RESUMO
BACKGROUND: The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases tumor cell survival and growth. The molecular events controlling mitochondrial integrity that facilitate the development of hepatocellular carcinoma (HCC) remain unclear. Here, we report that UBX domain-containing protein 1 (UBXN1) hyperactivation is essential for mitochondrial homeostasis and liver tumorigenesis. METHODS: Oncogene-induced mouse liver tumor models were generated with the Sleeping Beauty (SB) transposon delivery system. Assessment of HCC cell growth in vivo and in vitro, including tumour formation, colony formation, TUNEL and FACS assays, was conducted to determine the effects of UBXN1 on HCC cells, as well as the involvement of the UBXN1-prohibitin (PHB) interaction in mitochondrial function. Coimmunoprecipitation (Co-IP) was used to assess the interaction between UBXN1 and PHB. Liver hepatocellular carcinoma (LIHC) datasets and HCC patient samples were used to assess the expression of UBXN1. RESULTS: UBXN1 expression is commonly upregulated in human HCCs and mouse liver tumors and is associated with poor overall survival in HCC patients. UBXN1 facilitates the growth of human HCC cells and promotes mouse liver tumorigenesis driven by the NRas/c-Myc or c-Myc/shp53 combination. UBXN1 interacts with the inner mitochondrial membrane protein PHB and sustains PHB expression. UBXN1 inhibition triggers mitochondrial damage and liver tumor cell apoptosis. CONCLUSIONS: UBXN1 interacts with PHB and promotes mitochondrial homeostasis during liver tumorigenesis.
Assuntos
Carcinogênese , Carcinoma Hepatocelular , Homeostase , Neoplasias Hepáticas , Mitocôndrias , Proibitinas , Animais , Humanos , Camundongos , Apoptose , Carcinogênese/patologia , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Mitocôndrias/metabolismo , Ligação Proteica , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND AND AIMS: Liver tumorigenesis encompasses oncogenic activation and self-adaptation of various biological processes in premalignant hepatocytes to circumvent the pressure of cellular stress and host immune control. Ubiquitin regulatory X domain-containing proteins (UBXNs) participate in the regulation of certain signaling pathways. However, whether UBXN proteins function in the development of liver cancer remains unclear. APPROACH AND RESULTS: Here, we demonstrated that UBXN9 (Alveolar Soft Part Sarcoma Chromosomal Region Candidate Gene 1 Protein/Alveolar Soft Part Sarcoma Locus) expression was decreased in autochthonous oncogene-induced mouse liver tumors and ~47.7% of human HCCs, and associated with poor prognosis in patients with HCC. UBXN9 attenuated liver tumorigenesis induced by different oncogenic factors and tumor growth of transplanted liver tumor cells in immuno-competent mice. Mechanistically, UBXN9 significantly inhibited the function of the RNA exosome, resulting in increased expression of RLR-stimulatory RNAs and activation of the retinoic acid-inducible gene-I-IFN-Ι signaling in tumor cells, and hence potentiated T cell recruitment and immune control of tumor growth. Abrogation of the CD8 + T cell response or inhibition of tumor cell retinoic acid-inducible gene-I signaling efficiently counteracted the UBXN9-mediated suppression of liver tumor growth. CONCLUSIONS: Our results reveal a modality in which UBXN9 promotes the stimulatory RNA-induced retinoic acid-inducible gene-I-interferon signaling that induces anti-tumor T cell response in liver tumorigenesis. Targeted manipulation of the UBXN9-RNA exosome circuit may have the potential to reinstate the immune control of liver tumor growth.
RESUMO
BACKGROUND: Fibroblast growth factor receptor (FGFR)2 expression was decreased in hypertension patients while its role in hypertension was not explored. This experiment aimed to investigate the expression ofFGFR2 in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs) and the role of FGFR2 in improving AngII-induced hypertension-related endothelial dysfunction. METHODS: AngII-induced HUVECs simulated the hypertension model in vitro. The expression of FGFR2 in Ang II-induced HUVECs and transfected HUVECswas detected by RT-qPCR and western blot. The viability, apoptosis, migration and tube formation ability of Ang II-induced HUVECs were analyzed by Methyl Thiazolyl Tetrazolium (MTT) assay, flow cytometry analysis, wound healing assay and tube formation assay.Detectionof lactate dehydrogenase (LDH), caspase 3, Nitric Oxide (NO) and oxidative stress levels was conducted by assay kits and reactive oxygen species (ROS) level was detected by DCFH-DA assay. The expression of apoptosis-related proteins, protein kinase B(Akt)/nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway-related proteins, phospho(p)-endothelial nitric oxide synthase (eNOS) and eNOS was determined by western blot. RESULTS: The expression of FGFR2 was decreased in Ang II-induced HUVECs. FGFR2overexpression increased viability, suppressed apoptosis and oxidative stress, and improve endothelial dysfunction of AngII-induced HUVECs through activating the Akt/Nrf2/ARE signaling pathway. MK-2206 (Akt inhibitor) could weaken the effect of FGFR2overexpression to reduce viability, promote apoptosis and oxidative stress, and aggravate endothelial dysfunction of Ang II-inducedHUVECs. CONCLUSION: Inconclusion, FGFR2activated the Akt/Nrf2/ARE signaling pathway to improve AngII-induced hypertension-related endothelial dysfunction.
Assuntos
Hipertensão , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/genética , Angiotensina II/farmacologia , Elementos de Resposta Antioxidante , Transdução de Sinais , Estresse Oxidativo , Células Endoteliais da Veia Umbilical Humana , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Óxido Nítrico Sintase Tipo III/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
A novel Gram-stain-negative, aerobic strain, designated Y22T, was isolated from peanut field soil in Laoshan Mountain in China. Cells of strain Y22T were rod-shaped and motile by a single flagellum. The strain was found to be oxidase- and catalase-positive. 16S rRNA gene sequence based on phylogenetic analysis indicated that strain Y22T belonged to the genus Pseudomonas, and showed the highest 16S rRNA gene sequence similarity of 99.0% to Pseudomonas pelagia JCM 15562T, followed by Pseudomonas salina JCM 19469T (98.4%), Pseudomonas sabulinigri JCM 14963T (97.9%), Pseudomonas bauzanensis CGMCC 1.9095T (97.6%) and Pseudomonas litoralis KCTC23093T (97.5%). The phylogenetic analysis based on multilocus sequence analyses with concatenated 16S rRNA, gyrB, rpoD and rpoB genes indicated that strain Y22T belonged to Pseudomonas pertucinogena lineage. The average nucleotide identity scores between strain Y22T and closely related species were 74.6-82.8%, and the Genome-to-Genome Distance Calculator scores were 16.4-44.9%. The predominant cellular fatty acids of strain Y22T were C18:1ω7c (29.6%), C17:0 cyclo (17.5%) and summed feature 3 (C16:1ω7c and/or C16:1ω6c) (17.4%). The genomic DNA G+C content was 57.9 mol%. On the basis of phenotypic characteristics, phylogenetic analyses and in silico DNA-DNA relatedness, a novel species, Pseudomonas laoshanensis sp. nov. is proposed. The type strain is Y22T (= JCM 32580T = KCTC 62385T = CGMCC 1.16552T).
Assuntos
Filogenia , Pseudomonas/classificação , Microbiologia do Solo , Arachis , China , Genes Bacterianos/genética , Pseudomonas/genética , RNA Ribossômico 16S/genética , Especificidade da EspécieRESUMO
Homogeneous graphene dispersions with tunable concentrations are fundamental prerequisites for the preparation of graphene-based materials. Here, a strategy for effectively dispersing graphene using graphene oxide (GO) to produce homogeneous, tunable, and ultrahigh concentration graphene dispersions (>150 mg mL-1 ) is proposed. The structure of GO with abundant edge-bound hydrophilic carboxyl groups and in-plane hydrophobic π-conjugated domains allows it to function as a special "surfactant" that enables graphene dispersion. In acidic solutions, GO sheets tend to form edge-to-edge hydrogen bonds and expose the π-conjugated regions which interact with graphene, thereby promoting graphene dispersion. While in alkaline solutions, GO sheets tend to stack in a surface-to-surface manner, thereby blocking the π-conjugated regions and impeding graphene dispersion. As the concentration of GO-dispersed graphene dispersion (GO/G) increases, a continuous transition between four states is obtained, including a dilute dispersion, a thick paste, a free-standing gel, and a kneadable, playdough-like material. Furthermore, GO/G can be applied to create desirable structures including highly conductive graphene films with excellent flexibility, thereby demonstrating an immense potential in flexible composite materials.
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Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasm. Down-regulation of hsa-microRNA-378 (miR-378) has been proved in OSCC tissues, suggesting that miR-378 might play crucial roles in the progression of OSCC. The present study aimed to evaluate the effect of miR-378-3p/5p on the proliferation and apoptosis of OSCC in vitro and in vivo. According to the results, lentivirus-mediated overexpression of miR-378 lowered the colony formation efficiency, blocked cell cycle progression, and decreased the percentage of Ki-67 positive cells, whereas knockdown of miR-378-3p/5p led to the opposite results. Furthermore, the apoptosis of OSCC cells was induced by the overexpression of miR-378 as evidenced by decreasing Bcl-2/Bax ratio, increasing cleaved caspase-9, cleaved caspase-3, and cleaved PARP levels, and promoting the release of cytochrome c into the cytoplasm. However, the above results were reversed by miR-378-3p/5p silencing. In addition, the overexpression of miR-378 inhibited the activation of PI3K/AKT signalling pathway. Conversely, miR-378-3p/5p knockdown resulted in the inactivation of PI3K/AKT signalling pathway. Mechanically, we validated that miR-378-3p/5p could target kallikrein-related peptidase 4 (KLK4), and enforced overexpression of KLK4 counteracted miR-378 overexpression-induced apoptosis. Finally, tumourigenesis in nude mice was suppressed by the overexpression of miR-378, which was promoted by miR-378-3p/5p silencing. Taken together, these results suggest that miR-378 may be a potential target in the diagnoses and treatment of OSCC.
Assuntos
Apoptose/genética , Calicreínas/genética , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Ischemic stroke is a global disease with high disability and mortality rates. Cognitive impairment is one of the major clinical features of ischemic stroke, and microglia-mediated inflammation has been shown to be an important contributor to the pathogenesis of ischemic stroke. Kellerin, extracted from Ferula sinkiangensis, was previously shown to inhibit microglial activation and exert a strong anti-neuroinflammatory effect. However, there is no report of the potential therapeutic effect of kellerin on ischemic stroke by targeting microglial cells. In this study, we wanted to examine the effects of kellerin on ischemic stroke in the bilateral common carotid artery occlusion (BCCAO) model and the lipopolysaccharide (LPS)-activated microglia model. We found that kellerin alleviated cognitive impairment, decreased neuronal loss, suppressed microglial activation, and transformed microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype in BCCAO mice. Moreover, in in vitro studies, we found that kellerin regulated microglial polarization and inhibited the NLRP3 and MAPK signaling pathways after LPS treatment. These findings provide a new understanding of the function of kellerin in ischemic stroke, and suggest that kellerin could be a potential therapeutic agent for the treatment of ischemic stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Memória de Curto Prazo/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Lipopolissacarídeos/farmacologia , Masculino , CamundongosRESUMO
BACKGROUND: Microglia, the mononuclear immune cells of the central nervous system (CNS), are essential for the maintenance of CNS homeostasis. BAP31, a resident and ubiquitously expressed protein of the endoplasmic reticulum, serves as a sorting factor for its client proteins, mediating the subsequent export, retention, and degradation or survival. Recently, BAP31 has been defined as a regulatory molecule in the CNS, but the function of BAP31 in microglia has yet to be determined. In the present study, we investigated whether BAP31 is involved in the inflammatory response of microglia. METHODS: This study used the BV2 cell line and BAP31 conditional knockdown mice generated via the Cre/LoxP system. A BAP31 knockdown experiment was performed to elucidate the role of BAP31 in the endogenous inflammatory cytokine production by microglial BV2 cells. A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effect of BAP31 against neuroinflammation-induced memory deficits. Behavioral alterations were assessed with the open field test (OFT), Y maze, and Morris water maze. The activation of microglia in the hippocampus of mice was observed by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and reverse transcription quantitative real-time polymerase chain reaction (RT-PCR) were used to clarify the mechanisms. RESULTS: BAP31 deficiency upregulates LPS-induced proinflammatory cytokines in BV2 cells and mice by upregulating the protein level of IRAK1, which in turn increases the translocation and transcriptional activity of NF-κB p65 and c-Jun, and moreover, knockdown of IRAK1 or use of an IRAK1 inhibitor reverses these functions. In the cognitive impairment animal model, the BAP31 knockdown mice displayed increased severity in memory deficiency accompanied by an increased expression of proinflammatory factors in the hippocampus. CONCLUSIONS: These findings indicate that BAP31 may modulate inflammatory cytokines and cognitive impairment induced by neuroinflammation through IRAK1, which demonstrates that BAP31 plays an essential role in microglial inflammation and prevention of memory deficits caused by neuroinflammation.
Assuntos
Encefalite/metabolismo , Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Encefalite/induzido quimicamente , Encefalite/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Endplate inflammation remains a difficult disease to treat, in part due to its unclear pathology. Previous experiments showed that patients with idiopathic inflammation presented a systemic upregulation of Th17 cells. Here, we investigated how this change might affect the inflammatory environment in endplate inflammation. METHODS: Peripheral blood was obtained from patients and healthy controls, and Th17 cells were examined. RESULTS: Th17 cells significantly increased the differentiation of CD11c+ and DC-SIGN+ dendritic cells (DCs) from circulating monocytes in the absence of exogenous stimulation as well as in the presence of LPS stimulation. Th17 cells also increased CD80 and CD86 expression by DCs. Importantly, although Th17 cells from both healthy controls and patients with endplate inflammation could induce CD11c, DC-SIGN, CD80, and CD86 expression, Th17 cells from patients with endplate inflammation showed significantly more potent capacity. Both contact-dependent and IL-17-dependent mechanisms were employed by Th17 cells, since blocking cell-to-cell contact significantly inhibited Th17-mediated differentiation of CD11c+ DCs, and neutralization of IL-17 reduced the expression of CD80 and CD86. Strikingly, DCs following incubation with Th17 cells, but not the DCs derived directly from monocytes without Th17 cells, could significantly promote the expression of IL-17 from naive CD4+ T cells. CONCLUSIONS: These results demonstrated that Th17 cells from patients with endplate inflammation could potently induce the differentiation and activation of DCs that preferentially promoted IL-17 response in a positive feedback loop.
Assuntos
Células Dendríticas/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Osteoartrite da Coluna Vertebral/imunologia , Células Th17/imunologia , Adulto , Antígeno CD11c/metabolismo , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Células Cultivadas , Retroalimentação Fisiológica , Feminino , Humanos , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/metabolismoRESUMO
Endplate inflammation remains a difficult task to diagnose and treat, partly due to the absence of in-depth understanding of the cellular and molecular factors driving this condition. In the current study, we investigated the circulating immune cells in patients with idiopathic endplate inflammation. Compared to healthy controls, the patients with endplate inflammation presented a significant upregulation of Th17 cells, characterized by higher frequencies of circulating IL-17+CD4+ T cells examined directly ex vivo and after PMA and ionomycin (PMA/I) stimulation. The frequency of Th17 cells in patients was not correlated with patient age, sex, or smoking status, but was significantly correlated with patient BMI. The total CD4+ T cells from patients with end plate inflammation also presented significantly higher levels of IL-17 secretion directly ex vivo and after PMA/I stimulation. The IL-17 secretion was primarily mediated by CCR4+CCR6+ CD4+ T cells, followed by CCR4-CCR6+ CD4+ T cells and was nearly absent in CCR4-CCR6- CD4+ T cells. Monocytes incubated with CCR4+CCR6+ CD4+ T cells presented significantly higher MHC class II expression, as well as higher CD80 and CD86 expression. The secretion of IL-6 and TNF was significantly higher in cell cultures containing CCR4+CCR6+ CD4+ T cells than in cell cultures containing CCR4-CCR6- CD4+ T cells. These effects were reduced when the IL-17A cytokine was neutralized. Together, we identified a systemic upregulation of Th17 responses that could contribute to proinflammatory monocyte activation in patients with endplate inflammation.
Assuntos
Inflamação/metabolismo , Monócitos/imunologia , Células Th17/imunologia , Adulto , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Inflamação/imunologia , Interleucina-17/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Isofraxetin-6-O-ß-d-glucopyranoside, identified from traditional medicinal herbal Xanthoceras sorbifolia Bunge, has been demonstrated to be a natural neuroinflammatory inhibitor. In order to obtain more derivatives with potential anti-neuroinflammatory effects, biotransformation was carried out. According to the characteristics of coumarin skeleton, suspension cultures of Angelica sinensis (Oliv.) Diels callus (A. sinensis callus) were employed because of the presence of diverse phenylpropanoids biosynthetic enzymes. As a result, 15 products were yielded from the suspension cultures, including a new coumarin: 8'-dehydroxymethyl cleomiscosin A (1), together with 14 known compounds. Their structures were elucidated by extensive spectroscopic analysis. Furthermore, the biotransformed pathways were discussed. Among them, compound 13 was transformed from isofraxetin-6-O-ß-d-glucopyranoside, while compounds 1-6, 10-12, 14-15 were derived from the culture medium stimulated by the substrate. The biotransformation processes include hydroxylation, oxidation and esterification. Furthermore, their inhibitory effects on lipopolysaccharide (LPS)-activated nitric oxide (NO) production were evaluated in BV2 microglial cells. It is worth noting that, 1, 1'-methanediylbis(4-methoxybenzene) (3), obtucarbamates A (5), 2-nonyl-4-hydroxyquinoline N-oxide (10) and 1H-indole-3-carbaldehyde (11) exhibited significant inhibitory effect against neuroinflammation with IC50 values at 1.22, 10.57, 1.02 and 0.76µM respectively, much stronger than that of the positive control minocycline (IC50 35.82µM).
Assuntos
Angelica sinensis/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Animais , Anti-Inflamatórios/química , Biotransformação , Linhagem Celular , Cumarínicos/química , Relação Dose-Resposta a Droga , Glucosídeos/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-AtividadeRESUMO
Neuroinflammation is a key contributor to neuronal damage in neurodegenerative diseases. In our previous work on natural effective neuroinflammatory inhibitors, Alhagi sparsifolia Shap. (Leguminosae), a folk medicine widely distributed in Xinjiang, attracted our attention because of its significant anti-neuroinflammatory effect. Therefore, further investigation of the bioactive material basis was carried out. As a result, 33 major components were characterized and identified by chromatographic and spectral methods, respectively. Furthermore, the anti-neuroinflammatory effects of the extract and purified constituents were evaluated in LPS-induced N9 cells in vitro. The results displayed that compounds 1, 2, 3, 5, 6, 8, 11, 15, 16, 17, 22, 23, 25, 26, 28, 30, 33 could exhibit significant inhibitory activities without obvious cytotoxicities at their effective concentrations. Especially, isorhamnetin (1) (IC50 17.87µM), quercetin (2) (10.22µM), 3',7-dihydroxyl-4'-methoxylisoflavone (5) (17.43µM), 3',7-dihydroxyl-4',6-dimethoxylisoflavone (6) (11.21µM), syringgaresinol (16) (2.68µM), bombasinol A (17) (7.61µM), aurantiamide (23) (14.91µM) and 1,3,3,4-tetramethyl cyclopentene (33) (2.63µM) showed much stronger inhibiting effect than that of the positive control minocycline (19.89µM). Therefore, the effective compositions might be responsible for the significant neuroinflammation inhibitory activities exhibited by the herb. Moreover, compounds 16 and 33 could be good leading compounds for the development of potential therapeutic agents against neurodegenerative diseases.
Assuntos
Fabaceae/química , Inflamação/prevenção & controle , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Linhagem Celular , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Microglia/patologia , Fármacos Neuroprotetores/química , Extratos Vegetais/químicaRESUMO
Neuroinflammation mediated by microglia cells plays a critical role in the development of Alzheimer's disease. To identify novel natural neuroinflammation inhibitors, a bioactivity-guided phytochemical research was performed on the traditional Chinese medicine "Awei", that exhibited a significant inhibitory effect on nitric oxide production in over-activated microglia cells. The research identified sixteen bioactive sesquiterpene coumarins (two new and fourteen known ones) in the effective extract of Ferula sinkiangensis. Further, the anti-neuroinflammatory activities in BV-2 microglial cells were evaluated by monitoring LPS-induced nitric oxide production. In conclusion, the major constituent, (3'S, 5'S, 8'R, 9'S, 10'R)-kellerin (1.5â%, w/w), should be responsible for the anti-neuroinflammatory effect exhibited by Awei. Furthermore, it might be a potential natural therapeutic agent for Alzheimer's disease. The research indicated moreover, that its primary mechanism is the inhibition of mRNA expression of the inflammatory cytokines nitric oxide, tumor necrosis factor-α, cyclooxygenase-2, interleukin-6 and interleukin-1ß.
Assuntos
Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Ferula/química , Fármacos Neuroprotetores/farmacologia , Resinas Vegetais/química , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Cumarínicos/química , Cumarínicos/isolamento & purificação , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Camundongos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Óxido Nítrico/metabolismo , RNA Mensageiro/genética , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
Numerous studies have found that the age-associated structural and functional alterations in arteries were characterized by increased endothelial dysfunction. In this study, young (3 months), adult (9 months), and aging (20 months) male Sprague-Dawley rats were randomly divided into 6 groups, including control groups and FeTMPyP (peroxynitrite scavenger) groups receiving saline and FeTMPyP, respectively, for 5 administrations once every 3 days through intraperitoneal injection. The aged-related proteins beta-galactosidase, p53, and p16 as well as the nitrotyrosine and endothelial marker endothelial nitric oxide synthase and von Willebrand factor (vWF) in vascular tissues were measured by immunohistochemistry. Endothelium-dependent vasorelaxation and endothelium-independent vasorelaxation of rat thoracic aortas and mesenteric arteries were measured by acetylcholine and sodium nitroprusside, respectively. The amount of circulating endothelial progenitor cells (EPCs) was determined by flow cytometry. The endothelium-dependent/independent relaxation in mesenteric arteries and the amount of circulating EPCs (CD31/CD34) in peripheral blood of aging rats were reduced significantly compared with young and adult rats. Immunohistochemistry results showed that the nitrotyrosine levels and morphological damage in mesenteric arteries were increased significantly in aging rats. Adoption of peroxynitrite scavenger FeTMPyP intervention may not only improve the endothelium-dependent relaxation and the amount of circulating EPCs in aging rats but also reverse endothelial injury. In conclusion, this study demonstrates that enhanced nitrative stress may aggravate the endothelial injury and vascular dysfunction of resistance arteries in aging rats. Antiperoxynitrite treatment can ameliorate the vasorelaxation and may be involved with the protection of circulating EPCs.
Assuntos
Envelhecimento/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Ácido Peroxinitroso/antagonistas & inibidores , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/fisiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Metaloporfirinas/farmacologia , Técnicas de Cultura de Órgãos , Ácido Peroxinitroso/biossíntese , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Resistência Vascular/fisiologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
Vitamin K1 is used as a liver protection drug for cholestasis-induced liver fibrosis in China, but the mechanism of vitamin K1's action in liver fibrosis is unclear. In this study, a model of liver fibrosis was achieved via bile duct ligation in rats. The rats were then injected with vitamin K1, and the levels of serum aspartate aminotransferase, alanine transaminase, total bilirubin and the fibrotic grade score, collagen content, the expressions of α-smooth muscle actin (SMA) and cytokeratin 19 (CK19) were measured on day 28 after ligation. The levels of the biochemical parameters, fibrotic score and collagen content were significantly reduced by treatment with vitamin K1 in bile duct-ligated rats. In addition, α-SMA and CK19 expression was significantly reduced by vitamin K1 treatment in bile duct-ligated rats. These results suggested that vitamin K1 may attenuate liver fibrosis by inhibiting hepatic stellate cell activation in bile duct-ligated rats.
Assuntos
Cirrose Hepática/prevenção & controle , Fígado/patologia , Substâncias Protetoras/uso terapêutico , Vitamina K 1/uso terapêutico , Actinas/análise , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Ductos Biliares/cirurgia , Bilirrubina/sangue , Colágeno/análise , Modelos Animais de Doenças , Queratina-19/análise , Ligadura/efeitos adversos , Fígado/química , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Electrospinning is a widely recognized method for producing Janus or core-shell nanofibers. In this study, nanofibrous membranes were fabricated through co-axial electrospinning utilizing polycaprolactone (PCL) and silk fibroin (SF) as the Janus shell, and taxifolin (TAX) and SF as the core. The resulting nanofibers had diameters of 816 ± 161 nm and core diameters of 73 ± 5 nm. The morphology and properties of the PCL-SF@SF/TAX nanofibers were subsequently analyzed. The results demonstrated that the nanofibrous membranes achieved physical and chemical characteristics potential for tissue engineering and drug delivery. Specifically, the membranes exhibited a Young's modulus of 9.64 ± 0.29 MPa, a water contact angle of 79.1 ± 1.3°, and a weight loss of 17.3 ± 1.0 % over a period of 28 days. The incorporation of TAX endowed the membranes with antibacterial properties, effectively combating Escherichia coli and Staphylococcus aureus. Furthermore, the membranes demonstrated antioxidant capabilities, with a DPPH radical scavenging efficiency of 38.5 ± 5.6 % and a Trolox-equivalent antioxidant capacity of 0.24 ± 0.01 mM. The release of the antioxidant was sustained over 28 days, following first-order release kinetics. The nanofibrous membranes, referred to as PSST, exhibit promising potential for use as biomaterials, characterized by their antibacterial activity, antioxidant and cytocompatibility.
RESUMO
Pore type and pore structure evolves systematically across continuous black shale weathering profile. However, the extend and process of pore structure change is still an enigma. In this study, we try to unveil the pore structure evolution during weathering process through studying Cambrian Hetang shales in southern China. Fourteen shale samples, from protolith zone (PZ), fractured and weathered shale zone (FWZ), and saprolite zone (SZ), were collected to elucidate how porosity and pore structure develop during black shale weathering under subtropical condition. Through low pressure argon (Ar) gas adsorption (LP-ArGA), high pressure mercury intrusion (HPMI), nuclear magnetic resonance(NMR) and field emission scanning electron microscope (FESEM) observation, the results reveal significant differences in physical properties and pore structures among the PZ, FWZ, and SZ samples. Specifically, compared to PZ, FWZ and SZ samples are characterized by higher clay mineral content, lower organic matter (OM), and the absence of carbonates and pyrite. Total porosity, determined through HPMI and NMR, exhibits a gradual increase from PZ (6.70 % and 6.41 %) to FWZ (20.47 % and 13.45 %) and SZ (23.22 % and 12.48 %). Ar adsorption isotherms indicate a change in pore type from predominantly ink-bottle and slit-shaped in the PZ to mainly slit-shaped in FWZ and SZ. Integrated analysis of LP-ArGA, HPMI, NMR and SEM observation suggests a substantial decrease in the contribution of micropores to total pore volume (PV) and a concurrent increase in larger pores (meso-macropores) with the increase of weathering intensity. This results in smoother surfaces of micro-transition pores but rougher surfaces of macropores. Changes in mineralogy composition during weathering play a crucial role in influencing pore structure of shales and further accelerating the release and migration of toxic elements in black shale. Our study provides the essential theoretical foundation for the remediation of soil and water environmental pollution caused by black shale weathering.
RESUMO
Blockage is often generated in the air nozzle guide duct in a circulating fluidized-bed coal gasifier (CFBG), especially with Zhundong sub-bituminous coal (ZSBC) as the raw material. A typical example is found in one CFBG sample from Xinjiang Yihua Chemical Industry Co, Ltd. The serious blockage can be observed obviously. As so far, it is not clear for the characteristics and generation mechanism of the blockage. For analysis, the blockage can be classified into two parts, wall-layer blockage (WLB) and center-layer blockage (CLB). To inhibit its formation, it is of significance to analyze the composition, surface morphology, and formation mechanism of the two blockages. In our experiments, WLB and CLB were tested by XRF, XRD, FTIR, SEM-EDS, and SEM-mapping methods. Results showed that WLB presents high content of Fe, Cr, and Ni, and Fe mainly existed in the form of metal oxides. CLB is dominated by Si (43.04%), derived from silica and alkali and alkaline-earth metals silicates, and the migration of Fe, Cr, and Ni elements from the duct material was observed. Compared with WLB, from FTIR analysis, CLB contains more inorganic minerals, and the absorption peak of inorganic minerals is mainly attributed to asymmetric Si-O-Si. Many fine particles are attached to the surface of the WLB, while the surface of the CLB is smooth, and there is noticeable raised texture, which is presumed to be the result of particle melting and agglomerating as the bottom ash enters the duct in the gasification process. For the formation of the blockage, this paper speculates that it is mainly due to the difference in flow resistance near the air nozzle outlet, resulting in the formation of a flow dead zone at the bottom of the gasifier, which leads to large amounts of ash overcoming the outlet resistance and leaking into the air nozzle, and next, the ash corrodes in the tube, resulting in wall deposition and ultimately blocking the air guide duct. Two methods can be tried to avoid or inhibit the formation of blockage in the duct, including optimizing air nozzle with more wear-resistant and heat-resistant materials and adjusting the distance between air nozzles to avoid mutual interference from ash particles.
RESUMO
The continuous stimulation of periodontitis leads to a decrease in the number of stem cells within the lesion area and significantly impairing their regenerative capacity. Therefore, it is crucial to promote stem cell homing and regulate the local immune microenvironment to suppress inflammation for the regeneration of periodontitis-related tissue defects. Here, we fabricated a novel multifunctional bilayer nanofibrous membrane using electrospinning technology. The dense poly(caprolactone) (PCL) nanofibers served as the barrier layer to resist epithelial invasion, while the polyvinyl alcohol/chitooligosaccharides (PVA/COS) composite nanofiber membrane loaded with calcium beta-hydroxy-beta-methylbutyrate (HMB-Ca) acted as the functional layer. Material characterization tests revealed that the bilayer nanofibrous membrane presented desirable mechanical strength, stability, and excellent cytocompatibility. In vitro, PCL@PVA/COS/HMB-Ca (P@PCH) can not only directly promote rBMSCs migration and differentiation, but also induce macrophage toward pro-healing (M2) phenotype-polarization with increasing the secretion of anti-inflammatory and pro-healing cytokines, thus providing a favorable osteoimmune environment for stem cells recruitment and osteogenic differentiation. In vivo, the P@PCH membrane effectively recruited host MSCs to the defect area, alleviated inflammatory infiltration, and accelerated bone defects repair. Collectively, our data indicated that the P@PCH nanocomposite membrane might be a promising biomaterial candidate for guided tissue regeneration in periodontal applications.
Assuntos
Macrófagos , Células-Tronco Mesenquimais , Nanofibras , Nanofibras/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Diferenciação Celular/efeitos dos fármacos , Poliésteres/química , Periodontite/terapia , Periodontite/tratamento farmacológico , Membranas Artificiais , Regeneração/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Alicerces Teciduais/química , Camundongos , Ratos , Humanos , Álcool de Polivinil/químicaRESUMO
The expression of the chemorepellent Sema3a is inversely related to sympathetic innervation. We investigated whether overexpression of Sema3a in the myocardial infarction (MI) border zone could attenuate sympathetic hyper-innervation and decrease the vulnerability to malignant ventricular tachyarrhythmia (VT) in rats. Survived MI rats were randomized to phosphate buffered saline (PBS, n = 12); mock lentivirus (MLV, n = 13) and lentivirus-mediated overexpression of Sema3a (SLV, n = 13) groups. Sham-operated rats served as control group (CON, n = 20). Cardiac function and electrophysiological study (PES) were performed at 1 week later. Blood and tissue samples were collected for histological analysis, epinephrine (EPI), growth-associated factor 43 (GAP43) and tyrosine hydroxylase (TH) measurements. QTc intervals were significantly shorter in SLV group than in PBS and MLV groups (168.6 ± 7.8 vs. 178.1 ± 9.5 and 180.9 ± 8.2 ms, all P < 0.01). Inducibility of VT by PES was significantly lower in the SLV group [30.8% (4/13)] than in PBS [66.7% (8/12)] and MLV [61.5% (8/13)] groups (P < 0.05). mRNA and protein expressions of Sema3a were significantly higher and the protein expression of GAP43 and TH was significantly lower at 7 days after transduction in SLV group compared with PBS, MLV and CON groups. Myocardial EPI in the border zone was also significantly lower in SLV group than in PBS and MLV group (8.73 ± 1.30 vs. 11.94 ± 1.71 and 12.24 ± 1.54 µg/g protein, P < 0.001). Overexpression of Sema3a in MI border zone could reduce the inducibility of ventricular arrhythmias by reducing sympathetic hyper-reinnervation after infarction.