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Dopaminergic neurons in the substantia nigra (SN) expressing SUR1/Kir6.2 type ATP-sensitive potassium channels (K-ATP) are more vulnerable to rotenone or metabolic stress, which may be an important reason for the selective degeneration of neurons in Parkinson's disease (PD). Baicalein has shown neuroprotective effects in PD animal models. In this study, we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells. K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp recording. Drugs dissolved in the external solution at the final concentration were directly pipetted onto the cells. We showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC50 values of 0.438 µM and 6.159 µM, respectively. K-ATP channel blockers glibenclamide (50 µM) or 5-hydroxydecanoate (5-HD, 250 µM) attenuated the protective effects of baicalein in reducing reactive oxygen species (ROS) content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells, suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP channels. Administration of baicalein (150, 300 mg·kg-1·d-1, i.g.) significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of rats. We conducted surface plasmon resonance assay and molecular docking, and found that baicalein had a higher affinity with SUR1 protein (KD = 10.39 µM) than glibenclamide (KD = 24.32 µM), thus reducing the sensitivity of K-ATP channels to rotenone. Knockdown of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells, confirming that SUR1 was an important target for slowing dopaminergic neuronal degeneration in PD. Taken together, we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.
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Flavanonas , Neuroblastoma , Canales de Potasio de Rectificación Interna , Humanos , Ratas , Animales , Canales KATP , Rotenona/farmacología , Receptores de Sulfonilureas , Canales de Potasio de Rectificación Interna/metabolismo , Gliburida/farmacología , Simulación del Acoplamiento Molecular , Apoptosis , Neuronas Dopaminérgicas/metabolismo , Adenosina Trifosfato/farmacologíaRESUMEN
Glioblastoma (GBM) is a major type of primary brain tumor without ideal prognosis and it is therefore necessary to develop a novel compound possessing therapeutic effects. Chrysomycin A (Chr-A) has been reported to inhibit the proliferation, migration and invasion of U251 and U87-MG cells through the Akt/GSK-3ß signaling pathway, but the mechanism of Chr-A against glioblastoma in vivo and whether Chr-A modulates the apoptosis of neuroglioma cells is unclear. The present study aims to elucidate the potential of Chr-A against glioblastoma in vivo and how Chr-A modulates the apoptosis of neuroglioma cells. Briefly, the anti-glioblastoma activity was assessed in human glioma U87 xenografted hairless mice. Chr-A-related targets were identified via RNA-sequencing. Apoptotic ratio and caspase 3/7 activity of U251 and U87-MG cells were assayed via flow cytometry. Apoptosis-related proteins and possible molecular mechanisms were validated via Western blotting. The results showed that Chr-A treatment significantly inhibits glioblastoma progression in xenografted hairless mice, and enrichment analysis suggested that apoptosis, PI3K-Akt and Wnt signaling pathways were involved in the possible mechanisms. Chr-A increased the apoptotic ratio and the activity of caspase 3/7 in U251 and U87-MG cells. Western blotting revealed that Chr-A disturbed the balance between Bax and Bcl-2, activating a caspase cascade reaction and downregulating the expression of p-Akt and p-GSK-3ß, suggesting that Chr-A may contribute to glioblastoma regression modulating in the Akt/GSK-3ß signaling pathway to promote apoptosis of neuroglioma cells in vivo and in vitro. Therefore, Chr-A may hold therapeutic promise for glioblastoma.
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Glioblastoma , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Caspasa 3/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Pelados , Proliferación Celular , Transducción de Señal , Apoptosis , Glioblastoma/patología , Línea Celular TumoralRESUMEN
Sileneophioglossa Huan C. Wang & Feng Yang, a new species of Caryophyllaceae, is here described and illustrated based on morphological and molecular evidence. The new species was found in Sichuan and Yunnan provinces, southwest China. Phylogenetic analysis based on ITS sequences showed this new species belongs to section Cucubaloides. Morphologically, it resembles S.phoenicodonta and S.viscidula, which were also found in the southwest China, but clearly differs from the latter two species by having 5-7 mm long calyces with sparsely hirtellous and short glandular hairs, white petals, linear limbs and lobes, and absent or oblong-linear coronal scales. A distribution map and a table with morphological diagnostic characters of new species and its closest relatives are provided, as well as a preliminary conservation assessment of S.ophioglossa under the IUCN criteria.
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Surgical resection is the most common approach for the treatment of osteosarcoma. However, two major complications, including residual tumor cells and large bone defects, often arise from the surgical resection of osteosarcoma. Discovering new strategies for programmatically solving the two above-mentioned puzzles has become a worldwide challenge. Herein, a novel one-step strategy is reported for natural phenolic acid planted nanohybrids with desired physicochemical properties and steerable photothermal effects for efficacious osteosarcoma suppression and bone healing. Nanohybrids are prepared based on the self-assembly of chlorogenic acid and gold nanorods through robust Au-catechol interface actions, featuring precise nanostructures, great water solubility, good stability, and adjustable hyperthermia generating capacity. As expected, on the one hand, these integrated nanohybrids can severely trigger apoptosis and suppress tumor growth with strong hyperthermia. On the other hand, with controllable mild NIR irradiation, the nanohybrids promote the expression of heat shock proteins and induce prominent osteogenic differentiation. This work initiates a brand-new strategy for assisting osteosarcoma surgical excision to resolve the blockage of residual tumor cells elimination and bone regeneration.
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Neoplasias Óseas , Hipertermia Inducida , Osteosarcoma , Humanos , Osteogénesis , Ácido Clorogénico/farmacología , Neoplasia Residual/terapia , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Regeneración Ósea , Neoplasias Óseas/tratamiento farmacológicoRESUMEN
BACKGROUND: Common walnut (Juglans regia L.) has a long cultivation history, given its highly valuable wood and rich nutritious nuts. The Iranian Plateau has been considered as one of the last glaciation refugia and a centre of origin and domestication for the common walnut. However, a prerequisite to conserve or utilize the genetic resources of J. regia in the plateau is a comprehensive evaluation of the genetic diversity that is conspicuously lacking. In this regard, we used 31 polymorphic simple sequence repeat (SSR) markers to delineate the genetic variation and population structure of 508 J. regia individuals among 27 populations from the Iranian Plateau. RESULTS: The SSR markers expressed a high level of genetic diversity (HO = 0.438, and HE = 0.437). Genetic differentiation among the populations was moderate (FST = 0.124), and genetic variation within the populations (79%) significantly surpassed among populations (21%). The gene flow (Nm = 1.840) may have remarkably influenced the population genetic structure of J. regia, which can be attributed to anthropological activities and wind dispersal of pollen. The STRUCTURE analysis divided the 27 populations into two main clusters. Comparing the neighbor-joining and principal coordinate analysis dendrograms and the Bayesian STRUCTURE analysis revealed the general agreement between the population subdivisions and the genetic relationships among the populations. However, a few geographically close populations dispersed into different clusters. Further, the low genetic diversity of the Sulaymaniyah (SMR) population of Iraq necessitates urgent conservation by propagation and seedling management or tissue culture methods; additionally, we recommend the indispensable preservation of the Gonabad (RGR) and Arak (AKR) populations in Iran. CONCLUSIONS: These results reflected consistent high geographical affinity of the accession across the plateau. Our findings suggest that gene flow is a driving factor influencing the genetic structure of J. regia populations, whereas ecological and geological variables did not act as strong barriers. Moreover, the data reported herein provide new insights into the population structure of J. regia germplasm, which will help conserve genetic resources for the future, hence improving walnut breeding programs' efficiency.
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Juglans , Juglans/genética , Nueces/genética , Irán , Teorema de Bayes , Fitomejoramiento , Variación GenéticaRESUMEN
Walnuts are highly valued for their rich nutritional profile and wide medicinal applications. This demand has led to the intensification of breeding activities in major walnut production areas such as southwest China, in order to develop more superior cultivars. With the increasing number of cultivars, accurate identification becomes fundamental to selecting the right cultivar for grafting, industrial processing or development of new cultivars. To ensure proper identification of cultivars and understand the genetic structure of wild and cultivated material, we genotyped 362 cultivated and wild individuals of walnut trees from southwest China (with two additional populations from Xinjiang, plus three cultivars from Canada, France and Belgium) using 36 polymorphic microsatellite loci. We found relatively low indices of genetic diversity (H O = 0.570, H E = 0.404, N A = 2.345) as well as a high level of clonality (>85% of cultivars), indicating reliance on genetically narrow sources of parental material for breeding. Our STRUCTURE and PCoA analyses generally delineated the two species, though considerable levels of introgression were also evident. More significantly, we detected a distinct genetic group of cultivated Juglans sigillata, which mainly comprised individuals of the popular 'Yangbidapao' landrace. Finally, a core set of 18 SSR loci was selected, which was capable of identifying 32 cultivars. In a nutshell, our results call for more utilization of genetically disparate material, including wild walnut trees, as parental sources to breed for more cultivars. The data reported herein will significantly contribute towards the genetic improvement and conservation of the walnut germplasm in southwest China.
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Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in the treatment of cerebral ischemia. First, network pharmacology analysis identified the biological process of kaempferol, suggesting that kaempferol may partly help in treating ischemic stroke by regulating apoptosis and inflammatory response. Then, we evaluated the efficacy of kaempferol in the acute stage of ischemic stroke and elucidated its effects and possible mechanisms on cell apoptosis and neuroinflammation involved by neutrophils. The results showed that kaempferol could significantly reduce the modified neurological severity score (mNSS), and reduce the volume of cerebral infarction and the degree of cerebral edema. In terms of anti-apoptosis, kaempferol could significantly reduce the number of TUNEL-positive cells, inhibit the expression of pro-apoptotic proteins and promote the expression of anti-apoptotic proteins. Kaempferol may play an anti-apoptotic role by up-regulating the expression level of the BDNF-TrkB-PI3K/AKT signaling pathway. In addition, we found that kaempferol inhibited neuron loss and the activation of glial cells, as well as the expression level of the inflammatory protein COX-2 and the classic pro-inflammatory signaling pathway TLR4/MyD88/NF-κB in the ischemic brain, reduced MPO activity and neutrophil counts in peripheral blood, and down-regulated neutrophil aggregation and infiltration in the ischemic brain. Western blot revealed that kaempferol down-regulated the activation of the JAK1/STAT3 signaling pathway in neutrophils and ischemic brains. Our study showed that kaempferol inhibited the activation and number of neutrophils in the rat peripheral blood and brain, which may be related to the down-regulation of the JAK1/STAT3 pathway.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Animales , Ratas , Quempferoles/farmacología , Quempferoles/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neutrófilos/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor Toll-Like 4/metabolismo , Ciclooxigenasa 2/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedades Neuroinflamatorias , Farmacología en Red , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
Chrysomycin A (Chr-A), an antibiotic from Streptomyces, is reported to have anti-tumor and anti-tuberculous activities, but its anti-glioblastoma activity and possible mechanism are not clear. Therefore, the current study was to investigate the mechanism of Chr-A against glioblastoma using U251 and U87-MG human cells. CCK8 assays, EdU-DNA synthesis assays and LDH assays were carried out to detect cell viability, proliferation and cytotoxicity of U251 and U87-MG cells, respectively. Transwell assays were performed to detect the invasion and migration abilities of glioblastoma cells. Western blot was used to validate the potential proteins. Chr-A treatment significantly inhibited the growth of glioblastoma cells and weakened the ability of cell migration and invasion by down regulating the expression of slug, MMP2 and MMP9. Furthermore, Chr-A also down regulated Akt, p-Akt, GSK-3ß, p-GSK-3ß and their downstream proteins, such as ß-catenin and c-Myc in human glioblastoma cells. In conclusion, Chr-A may inhibit the proliferation, migration and invasion of glioblastoma cells through the Akt/GSK-3ß/ß-catenin signaling pathway.
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Glioblastoma , beta Catenina , Aminoglicósidos , Antibacterianos/farmacología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , ADN/farmacología , Glioblastoma/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismoRESUMEN
Increasing severity of drought stress due to global change and extreme weather has been affecting the biodiversity, function, and stability of forest ecosystems. However, despite being an important component in the alpine and subalpine vegetation in forest ecosystems, Rhododendron species have been paid rare attention in the study of molecular mechanism of tolerance or response to drought. Herein, we investigated the correlation of transcriptomic changes with the physiological and biochemical indicators of Rhododendron rex under drought stress by using the co-expression network approach and regression analysis. Compared with the control treatment, the number of significantly differentially expressed unigenes (DEGs) increased with the degree of drought stress. The DEGs were mainly enriched in the cell wall metabolic process, signaling pathways, sugar metabolism, and nitrogen metabolism. Coupled analysis of the transcriptome, physiological, and biochemical parameters indicated that the metabolic pathways were highly correlated with the physiological and biochemical indicators under drought stress, especially the chlorophyll fluorescence parameters, such as the actual photosynthetic efficiency of photosystem II, electron transport rate, photochemical quenching coefficient, and the maximum quantum efficiency of photosystem II photochemistry. The majority of the response genes related to the metabolic pathways, including photosynthesis, sugar metabolism, and phytohormone signal pathway, were highly expressed under drought stress. In addition, genes associated with cell wall, pectin, and galacturonan metabolism also played crucial roles in the response of R. rex to drought stress. The results provided novel insight into the molecular response of the alpine woody species under drought stress and may improve the understanding of the response of forest ecosystems to the global climate change.
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Neuroinflammation characterized by microglia activation is the mechanism of the occurrence and development of various central nervous system diseases. ST2825, as a peptide-mimetic MyD88 homodimerization inhibitor, has been identified as crucial molecule with an anti-inflammatory role in several immune cells, especially microglia. The purpose of the study was to investigate the anti-neuroinflammatory effects and the possible mechanism of ST2825. Methods: Lipopolysaccharide (LPS) was used to stimulate neuroinflammation in male BALB/c mice and BV2 microglia cells. The NO level was determined by Griess Reagents. The levels of pro-inflammatory cytokines and chemokines were determined by ELISA. The expressions of inflammatory proteins were determined by real-time PCR and Western blotting analysis. The level of ROS was detected by DCFH-DA staining. Results: In vivo, the improved levels of LPS-induced pro-inflammatory factors, including TNF-α, IL-6, IL-1ß, MCP-1 and ICAM-1 in the cortex and hippocampus, were reduced after ST2825 treatment. In vitro, the levels of LPS-induced pro-inflammatory factors, including NO, TNF-α, IL-6, IL-1ß, MCP-1, iNOS, COX2 and ROS, were remarkably decreased after ST2825 treatment. Further research found that the mechanism of its anti-neuroinflammatory effects appeared to be associated with inhibition of NF-κB activation and down-regulation of the NLRP3/cleaved caspase-1 signaling pathway. Conclusions: The current findings provide new insights into the activity and molecular mechanism of ST2825 for the treatment of neuroinflammation.
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Lipopolisacáridos , FN-kappa B , Animales , Caspasa 1/metabolismo , Compuestos Heterocíclicos con 2 Anillos , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Microglía , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Compuestos de Espiro , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The mechanism underlying the hypoglycemic effect of the simultaneous use of metformin and anthocyanin-rich foods is not yet clear. Hence, the effects and possible mechanisms of action of these substances, alone and in combination, were evaluated in insulin-resistant HepG2 cells and a diabetic mouse model. The results indicated that anthocyanin and metformin had a significant synergistic effect on glucose consumption (CI < 0.9) compared with metformin alone in HepG2 cells. In the mouse model, combined treatment (50 and 100 mg/kg metformin + anthocyanin groups) demonstrated synergistic restorative effects on the blood glucose level, insulin resistance, and organ damage in the liver, pancreas, and ileum. Additionally, combined metformin and anthocyanin treatment suppressed protein tyrosine phosphatase 1B expression and regulated the PI3K/AKT/GSK3ß pathway. Combined treatment also altered the gut microbial composition and structure by increasing the relative abundance of beneficial bacteria and the short-chain fatty acid content. These results suggest that the use of anthocyanins can enhance the efficacy of metformin treatment for hyperglycemia and provide a reference for further clinical research regarding nutrition and supplementary treatment.
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Hiperglucemia , Resistencia a la Insulina , Metformina , Animales , Antocianinas , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Ratones , Fosfatidilinositol 3-QuinasasRESUMEN
TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1ß, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.
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Lipopolisacáridos , FN-kappa B , Línea Celular , Lipopolisacáridos/farmacología , Microglía/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Understanding the molecular mechanisms and evolutionary process of plant adaptation to the heterogeneous environment caused by altitude gradients in plateau mountain ecosystems can provide novel insight into species' responses to global changes. Flower color is the most conspicuous and highly diverse trait in nature. Herein, the gene expression patterns, evolutionary adaptation and metabolites changes of different-colored flowers of alpine Rhododendron L. species along altitude gradients were investigated based on a combined analysis of transcriptomics and metabolomics. Differentially expressed genes were found to be related to the biosynthesis of carbohydrates, fatty acids, amino acids and flavonoids, suggesting their important roles in the altitude adaptability of Rhododendron species. The evolution rate of high-altitude species was faster than that of low-altitude species. Genes related to DNA repair, mitogen-activated protein kinase and ABA signal transduction, and lipoic acid and propanoate metabolism were positively selected in the flowers of high-altitude Rhododendron species and those associated with carotenoid biosynthesis pathway, ABA signal transduction and ethylene signal transduction were positively selected in low-altitude species. These results indicated that the genes with differentiated expressions or functions exhibit varying evolution during the adaptive divergence of heterogeneous environment caused by altitude gradients. Flower-color variation might be attributed to the significant differences in gene expression or metabolites related to sucrose, flavonoids and carotenoids at the transcription or metabolism levels of Rhododendron species. This work suggests that Rhododendron species have multiple molecular mechanisms in their adaptation to changing environments caused by altitude gradients.
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Rhododendron , Altitud , Ecosistema , Flavonoides/metabolismo , Flores/genética , Flores/metabolismo , Metabolómica , Rhododendron/genética , Rhododendron/metabolismo , TranscriptomaRESUMEN
In this study, we determined the complete chloroplast genome of Cycas hongheensis (Cycadaceae), one of the first-class protected plants in China. The chloroplast genome is 162,048 bp in length with 133 genes, including 87 protein-coding genes, eight ribosomal RNA genes, and 37 transfer RNA genes. The overall GC content is 39.4%. Phylogenomic analysis showed that C. hongheensis as sister to all other Cycas species that with reported chloroplast genomes. The chloroplast genome of C. hongheensis reported here will contribute to further comparative chloroplast genome of Cycads and helpful to study the phylogeography of Cycadaceae.
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BACKGROUND: Aesculin (AES), an effective component of Cortex fraxini, is a hydroxycoumarin glucoside that has diverse biological properties. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing 3 (NLRP3) inflammasome has been heavily interwoven with the development of myocardial ischemia/reperfusion injury (MIRI). Nevertheless, it remains unclear whether AES makes a difference to the changes of the NLRP3 inflammasome in MIRI. PURPOSE: We used rats that were subjected to MIRI and neonatal rat cardiomyocytes (NRCMs) that underwent oxygen-glucose deprivation/restoration (OGD/R) process to investigate what impacts AES exerts on MIRI and the NLRP3 inflammasome activation. METHODS: The establishment of MIRI model in rats was conducted using the left anterior descending coronary artery ligation for 0.5 h ischemia and then untying the knot for 4 h of reperfusion. After reperfusion, AES were administered intraperitoneally using 10 and 30 mg/kg doses. We evaluated the development of reperfusion ventricular arrhythmias, hemodynamic changes, infarct size, and the biomarkers in myocardial injury. The inflammatory mediators and pyroptosis were also assessed. AES at the concentrations of 1, 3, and 10 µM were imposed on the NRCMs immediately before the restoration process. We also determined the cell viability and cell death in the NRCMs exposed to OGD/R insult. Furthermore, we also analyzed the levels of proteins that affect the NLRP3 inflammasome activation, pyroptosis, and the AKT serine/threonine kinase (Akt)/glycogen synthase kinase 3 beta (GSK3ß)/nuclear factor-kappa B (NF-κB) signaling pathway via western blotting. RESULTS: We found that AES notably attenuated reperfusion arrhythmias and myocardia damage, improved the hemodynamic function, and ameliorated the inflammatory response and pyroptosis of cardiomyocytes in rats and NRCMs. Additionally, AES reduced the NLRP3 inflammasome activation in rats and NRCMs. AES also enhanced the phosphorylation of Akt and GSK3ß, while suppressing the phosphorylation of NF-κB. Moreover, the allosteric Akt inhibitor, MK-2206, abolished the AES-mediated cardioprotection and the NLRP3 inflammasome suppression. CONCLUSIONS: These findings indicate that AES effectively protected cardiomyocytes against MIRI by suppressing the NLRP3 inflammasome-mediated pyroptosis, which may relate to the upregulated Akt activation and disruption of the GSK3ß/NF-κB pathway.
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Inflamasomas , Daño por Reperfusión Miocárdica , Animales , Esculina , Glucógeno Sintasa Quinasa 3 , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Proto-Oncogénicas c-akt , Piroptosis , RatasRESUMEN
RKC-B1 is a novel fermentation product obtained from the marine micromonospora FIM02-523A. Thus far, there have been few reports about the pharmacological activity of RKC-B1. In our present study, we investigated the anti-neuroinflammatory effects and the possible mechanism of RKC-B1 in LPS-stimulated mice. After treatment with RKC-B1, RNA-seq transcriptome of the cerebral cortex tissue was conducted to find the differentially expressed genes (DEGs). Inflammatory cytokines and proteins were evaluated by ELISA and WB. In RNA-seq analysis, there were 193 genes screened as core genes of RKC-B1 for treatment with neuroinflammation. The significant KEGG enrichment signaling pathways of these core genes were mainly included TNF signaling pathway, IL-17 signaling pathway, NOD-like receptor signaling pathway, NF-κB signaling pathway and others. The corresponding top five KEGG enrichment pathways of three main clusters in PPI network of core genes were closely related to human immune system and immune disease. The results showed that RKC-B1 reduced the levels of pro-inflammatory factors (IL-6, IL-1ß, MCP-1, and ICAM-1) and the expression of COX2 in cerebral cortex tissue. Additionally, we found that the anti-neuroinflammation activity of RKC-B1 might be related to suppress activating of NF-κB and NLRP3/cleaved caspase-1 signaling pathways. The current findings suggested that RKC-B1 might be a promising anti-neuroinflammatory agent.
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Antiinflamatorios/farmacología , Organismos Acuáticos , Microglía , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Transducción de Señal/efectos de los fármacosRESUMEN
Chrysomycin A (Chr-A), an antibiotic chrysomycin, was discovered in 1955 and is used to treat cancer and tuberculosis. In the present study, the anti-neuroinflammatory effects and possible mechanism of Chr-A in BALB/c mice and in BV2 microglia cells stimulated by lipopolysaccharide (LPS) were investigated. Firstly, the cortex tissues of mice were analyzed by RNA-seq transcriptome to identify differentially expressed genes (DEGs) regulated by Chr-A in LPS-stimulated mice. Inflammatory cytokines and inflammatory proteins were detected by enzyme-linked immunosorbent assay and Western blot. In RNAseq detection, 639 differential up-regulated genes between the control group and LPS model group and 113 differential down-regulated genes between the LPS model group and Chr-A treatment group were found, and 70 overlapping genes were identified as key genes for Chr-A against neuroinflammation. Subsequent GO biological process enrichment analysis showed that the anti-neuroinflammatory effect of Chr-A might be related to the response to cytokine, cellular response to cytokine stimulus, and regulation of immune system process. The significant signaling pathways of KEGG enrichment analysis were mainly involved in TNF signaling pathway, cytokine-cytokine receptor interaction, NF-κB signaling pathway, IL-17 signaling pathway and NOD-like receptor signaling pathway. Our results of in vivo or in vitro experiments showed that the levels of pro-inflammatory factors including NO, IL-6, IL-1ß, IL-17, TNF-α, MCP-1, CXCL12, GM-CSF and COX2 in the LPS-stimulated group were higher than those in the control group, while Chr-A reversed those conditions. Furthermore, the Western blot analysis showed that its anti-neuroinflammation appeared to be related to the down-regulation of NLRP3/cleaved caspase-1 signaling pathway. The current findings provide new insights into the activity and molecular mechanisms of Chr-A for the treatment of neuroinflammation.
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Aminoglicósidos/farmacología , Caspasa 1/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamación Neurogénica/metabolismo , Transducción de Señal/efectos de los fármacos , Aminoglicósidos/química , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/inmunología , Ratones , Microglía/inmunología , Estructura Molecular , Inflamación Neurogénica/etiología , Proteolisis , TranscriptomaRESUMEN
Trachycarpus nanus is an endangered plant that is endemic to southwest of China. In the present study, the complete chloroplast genome of this species was assembled and characterized using whole genome next-generation sequencing. The complete chloroplast genome showed a circular genome of 158,713 bp size with 36.6% GC content. The genome is of typical structure and contain a pair of inverted repeat (IR) regions with 27,240 bp, separated by one large single-copy (LSC) with 86,395 bp, and one small single-copy (SSC) regions with 17,838 bp. The genome contained 132 genes, including 86 protein-coding genes, 8 rRNA genes and 38 tRNA genes. A phylogenetic tree reconstructed based on 21 chloroplast genomes reveals that Trachycarpus nanus is most related with Chamaerops humilis. The information provides important genetic basis for the species' future studies on phylogenetic and utilization.