rheumatic traditional Chinese medicines (TCMs) ameliorate rheumatoid arthritis (RA) and osteoarthritis (OA) through regulating the abnormal production, assembly, and activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome. These TCMs include monomers isolated from Chinese herbs, extracts of Chinese herbs, and Chinese medical formulae with a lengthy application history. AIM OF THE STUDY: This review aimed to summarize and analyze the published articles about the NLRP3 inflammasome and its role in the pathogenesis of RA and OA. We also reviewed existing knowledge on the therapeutic mechanism of TCMs in RA and OA via the regulation of the NLRP3 inflammasome. MATERIALS AND METHODS: We searched for relevant articles with the keywords "NLRP3 inflammasome", "traditional Chinese medicine," "Chinese herbal drugs," "rheumatoid arthritis," and "osteoarthritis." The information retrieval was conducted in medical Chinese and English databases from the date of construction to April 19, 2023, including PubMed, MEDLINE, Web of Science, Scopus, Ovid, China National Knowledge Infrastructure (CNKI), Chinese Biomedicine Literature Database (CBM), Chinese Science and Technology Periodicals Database (VIP), and China Online Journals (COJ). RESULTS: According to retrieval results, 35 TCMs have been demonstrated to relieve RA by targeting the NLRP3 inflammasome, including six traditional Chinese prescriptions, seven extracts of Chinese herbs, and 22 monomers extracted from traditional Chinese herbs and formulae. Additionally, 23 TCMs have shown anti-OA effects with abilities to modulate the NLRP3 inflammasome, including five traditional Chinese prescriptions, one extract of Chinese herbs, and 17 monomers from Chinese herbs. CONCLUSIONS: We summarized mechanism research about the pivotal roles of the NLRP3 inflammasome in the pathogenesis of RA and OA. Moreover, a review of TCMs with targets of the NLRP3 inflammasome in RA and OA treatment was also conducted. Our work is conducive to a better application of TCMs in complementary and alternative therapies in RA and OA.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Medicamentos Herbarios Chinos , Osteoartritis , Humanos , Inflamasomas , Medicina Tradicional China , Proteína con Dominio Pirina 3 de la Familia NLR , Artritis Reumatoide/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Antirreumáticos/farmacología , Antirreumáticos/uso terapéuticoRESUMEN
BACKGROUND: The blood pressure (BP) etiologic study is complex due to multifactorial influences, including genetic, environmental, lifestyle, and their intricate interplays. We used a metabolomics approach to capture internal pathways and external exposures and to study BP regulation mechanisms after well-controlled dietary interventions. METHODS: In the ProBP trail (Protein and Blood Pressure), a double-blinded crossover randomized controlled trial, participants underwent dietary interventions of carbohydrate, soy protein, and milk protein, receiving 40 g daily for 8 weeks, with 3-week washout periods. We measured plasma samples collected at baseline and at the end of each dietary intervention. Multivariate linear models were used to evaluate the association between metabolites and systolic/diastolic BP. Nominally significant metabolites were examined for enriching biological pathways. Significant ProBP findings were evaluated for replication among 1311 participants of the BHS (Bogalusa Heart Study), a population-based study conducted in the same area as ProBP. RESULTS: After Bonferroni correction for 77 independent metabolite clusters (α=6.49×10-4), 18 metabolites were significantly associated with BP at baseline or the end of a dietary intervention, of which 11 were replicated in BHS. Seven emerged as novel discoveries, which are as follows: 1-linoleoyl-GPE (18:2), 1-oleoyl-GPE (18:1), 1-stearoyl-2-linoleoyl-GPC (18:0/18:2), 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), maltose, N-stearoyl-sphinganine (d18:0/18:0), and N6-carbamoylthreonyladenosine. Pathway enrichment analyses suggested dietary protein intervention might reduce BP through pathways related to G protein-coupled receptors, incretin function, selenium micronutrient network, and mitochondrial biogenesis. CONCLUSIONS: Seven novel metabolites were identified to be associated with BP at the end of different dietary interventions. The beneficial effects of protein interventions might be mediated through specific metabolic pathways.
Asunto(s)
Presión Sanguínea , Estudios Cruzados , Hipertensión , Humanos , Masculino , Femenino , Presión Sanguínea/fisiología , Método Doble Ciego , Hipertensión/dietoterapia , Hipertensión/fisiopatología , Persona de Mediana Edad , Adulto , Metabolómica/métodos , Carbohidratos de la Dieta/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Wutou Decoction (WTD) is a classic traditional Chinese medicine formula, which has shown clinical efficacy in treating rheumatoid arthritis (RA). The Treg stability and Th17/Treg imbalance is an important immunological mechanism in RA progression. Whether WTD regulates CD4+ T cell subsets has not been thoroughly investigated yet. AIM OF THE STUDY: This study aimed to explore the potential role and mechanisms of WTD in regulating the diminished stability of Treg cells and the imbalance of CD4+ T cell subsets via in vivo and in vitro experiments. MATERIALS AND METHODS: Firstly, the therapeutic effects of WTD on the collagen-induced arthritis (CIA) mouse and its potential regulatory function on CD4+ T cell subsets were evaluated in vivo. Animal specimens were collected after 31 days of treatment with WTD. The anti-arthritic and anti-inflammatory effects of WTD were assessed through arthritis scoring, body weight, spleen index, serum IL-6 levels, and micro-PET/CT imaging. Gene enrichment analysis was performed to evaluate the activation T cell-related signaling pathway. Flow cytometry was used to determine the proportions of CD4+ T cell subsets in vitro and in vitro. Additionally, ELISA was used to assess the secretion of IL-10 and TGF-ß by Treg cells under inflammatory conditions. The suppressive function of Treg cells on cell proliferation under inflammatory conditions was examined using CFSE labeling. Immunofluorescence staining was performed to detect the phosphorylation levels of STAT3 in CD4+ T cells from mouse spleen tissues. Western blotting was used to evaluate the phosphorylation levels of JAK2/STAT3 in Treg cells. RESULTS: WTD significantly alleviated joint inflammation in CIA mice. WTD reduced serum IL-6 levels in CIA mice, improved their body weight and spleen index. WTD treatment inhibited the activation of CD4+ T cell subgroup-related signaling in the joint tissues of CIA mice. In vitro and in vitro experiments showed that WTD increased the proportion of Treg cells and decreased the proportion of Th17 cells in CIA mice spleen. Furthermore, WTD promoted the secretion of IL-10 and TGF-ß by Treg cells and enhanced the inhibitory capacity of Treg cells on cell proliferation under inflammatory conditions. Immunofluorescence detected decreased STAT3 phosphorylation levels in CD4+ T cells from CIA mice spleen, while western blotting revealed a decrease in JAK2/STAT3 phosphorylation levels in Treg cells in vitro. CONCLUSIONS: Inhibiting JAK2/STAT3 phosphorylation is a potential mechanism through which WTD improves Treg cell stability, balances CD4+ T cell subsets, and attenuates RA joint inflammation.
Asunto(s)
Artritis Experimental , Medicamentos Herbarios Chinos , Janus Quinasa 2 , Ratones Endogámicos DBA , Factor de Transcripción STAT3 , Transducción de Señal , Linfocitos T Reguladores , Células Th17 , Animales , Factor de Transcripción STAT3/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Janus Quinasa 2/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Transducción de Señal/efectos de los fármacos , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
INTRODUCTION: Currently, the cause of psoriatic arthritis (PsA) is unknown, and the effectiveness of current drug treatments is unsatisfactory. In March 2019, the US Food and Drug Administration (FDA) approved risankizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, for the treatment of PsA in adults. This study aimed to conduct a meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the effectiveness and safety of risankizumab in moderate-to-severe PsA. METHODS: We conducted a thorough search of relevant databases from the establishment of the databases to October 1, 2023. We conducted a meta-analysis using Stata 12.0 and utilized I2 and Egger tests to assess heterogeneity and publication bias among the studies. Bias assessment was performed using the risk bias map and bias risk summary diagram generated by Revman5.4 software. The review protocols were registered on PROSPERO (CRD42023451894) and adhered to the preferred reporting item of system evaluation (PRISMA) guideline. RESULTS: Six randomized controlled trials (RCTs) involving 5038 patients with PsA treated with either risankizumab or placebo were included in the analysis. At 24 weeks, the risankizumab group demonstrated a significantly higher American College of Rheumatology-20 (ACR20) response rate compared to the placebo group (RR 1.760, 95% CI 1.568-1.977, P < 0.001). Additionally, the risankizumab group showed a significantly higher Minimal Disease Activity (MDA) response rate compared to the placebo group (RR 1.827, 95% CI 1.048-3.184, P < 0.05). The risankizumab group also exhibited improvement in Short Form 36 Questionnaire (SF-36) score (SMD 0.51, 95% CI 0.33-0.69, P < 0.001), with significantly lower Health Assessment Questionnaire Disability Index (HAQ-DI) score (SMD - 0.27, 95% CI - 0.37 to - 0.17, P < 0.001) and higher Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (SMD 0.27, 95% CI 0.20-0.35, P < 0.001) compared to the placebo group. Moreover, the risankizumab group had a significantly lower Psoriasis Area and Severity Index (PASI) score (SMD - 6.12, 95% CI - 10.02 to 2.23, P < 0.001). A study by Mease et al. indicated that patients receiving risankizumab generally demonstrated numerical improvements in the Leeds Enthesitis Index (LEI), although the small sample size limits the evidence. Further research is necessary to provide evidence-based guidelines. There were no significant differences in the incidence of serious adverse events (SAE) and serious treatment-emergent adverse events (STEAE) between the risankizumab and placebo groups (RR 0.76, 95% CI 0.45-1.28, P = 0.31; RR 0.99, 95% CI 0.49-1.99, P = 0.97, respectively), and the overall incidence of adverse events (AE) was not comparable (RR 1.10, 95% CI 0.63-1.94, P = 0.73). CONCLUSION: Risankizumab showed superior efficacy across multiple outcome measures compared to placebo, with no significant increase in adverse events. Our findings endorse risankizumab as an excellent treatment option for PsA, offering valuable insights for clinicians and patients when choosing appropriate therapeutic interventions. TRIAL REGISTRATION: Retrospectively registered (CRD42023451894, 16 August 2023).
RESUMEN
In recent years, surface-enhanced Raman spectroscopy (SERS) has been widely used in various fields for the rapid detection of trace-level molecular targets. In this study, we have developed a simple and effective solution-based SERS protocol to improve the activity for the detection of cationic dye molecules in aquaculture. The polystyrene sulfonate functionalized gold nanobipyramids (PSS-Au BPs) were synthesized from the cetyltrimethylammonium bromide (CTAB) reaction system followed by the ligand exchange process. The halide ions-induced aggregation of PSS-Au BPs was carried out by using four type of different salts such as NaCl, NaBr, MgCl2 and MgSO4 to investigate their influence on the SERS activity. The results demonstrate that the ionic strength of the solution has an important impact on the colloidal stability and SERS activity. The PSS-Au BPs show an improved SERS sensitivity at lower concentrations of the aggregating agents in solution-based SERS by detecting the crystal violet (CV) molecules with a limit of detection (LOD) to 3.28 × 10-11 M. Furthermore, to demonstrate the generality of our proposed strategy, trace amounts of three more dyes such as malachite green (MG), methylene blue (MB), and rhodamine 6G (R-6G), as well as other molecules such as thiram and bisphenol-S were also detected. This protocol not only provides a method for rapid on-site detection of trace-level molecules but can also be applied to other SERS-based analysis.
Asunto(s)
Oro , Nanopartículas del Metal , Acuicultura , Cetrimonio , Colorantes , Violeta de Genciana/análisis , Oro/química , Ligandos , Nanopartículas del Metal/química , Azul de Metileno , Poliestirenos , Sales (Química) , Cloruro de Sodio , Espectrometría Raman/métodos , Tiram/análisisRESUMEN
Emerging epidemiological evidence indicates potential associations between gestational perfluorobutane sulfonate (PFBS) exposure and adverse metabolic outcomes in offspring. However, the underlying mechanisms remain unclear. Our study aimed to investigate PFBS exposure effects during pregnancy and lactation on rat offspring lipid profiles and the possible underlying mechanisms. Although the biochemical index difference including total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), alanine amino transaminase (ALT), aspartate amino transferase (AST), and fasting blood glucose between exposed groups and the control group was not significant, transcriptome analyses showed that the differentially expressed genes (DEGs) in the 50 mg/kg/day PFBS exposure group were significantly related to protein digestion and absorption, peroxisome proliferator activated-receptor (PPAR) signaling pathway, xenobiotic metabolism by cytochrome P450, glycine, serine and threonine metabolism, ß-alanine metabolism, bile secretion, unsaturated fatty acid (FA) biosynthesis, and alanine, aspartate and glutamate metabolism. Untargeted metabolomics analyses identified 17 differential metabolites in the 50 mg/kg/day PFBS exposure group. Among these, phosphatidylserine [PS (18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z))], lysoPE (18:1(11Z)/0:0), and PS (14:0/20:4(5Z,8Z,11Z,14Z)) were significantly correlated with phospholipid metabolism disorders. Correlation analysis indicated the DEGs, including FA binding protein (Fabp4), spermine oxidase (Smox), Fabp2, acyl-CoA thioesterase 5 (Acot5), sarcosine dehydrogenase (Sardh), and amine oxidase, copper-containing 3 (Aoc3) that significantly enriched in xenobiotic metabolism by cytochrome P450 and glycine, serine, and threonine metabolism signaling pathways were highly related to the differential metabolite pantetheine 4'-phosphate. Pantetheine 4'-phosphate was significantly negatively associated with non-high-density lipoprotein (non-HDL) and TC levels. Collectively, our study indicated that maternal PFBS exposure at a relatively low level could alter gene expression and metabolic molecules in lipid metabolism-related pathway series in rat offspring, although the effects on metabolic phenotypes were not significant within the limited observational period, using group-wise and trend analyses.