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AIMS: Certain critical risk factors of heart failure with preserved ejection fraction (HFpEF) patients were significantly different from those of heart failure with reduced ejection fraction (HFrEF) patients, resulting in the limitations of existing predictive models in real-world situations. This study aimed to develop a machine learning model for predicting 90 day readmission for HFpEF patients. METHODS AND RESULTS: Data were extracted from electronic health records from 1 August 2020 to 1 August 2021 and follow-up records of patients with HFpEF within 3 months after discharge. Feature extraction was performed by univariate analysis combined with the least absolute shrinkage and selection operator (LASSO) algorithms. Machine learning models like eXtreme Gradient Boosting (XGBoost), random forest, neural network and logistic regression were adopted to construct models. The discrimination and calibration of each model were compared, and the Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model. The cohort included 746 patients, of whom 103 (13.8%) were readmitted within 90 days. XGBoost owned the best performance [area under the curve (AUC) = 0.896, precision-recall area under the curve (PR-AUC) = 0.868, sensitivity = 0.817, specificity = 0.837, balanced accuracy = 0.827]. The Kolmogorov-Smirnov (KS) statistic was 0.694 at 0.468 in the XGBoost model. SHAP identified the top 12 risk features, including activities of daily living (ADL), left atrial dimension (LAD), left ventricular end-diastolic diameter (LVDD), shortness, nitrates, length of stay, nutritional risk, fall risk, accompanied by other symptoms, educational level, anticoagulants and edema. CONCLUSIONS: Our model could help medical agencies achieve the early identification of 90 day readmission risk in HFpEF patients and reveal risk factors that provide valuable insights for treatments.
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Acovenosigenin A ß-glucoside (AAG) is a cardiac glycoside derived from Streptocaulon juventas (Lour.) Merr, which exhibited the potential in treating lung cancer in our previous research. However, the action mechanism remains unclear. In this research, JAK2-STAT3 signaling pathway was predicted to be the critical regulation pathway based on the integrative analysis of transcriptome and proteome. Western blotting and qPCR assays were performed to identify that AAG can regulate JAK2-STAT3 signaling pathway and its downstream genes, such as c-Myc, Survivin, Cyclin B1, CDK1, Bcl-2. And this action of AAG depended on the suppression of STAT3 phosphorylation and its nuclear translocation through the experiments of Immunofluorescence, transient transfection and cryptotanshinone treatment. Additionally, AAG was discovered to mediate the JAK2-STAT3 pathway in IL-6-driven A549 and H460 cells, which in turn inhibited cell proliferation, promoted mitochondria-related apoptosis, and arrested the cell cycle progression. By molecular docking analysis, CETSA and SIP experiments, the protein of GP130 was identified as the specific target of AAG in A549 and H460 cells. Further studies suggested that AAG inhibited JAK2-STAT3 pathway and its downstream genes by targeting GP130 in nude mice xenograft model in vivo. This research presented that AAG exhibits the promising potential in the treatment of NSCLC.
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Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated polyï¼lactic-co-glycolic acidï¼ï¼PLGAï¼, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-ßï¼TGF-ßï¼, and Lnterleukin-10ï¼IL-10ï¼, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8ï¼TLR7/8ï¼ agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.
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Carcinoma de Células Renales , Citocinas , Inmunoterapia , Neoplasias Renales , Macrófagos , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Animales , Inmunoterapia/métodos , Neoplasias Renales/terapia , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Citocinas/metabolismo , Ratones , Humanos , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Microambiente Tumoral/efectos de los fármacosRESUMEN
A novel polysaccharide (GSPA-0.3) was isolated and purified from the root of cultivated Panax ginseng C. A. Meyer, and its structure, adjuvant activities, and mechanisms for inducing the maturation of mouse dendritic 2.4 cells (DC2.4) were extensively studied. Fraction GSPA-0.3, mainly composed by the galacturonic acid, galactose, arabinose, glucose, rhamnose, mannose, and xylose, had a molecular weight of 62,722 Da. The main chain of GSPA-0.3 was composed of â3)-α-L-Rhap-(1â, â4)-α-D-GalpA-(1â, and â3, 4)-α-D-GalpA-(1â. Branched chains comprised α-L-Araf-(1â3, 5)-α-L-Araf-(1â5)-α-L-Araf-(1â, α-D-Glcp-(1â6)-α-D-Glcp-(1â6)-α-D-Glcp-(1â, ß-D-Galp-(1â4)-ß-D-Galp-(1â4)-ß-D-Galp-(1â, and α-D-GalpA-(1â units connected to the C3 position of â3, 4)-α-D-GalpA-(1â. In vivo, GSPA-0.3 was found to stimulate the production of IgG, IgG1, and IgG2a; increase the splenocyte proliferation index; and promote the expression of GATA-3, T-bet, IFN-γ, and IL-4 in H1N1 vaccine-immunized mice. Moreover, GSPA-0.3 significantly increased the levels of neutralizing antibodies in the mice, and its adjuvant activity was found to be superior to aluminum adjuvant (Alum adjuvant). Mechanistic investigations showed that GSPA-0.3 activated the TLR4-dependent pathway by upregulating the expressions of TLR4, MyD88, TRAF-6, and NF-κB proteins and gens. The results presented herein suggested that GSPA-0.3 could significantly promote the efficacy of the H1N1 vaccine by modulating Th1/Th2 response via the TLR4-MyD88-NF-κB signaling pathway.
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Subtipo H1N1 del Virus de la Influenza A , Panax , Vacunas , Ratones , Animales , Panax/química , Factor 88 de Diferenciación Mieloide , FN-kappa B , Receptor Toll-Like 4 , Polisacáridos/química , Adyuvantes Inmunológicos/farmacologíaRESUMEN
Background: Colorectal cancer (CRC) is linked to distinct gut microbiome patterns. The efficacy of gut bacteria as diagnostic biomarkers for CRC has been confirmed. Despite the potential to influence microbiome physiology and evolution, the set of plasmids in the gut microbiome remains understudied. Methods: We investigated the essential features of gut plasmid using metagenomic data of 1,242 samples from eight distinct geographic cohorts. We identified 198 plasmid-related sequences that differed in abundance between CRC patients and controls and screened 21 markers for the CRC diagnosis model. We utilize these plasmid markers combined with bacteria to construct a random forest classifier model to diagnose CRC. Results: The plasmid markers were able to distinguish between the CRC patients and controls [mean area under the receiver operating characteristic curve (AUC = 0.70)] and maintained accuracy in two independent cohorts. In comparison to the bacteria-only model, the performance of the composite panel created by combining plasmid and bacteria features was significantly improved in all training cohorts (mean AUCcomposite = 0.804 and mean AUCbacteria = 0.787) and maintained high accuracy in all independent cohorts (mean AUCcomposite = 0.839 and mean AUCbacteria = 0.821). In comparison to controls, we found that the bacteria-plasmid correlation strength was weaker in CRC patients. Additionally, the KEGG orthology (KO) genes in plasmids that are independent of bacteria or plasmids significantly correlated with CRC. Conclusion: We identified plasmid features associated with CRC and showed how plasmid and bacterial markers could be combined to further enhance CRC diagnosis accuracy.
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BACKGROUND: Understanding the relationship between nutrition risk at admission to the intensive care unit (ICU) and the prognosis of patients with traumatic brain injury (TBI) may aid early recognition of high-risk patients. METHODS: We extracted data from the Medical Information Mart for Intensive Care III and the electronic ICU Collaborative Research Databases. Using modified Nutrition Risk in the Critically ill score (mNUTRIC) within the first 24 h of ICU admission, 5153 patients were divided into three groups: low (≤1, n = 1765), moderate (2-4, n = 2574), and high (≥5, n = 814). The primary outcome was 28-day in-hospital mortality, and the secondary outcomes were 7-day in-hospital mortality, length of ICU stay, and duration of mechanical ventilation. RESULTS: During the median follow-up time of 6.69 days, 647 deaths occurred in total. After adjustment for potential confounding factors, setting the low mNUTRIC group as a reference, the risk of 28-day mortality was increased in the high and moderate mNUTRIC groups (hazard ratio [HR]high vs low [95% CI]: 4.21 [2.70-6.58] and 2.84 [1.95-4.14], respectively). Similarly, high and moderate mNUTRIC scores are linked to a higher risk of 7-day mortality (PTrend < 0.001) and a longer duration of mechanical ventilation (PTrend < 0.001). The effect of mNUTRIC on mortality varied by serum glucose level (PInteraction = 0.01). Lastly, those whose mNUTRIC scores deteriorated within the first 3 days have a 1.46 times greater risk of dying compared with patients with improved mNUTRIC scores. CONCLUSIONS: Nutrition risk screening by mNUTRIC score at the time of admission to the ICU may improve mortality prediction.
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Lesiones Traumáticas del Encéfalo , Enfermedad Crítica , Humanos , Enfermedad Crítica/terapia , Estado Nutricional , Factores de Riesgo , Unidades de Cuidados Intensivos , Lesiones Traumáticas del Encéfalo/terapia , Estudios RetrospectivosRESUMEN
For centuries, dried unripe fruits of Rubus chingii Hu (Chinese name "Fu-pen-zi") have been widely used in traditional Chinese medicine for the treatment of various diseases, commonly associated with kidney deficiency. Rubi Fructus is an edible berry suitable for consumption either directly or in the form of juice and jam. The phytochemical investigation focused on the bioactive non-nutrient ingredient from the fruit of R. chingii, especially diterpenoid compounds. Seven diterpenoid glucosides, including three new (1-3) and four known (4-7) compounds, were obtained from the fruits of R. chingii. The structures along with the absolute configurations of the new compounds were determined by extensive NMR spectroscopic analysis. Compounds 1, 2, 4, 5, and 7 showed anti-inflammatory activity against LPS-induced NO production in RAW 264.7 macrophages. Further, the preliminary structure-activity relationships of these active compounds have been scientifically evaluated and discussed in this study.
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Diterpenos , Frutas , Frutas/química , Glucósidos/farmacología , Glucósidos/análisis , Estructura Molecular , Antiinflamatorios/farmacología , Diterpenos/farmacologíaRESUMEN
Kiwifruit (Actinidia spp) is a woody, perennial and deciduous vine. In this genus, there are multiple ploidy levels but the main cultivated cultivars are polyploid. Despite the availability of many genomic resources in kiwifruit, SNP genotyping is still a challenge given these different levels of polyploidy. Recent advances in SNP array technologies have offered a high-throughput genotyping platform for genome-wide DNA polymorphisms. In this study, we developed a high-density SNP genotyping array to facilitate genetic studies and breeding applications in kiwifruit. SNP discovery was performed by genome-wide DNA sequencing of 40 kiwifruit genotypes. The identified SNPs were stringently filtered for sequence quality, predicted conversion performance and distribution over the available Actinidia chinensis genome. A total of 134 729 unique SNPs were put on the array. The array was evaluated by genotyping 400 kiwifruit individuals. We performed a multidimensional scaling analysis to assess the diversity of kiwifruit germplasm, showing that the array was effective to distinguish kiwifruit accessions. Using a tetraploid F1 population, we constructed an integrated linkage map covering 3060.9 cM across 29 linkage groups and performed QTL analysis for the sex locus that has been identified on Linkage Group 3 (LG3) in Actinidia arguta. Finally, our dataset presented evidence of tetrasomic inheritance with partial preferential pairing in A. arguta. In conclusion, we developed and evaluated a 135K SNP genotyping array for kiwifruit. It has the advantage of a comprehensive design that can be an effective tool in genetic studies and breeding applications in this high-value crop.
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Actinidia , Genotipo , Actinidia/genética , Polimorfismo de Nucleótido Simple/genética , Fitomejoramiento , Mapeo Cromosómico/métodos , PoliploidíaRESUMEN
Syringae Folium (SF) is a traditional Chinese medicine with excellent antibacterial, anti-inflammatory, and antiviral properties. It is widely distributed in northeast China and has three origins. However, the differences between the three origins have never been compared. Here, we used the five-wavelength fusion HPLC fingerprint technique combined with chemometric analysis and the comprehensive quantitative analysis of active constituents to evaluate the quality of SF from different origins, localities, and harvesting times. As a result, SF from different origins and localities showed no differences by similarity analysis, chemometric analysis, and quantitative analysis, whereas the harvesting time was found to be the key factor inducing the variation of the SF composition. In summary, the differences in origins and localities would not cause apparent disparities, while the harvest time should be considered in the SF development and application.
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Medicamentos Herbarios Chinos , Quimiometría , Medicina Tradicional China , Cromatografía Líquida de Alta Presión , Hojas de la PlantaRESUMEN
Background: Alzheimer's disease (AD) is a serious neurodegenerative disease associated with the memory and cognitive impairment. The occurrence of AD is due to the accumulation of amyloid ß-protein (Aß) plaques and neurofibrillary tangles (NFTs) in the brain tissue as well as the hyperphosphorylation of Tau protein in neurons, doing harm to the human health and even leading people to death. The development of neuroprotective drugs with small side effects and good efficacy is focused by scientists all over the world. Natural drugs extracted from herbs or plants have become the preferred resources for new candidate drugs. Lignans were reported to effectively protect nerve cells and alleviate memory impairment, suggesting that they might be a prosperous class of compounds in treating AD. Objective: To explore the roles and mechanisms of lignans in the treatment of neurological diseases, providing proofs for the development of lignans as novel anti-AD drugs. Methods: Relevant literature was extracted and retrieved from the databases including China National Knowledge Infrastructure (CNKI), Elsevier, Science Direct, PubMed, SpringerLink, and Web of Science, taking lignan, anti-inflammatory, antioxidant, apoptosis, nerve regeneration, nerve protection as keywords. The functions and mechanisms of lignans against AD were summerized. Results: Lignans were found to have the effects of regulating vascular disorders, anti-infection, anti-inflammation, anti-oxidation, anti-apoptosis, antagonizing NMDA receptor, suppressing AChE activity, improving gut microbiota, so as to strengthening nerve protection. Among them, dibenzocyclooctene lignans were most widely reported and might be the most prosperous category in the develpment of anti-AD drugs. Conclusion: Lignans displayed versatile roles and mechanisms in preventing the progression of AD in in vitro and in vivo models, supplying potential candidates for the treatment of nerrodegenerative diseases.
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In this study, a chemical investigation on the fruits of Livistona chinensis (FLC) led to the isolation and identification of 45 polyphenols and 5 alkaloids, including two new compounds (Livischinol (1) and Livischinine A (46)), an undescribed compound (47) and 47 known compounds. FLC was predicted with novel potential antidiabetic function by collecting and analyzing the potential targets of the ingredients. Compound 32 exhibited significant α-glucosidase inhibitory activity (IC50 = 5.71 µM) and 1, 6, and 44 showed the PTP1B inhibitory activity with IC50 values of 9.41-22.19 µM, while that of oleanolic acid was 28.58 µM. The competitive inhibitors of PTP1B (compounds 1 and 44) formed strong binding affinity, with catalytic active sites, proved by kinetic analysis, fluorescence spectra measurements, and computational simulations, and stimulated glucose uptake in the insulin-resistant HepG2 cells at the dose of 50 µM. In addition, FLC was rich in antioxidant and anti-inflammatory bioactive compounds so that they could be developed as nutraceuticals against diabetes.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Arecaceae , Frutas , Inhibidores de Glicósido Hidrolasas/farmacología , Farmacología en Red , Extractos Vegetales/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Arecaceae/química , Frutas/química , Glucosa/metabolismo , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Resistencia a la Insulina , Cinética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Simulación de Dinámica Molecular , Extractos Vegetales/aislamiento & purificación , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Células RAW 264.7RESUMEN
Silverweed cinquefoil roots, as dietary supplements, foods, and medicines, are widely used in western areas of China, specifically in Tibet Autonomous Region and Gansu and Qinghai Provinces. In this paper, 10 new natural pentacyclic triterpenoid saponins (1-10), named poterinasides A-J, along with 14 known compounds (11-24) were isolated and purified from silverweed cinquefoil roots. The chemical structures of 1-10 were established by extensive analysis of 1D and 2D NMR data and mass spectrometric data. Poterinasides A (1), B (2), and G (7) with the unique position of substituents on the E ring had never been discovered in natural products before. Saponins 1-8, 14, and 22 displayed potent hepatoprotective activities, and 1-8, 10, 11, 14, 16, 19, and 22-24 showed outstanding anti-inflammatory effects. On the basis of the present results, some structure-activity relationships were summarized, in which 3α-OH, 19ß-CH3, 20α-CH3, 20ß-CH3, 21α-OH, and 30-OH groups in isolated pentacyclic triterpenoid saponins were found to strengthen the hepatoprotective and anti-inflammatory activities, respectively. Further, the following pharmacophore-based virtual screening and docking studies on special targets proteins, SIRT1 and COX-2, revealed roughly similar results with the structure-activity relationships, and this combination method was used for the first time for active natural compound screening.
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Potentilla , Saponinas , Triterpenos , Antiinflamatorios/farmacología , Estructura Molecular , Raíces de Plantas , Saponinas/farmacologíaRESUMEN
Five new flavonoids (1-5), along with 25 known compounds, were isolated from the rhizomes of Potentilla anserina L. and their structures were identified using spectroscopic and chemical evidence. The extract, all fractions, and all isolated compounds were evaluated for their antioxidant, α-glucosidase, and tyrosinase inhibitory activities, and their structure-activity relationship was interpreted. The biflavanols and quercetin-3-O-α-l-rhamnopyranoside-2â³-gallate (14) exhibited significant antioxidant and α-glucosidase inhibition activities. In this study, anti-tyrosinase activity and its mechanism of active compounds (potenserin C (4), potenserin D (5), and quercetin-3-O-α-l-rhamnopyranoside-2â³-gallate (14)) were explored by a combination of computational simulations and kinetic studies. Kinetic studies indicated that potenserin C (4) and quercetin-3-O-α-l-rhamnopyranoside-2â³-gallate (14) inhibited tyrosinase in a competitive manner, whereas potenserin D (5) acted in a reversible noncompetitive manner. The molecular docking result indicated that the substitution of the glucose moiety with galloyl and the presence of 3', 4', 5'-OH in flavonoid aglycones played a crucial role for the tyrosinase inhibiting effect. Moreover, the presence of biflavanols increased the activity against tyrosinase because of strong hydrogen binding, π-alkyl binding, and electrostatic interaction. Thus, the presented experiments developed several new lead compounds that could act as antioxidants and α-glucosidase inhibitors. Furthermore, biflavanols and quercetin-3-O-α-l-rhamnopyranoside-2â³-gallate played important roles in the anti-browning activity during food processing.
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Antioxidantes/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Potentilla/química , Relación Estructura-Actividad , Antioxidantes/química , Evaluación Preclínica de Medicamentos , Flavonoides/química , Flavonoides/farmacología , Inhibidores de Glicósido Hidrolasas/química , Glicósidos/química , Glicósidos/farmacología , Cinética , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa/metabolismo , Extractos Vegetales/química , Quercetina/análogos & derivados , Quercetina/química , Quercetina/farmacología , Rizoma/metabolismoRESUMEN
In the present study, petroleum ether, dichloromethane, ethyl acetate, and n-butanol fractions of mango seed kernel exhibited different degrees of antioxidant and α-glucosidase inhibitory activity. Thus, quantitative and qualitative analysis of the petroleum ether fraction was conducted by GC-MS. Among identified components, four unsaturated fatty acids had never been reported in natural products before, together with 19 known components. In addition, 17 compounds were isolated and elucidated from other active fractions. Compounds 2, 9, 15, and 17 were isolated for the first time from Mangifera genus. Compounds 1 and 2 exhibited prominent DPPH radical scavenging and α-glucosidase inhibitory effects. In order to further explore their mechanism of α-glucosidase inhibition, their enzyme kinetics and in silico modeling experiments were performed. The results indicated that 1 inhibited α-glucosidase in a noncompetitive manner, whereas 2 acted in a competitive manner. In molecular docking, the stability of binding was enhanced by π-π T-shaped, π-alkyl, π-π stacked, hydrogen bond, and electrostatic interactions. Thus, compounds 1 and 2 were determined to be new potent antioxidant and α-glucosidase inhibitors for preventing food oxidation and enhancing hypoglycemic activity.
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Antioxidantes/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Mangifera/química , Semillas/química , alfa-Glucosidasas/metabolismo , Compuestos de Bifenilo/química , Depuradores de Radicales Libres/química , Cromatografía de Gases y Espectrometría de Masas , Cinética , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , Picratos/química , Extractos Vegetales/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Chinese patent medicine Zhixiong Capsule (ZXC) is the equal mixture of the extract of leech, Ligusticum chuanxiong Hort., Salvia miltiorrhiza Bunge, Leonurus japonicus Houtt., and Pueraria lobate (Willd.) Ohwi, which have been long used against inflammation, hyperlipidemia or blood stasis. In our previous study, ZXC showed good efficacy in preventing atherosclerosis (AS) plaque formation in rabbits. AIM OF THE STUDY: In actual clinic practice, patients are more likely to receive treatments after AS plaque formation. Therefore, the efficacy of ZXC on formed AS plaques and the underlying mechanisms were further investigated in this study. MATERIALS AND METHODS: Simvastatin (positive control) and ZXC (420 mg/kg and 840 mg/kg) were administrated to rats which first received long-term high fat diet administration (12 weeks). The blood lipid profiles of rats were monitored during the whole experiment, and the thoracic arteries were collected at the end of experiment for AS assessment (18th week). The blood-dissolved ZXC components were determined using an UPLC-QTOF-MS method, and the attained components were then used for network pharmacology analysis to predict the key ZXC components and targets. At last, the predicted targets were validated by ELISA and western blot methods. RESULTS: ZXC administration showed good blood lipid-lowering effect by significantly reduced LDL-C and TC levels in rats while significantly increased HDL-C level. Compared with model group, simvastatin, low- and high-dose of ZXC administration decreased the ratio of intimal area and medial area by 81.1%, 71.1% and 71.4%, respectively (p < 0.01), and significantly alleviated collagen deposition and mineralization in rat arteries. It was found by network pharmacology analysis that leech and four components (namely daidzein, 4-methylenemiltirone, isorhamnetin and 2-isopropyl-8-methylphenanthrene-3,4-dione) are vital components for the anti-AS efficacy of ZXC. Combing the results from biochemical validation, IL-4, IL-13, MAPK1, MAPK14, JUN and P53 were confirmed as key targets of ZXC. CONCLUSION: It could be concluded that ZXC has value as an anti-AS agent in clinical treatment against formed AS plaque at the current application dosage.
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Placa Aterosclerótica/tratamiento farmacológico , Arterias Torácicas/patología , Animales , Dieta Alta en Grasa/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Expresión Génica/efectos de los fármacos , Lípidos/sangre , Masculino , Ratas , Simvastatina/uso terapéuticoRESUMEN
Chronic renal failure (CRF) is a progressive disease with severe pruritus and dry skin as the major symptoms. However, the mechanisms of CRF-induced pruritus remain unclear. In this study, 5/6 nephrectomized (NPCT) mice were used as a mouse model of CRF. Serum concentrations of blood urea nitrogen and creatinine in 5/6 NPCT mice were increased. The stratum corneum water content in the skin of 5/6 NPCT mice was decreased. These findings suggest that 5/6 nephrectomy in mice results in a phenotype resembling human CRF. 5/6 NPCT mice showed spontaneous scratching, which was inhibited by µ-opioid receptor antagonist, suggesting that the scratching is an itch-related response. The number of cutaneous mast cells was not altered in 5/6 NPCT mice compared with sham-operated mice. The H1 histamine-receptor antagonist, proteinase-activated receptor 2-neutralizing antibody, and 5-HT3-receptor antagonist did not inhibit spontaneous scratching in 5/6 NPCT mice; therefore, the role of mast cells and serotonin in spontaneous scratching appears to be minimal. The anti-allergy agent azelastine, BLT leukotriene (LT) B4 receptor antagonist, and TP thromboxane (TX) A2 receptor antagonist inhibited spontaneous scratching in 5/6 NPCT mice, suggesting that LTB4 and TXA2 are involved in CRF-induced pruritus. Interestingly, in the skin of 5/6 NPCT mice, levels of two newly identified pruritogens (ß2-microglobulin and interleukin-31) were increased. Taken together, these findings suggest that 5/6 NPCT mice are useful for the study of itching in CRF. In addition to LTB4 and TXA2, it is also suggested that ß2-microglobulin and interleukin-31 are involved in itching associated with CRF-induced pruritus.
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Ácido Araquidónico/metabolismo , Globulinas/metabolismo , Interleucinas/metabolismo , Fallo Renal Crónico/metabolismo , Leucotrieno B4/metabolismo , Prurito/metabolismo , Tromboxano A2/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Ratones Endogámicos ICR , Antagonistas de Narcóticos/farmacologíaRESUMEN
BACKGROUND: Atopic dermatitis is a chronic and severe pruritic skin disease. Interlukin-31 (IL-31) has been recently demonstrated to be one of the key pruritogens in atopic dermatitis. However, the mechanisms underlying IL-31-induced itching remains unclear. In our previous study, we have shown that thromboxane (TX) A2 is involved in itch-associated responses in mice with atopy-like skin diseases. METHODS: IL-31 was given intradermally into the rostral back of ICR mice and the hind-paw scratching to the injection site were counted. Expression of TX synthase and IL-31 receptors were analyzed using immunohistochemical staining or RT-PCR in mouse skin or primary cultures of mouse keratinocytes. The concentration of TXB2, a metabolite of TXA2, in the skin and the culture medium of primary cultures of mouse keratinocytes was measured using enzyme immunoassay. The concentration of intracellular Ca2+ ions in mouse keratinocytes was measured using the calcium imaging method. RESULTS: An intradermal injection of IL-31 elicited scratching, an itch-related response, in mice. The scratching was inhibited by TP TXA2 receptor antagonist DCHCH. The distribution of TX synthase and IL-31RA receptor was mainly epidermal keratinocytes in the skin. The primary cultures of keratinocytes expressed the mRNAs of TX synthase and IL-31 receptors. IL-31 increased the concentration of TXB2, which was inhibited by TX synthase inhibitor sodium ozagrel and EGTA, in the skin and the culture medium of primary cultures of keratinocytes. IL-31 increased the concentration of intracellular Ca2+ ions in mouse keratinocytes. CONCLUSION: It is suggested that IL-31 elicits itch-associated responses through TXA2 produced from keratinocytes.
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Interleucinas/metabolismo , Prurito/metabolismo , Tromboxano A2/metabolismo , Animales , Calcio/metabolismo , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Piel/metabolismoRESUMEN
Uremic pruritus is an unpleasant symptom in patients undergoing hemodialysis, and the underlying mechanisms remain unclear. ß2-Microglobulin (ß2-MG) is well-known as an MHC class I molecule and its level is increased in the plasma of patients undergoing hemodialysis. In this study, we investigated whether ß2-MG was a pruritogen in mice. Intradermal injections of ß2-MG into the rostral back induced scratching in a dose-dependent manner. Intradermal injection of ß2-MG into the cheek also elicited scratching, but not wiping. ß2-MG-induced scratching was inhibited by the µ-opioid receptor antagonist naltrexone hydrochloride. ß2-MG-induced scratching was not inhibited by antagonists of itch-related receptors (e.g., H1 histamine receptor (terfenadine), TP thromboxane receptor (DCHCH), BLT1 leukotriene B4 receptor (CMHVA), and proteinase-activated receptor 2 (FSLLRY-NH2)). However, ß2-MG-induced scratching was attenuated in mice desensitized by repeated application of capsaicin and also by a selective transient receptor potential vanilloid 1 (TRPV1) antagonist (BCTC). In addition, ß2-MG induced phosphorylation of extracellular signal-regulated kinase (a marker of activated neurons) in primary culture of dorsal root ganglion neurons that expressed TRPV1. These results suggest that ß2-MG is a pruritogen and elicits itch-related responses, at least in part, through TRPV1-expressing primary sensory neurons.