RESUMO
BACKGROUND: To differentiate between pseudo occlusion (PO) and true occlusion (TO) of internal carotid artery (ICA) is important in thrombectomy treatment planning for patients with acute ischemic stroke. Although delayed contrast filling has been differentiated carotid PO from TO, its application has been limited by the implementations of multiphasic computed tomography angiography. In this study, we hypothesized that carotid ring sign, which is readily acquired from single-phasic CTA, can sufficiently differentiate carotid TO from PO. METHODS: One thousand four hundred and twenty patients with anterior circulation stroke receiving endovascular therapy were consecutively recruited through a hospital- and web-based registry. Two hundred patients with nonvisualization of the proximal ICA were included in the analysis after a retrospective screening. Diagnosis of PO or TO of the cervical segment of ICA was made based on digital subtraction angiography. Diagnostic performances of carotid ring sign on arterial-phasic CTA and delayed contrast filling on multiphasic computed tomography angiography were evaluated and compared. RESULTS: One-hundred twelve patients had ICA PO and 88 had TO. Carotid ring sign was more common in patients with TO (70.5% versus 6.3%; P<0.001), whereas delayed contrast filling was more common in PO (94.9% versus 7.7%; P<0.001). The sensitivity and specificity of carotid ring sign in diagnosing carotid TO were 0.70 and 0.94, respectively, whereas sensitivity and specificity of delayed contrast filling was 0.95 and 0.92 in judging carotid PO. CONCLUSIONS: Carotid ring sign is a potent imaging marker in diagnosing ICA TO. Carotid ring sign could be complementary to delayed contrast filling sign in differentiating TO from PO, in particular in centers with only single-phasic CTA.
Assuntos
Doenças das Artérias Carótidas , Estenose das Carótidas , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Angiografia por Tomografia Computadorizada/métodos , Estudos Retrospectivos , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Angiografia Digital/métodosRESUMO
It is urgent to explore factors affecting immunotherapy efficacy to benefit non-small cell lung cancer (NSCLC) patient survival. Bioinformatics predicted genes associated with programmed cell death ligand 1 (PD-L1) expression and analysed phospholipase A2 group IID (PLA2G2D) expression in NSCLC. BODIPY 493/503 dye staining and kits detected lipids, triglycerides, and phospholipids in H1299 cells, respectively. Extracellular vesicles (EVs) were extracted for morphology and size assessment using electron microscopy. Western blot assayed CD9, CD63, HSP90, EVs-PD-L1, PD-L1, and PLA2G2D expression. CCK-8, LDH, and ELISA tested proliferation and toxicity of CD8+ T cells, interleukin-2, and interferon-gamma secretion, respectively. PLA2G2D, PD-L1, and Ki67 expression was detected by immunohistochemistry. Immunofluorescence assayed PLA2G2D localisation and CD8+ T cell content. Flow cytometry assessed PD-L1 and CD8 expression. In NSCLC, upregulated EVs-PD-L1 and clinical characteristics showed a strong correlation. H1299 cells with overexpression PD-L1 significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. Bioinformatics revealed positive correlations between PLA2G2D and overexpressed PD-L1. PLA2G2D was expressed in macrophages and dendritic cells in NSCLC tissue. Overexpression PLA2G2D (oe-PLA2G2D) increased lipids, triglycerides, and phospholipids contents in H1299 cells. oe-PLA2G2D significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. si-PD-L1 restored inhibition of oe-PLA2G2D on CD8+ T cells. oe-PLA2G2D significantly increased mice tumour volume and weight, upregulated expression of blood EVs-PD-L1 and tissue PD-L1, PLA2G2D, Ki67, and decreased CD8+ T cell content. PLA2G2D facilitated immune escape in NSCLC by regulating CD8+ T cell immune function by upregulating EVs-PD-L1.
Assuntos
Antígeno B7-H1 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/imunologia , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Animais , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Evasão Tumoral/imunologia , Feminino , Masculino , Proliferação de Células , Pessoa de Meia-IdadeRESUMO
The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular responses in the tumor microenvironment and has been extensively studied in hematopoietic cancer, but its respective functions in tumor cells and immune cells in the context of tumor growth regulation of solid tumor is still incompletely understood. We report here that WDR5 exhibits a higher expression level in human pancreatic tumor tissues compared with adjacent normal pancreas. Moreover, WDR5 expression is negatively correlated with patients' response to chemotherapy or immunotherapy in human colon cancer and melanoma. However, WDR5 expression is positively correlated with the HLA level in human cancer cells, and H3K4me3 enrichment is observed at the promoter region of the HLA-A, HLA-B, and HLA-C genes in pancreatic cancer cells. Using mouse tumor cell lines and in vivo tumor models, we determined that WDR5 deficiency or inhibition significantly represses MHC I expression in vitro and in vivo in pancreatic tumor cells. Mechanistically, we determine that WDR5 deficiency inhibits H3K4me3 deposition at the MHC I (H2K) promoter region to repress MHC I (H2K) transcription. On the other hand, WDR5 depletion leads to the effective downregulation of immune checkpoints and immunosuppressive cytokines, including TGFß and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activates immune suppressive pathways to promote tumor immune evasion. Selective activation of the WDR5-MHC I pathway and/or selective inhibition of the WDR5-immune checkpoint and WDR5-cytokine pathways should be considered in WDR5-based epigenetic cancer immunotherapy.
Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histonas , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pancreáticas , Humanos , Animais , Histonas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Linhagem Celular Tumoral , Regiões Promotoras Genéticas , Microambiente Tumoral/imunologia , Microambiente Tumoral/genéticaRESUMO
The roots of legume plant play a crucial role in nitrogen fixation. However, the transcriptomes of different cell types of legume root and their functions remain largely unknown. Here, we performed single-cell RNA sequencing and profiled more than 22,000 single cells from root tips of Lotus japonicus, a model species of legume. We identified seven clusters corresponding to seven major cell types, which were validated by in situ hybridization. Further analysis revealed regulatory programs including phytohormone and nodulation associated with specific cell types, and revealed conserved and diverged features for the cell types. Our results represent the first single-cell resolution transcriptome for legume root tips and a valuable resource for studying the developmental and physiological functions of various cell types in legumes.
Assuntos
Lotus , Lotus/genética , Lotus/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Análise da Expressão Gênica de Célula Única , Simbiose/genética , Fixação de Nitrogênio/genética , Nódulos Radiculares de Plantas/genética , Regulação da Expressão Gênica de Plantas/genéticaRESUMO
Objective: To investigate the efficiency and potential mechanisms of exosomes from dendritic cells (DCs) transfected with Forkhead box protein P3 (FOXP3) in the development of experimental autoimmune encephalomyelitis (EAE). Method: Mouse bone marrow-derived immature DCs were loaded with adenovirus carrying FOXP3 gene, and exosomes were generated. Then the exosomes with FOXP3 (FOXP3-EXOs) were co-cultured with CD4+T cell in vitro to evaluate their potential on CD4+T cell proliferation and differentiation, and injected into EAE mice to assess their effects on the development of EAE. Result: FOXP3-EXOs were effective to inhibit the CD4+T cell proliferation and the production of Interferon gamma (IFN-γ), interleukin (IL)-6, and IL-17, while they promoted the production of IL-10 in vitro. Moreover, FOXP3-EXOs treatment significantly decreased the neurological scores, reduced the infiltration of inflammatory cells into the spinal cord, and decreased demyelination in comparison to saline and Con-EXOs treated EAE mice. Moreover, the FOXP3-EXOs treatment resulted in obvious increases in the levels of regulatory T (Treg) cells and IL-10, whereas levels of T helper 1 (Th1) cells, Th17 cells, IFN-γ, IL-6, and IL-17 decreased significantly in the splenocyte culture of EAE mice. Conclusion: The present study preliminarily investigated the effects and potential mechanisms of FOXP3-EXOs in EAE and revealed that the FOXP3-EXOs could inhibit the production of Th1 and Th17 cells and promote the production of Treg cells as well as ameliorate the development of EAE. The neuroprotective effects of FOXP3-EXOs on EAE are likely due to the regulation of Th/Treg balance.
Assuntos
Células Dendríticas , Encefalomielite Autoimune Experimental , Exossomos , Fatores de Transcrição Forkhead , Animais , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Exossomos/genética , Exossomos/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores , Células Th17RESUMO
Viral pneumonia is a common complication caused by Influenza A virus infection and is characterized by severe pulmonary inflammation. A previous study showed that berberine (BBR) significantly ameliorated the pulmonary inflammation in mice with influenza viral pneumonia but its underlying mechanism is not entirely understood. In this study, we reproduced the mouse model of influenza viral pneumonia through intranasal infection of A/Puerto Rico/8/34 (H1N1), to further investigate the anti-inflammatory mechanism of BBR based on nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome activation and Gasdermin D (GSDMD)-mediated pyroptosis. Consistent with MCC950 (10 mg/kg, a specific NLRP3 inflammasome inhibitor), BBR (10 mg/kg) obviously improved the weight loss and survival rate of infected mice, alleviated their pulmonary inflammation, and suppressed the accumulation of tumor necrosis factor and interleukin (IL)-6 in lungs without obvious inhibition on viral multiplication (hemagglutinin titer and nucleoprotein messenger RNA). Moreover, BBR (10 mg/kg) reduced the expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cysteinyl aspartate-specific proteinase (Caspase)1 (Caspase1 precursor [Pro-caspase1] + Caspase1p20 subunit) and the ratio of Caspase1p20 subunit to Caspase1, thus inhibiting the NLRP3 inflammasome activation and resulting in the decreased contents of mature IL-1ß and IL-18 in lungs. The GSDMD expression (GSDMD precursor [Pro-GSDMD] + GSDMD-N terminal [NT]) and the ratio of GSDMD-NT to GSDMD were also declined by BBR (10 mg/kg). These evidence indicate that BBR may ameliorate pulmonary inflammation in mice with influenza viral pneumonia through inhibiting NLRP3 inflammasome activation, as well as depressing GSDMD-mediated pyroptosis via declining GSDMD expression and restraining NLRP3 inflammasome-mediated GSDMD activation.
Assuntos
Berberina , Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae , Pneumonia Viral , Animais , Camundongos , Berberina/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/tratamento farmacológico , Piroptose , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/tratamento farmacológicoRESUMO
Colorectal cancer (CRC) is a serious public health issue, and it has the leading incidence and mortality among malignant tumors worldwide. CRC patients with metastasis in the liver, lung or other distant sites always have poor prognosis. Thus, there is an urgent need to discover the underlying mechanisms of metastatic colorectal cancer (mCRC) and to develop optimal therapy for mCRC. Transforming growth factor-ß (TGF-ß) signaling plays a significant role in various physiologic and pathologic processes, and aberrant TGF-ß signal transduction contributes to mCRC progression. In this review, we summarize the alterations of the TGF-ß signaling pathway in mCRC patients, the functional mechanisms of TGF-ß signaling, its promotion of epithelial-mesenchymal transition, its facilitation of angiogenesis, its suppression of anti-tumor activity of immune cells in the microenvironment and its contribution to stemness of CRC cells. We also discuss the possible applications of TGF-ß signaling in mCRC diagnosis, prognosis and targeted therapies in clinical trials. Hopefully, these research advances in TGF-ß signaling in mCRC will improve the development of new strategies that can be combined with molecular targeted therapy, immunotherapy and traditional therapies to achieve better efficacy and benefit mCRC patients in the near future.
Assuntos
Neoplasias do Colo , Neoplasias Retais , Humanos , Fator de Crescimento Transformador beta , Transdução de Sinais , Transição Epitelial-Mesenquimal , Microambiente TumoralRESUMO
BACKGROUND: The APETALA2/ethylene response factor (AP2/ERF) family are important regulatory factors involved in plants' response to environmental stimuli. However, their roles in salt tolerance in Lotus corniculatus remain unclear. RESULTS: Here, the key salt-responsive transcription factor LcERF056 was cloned and characterised. LcERF056 belonging to the B3-1 (IX) subfamily of ERFs was considerably upregulated by salt treatment. LcERF056-fused GFP was exclusively localised to nuclei. Furthermore, LcERF056- overexpression (OE) transgenic Arabidopsis and L. corniculatus lines exhibited significantly high tolerance to salt treatment compared with wild-type (WT) or RNA interference expression (RNAi) transgenic lines at the phenotypic and physiological levels. Transcriptome analysis of OE, RNAi, and WT lines showed that LcERF056 regulated the downstream genes involved in several metabolic pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) and yeast one-hybrid (Y1H) assay demonstrated that LcERF056 could bind to cis-element GCC box or DRE of reactive oxygen species (ROS)-related genes such as lipid-transfer protein, peroxidase and ribosomal protein. CONCLUSION: Our results suggested that the key regulator LcERF056 plays important roles in salt tolerance in L. corniculatus by modulating ROS-related genes. Therefore, it may be a useful target for engineering salt-tolerant L. corniculatus or other crops.
Assuntos
Regulação da Expressão Gênica de Plantas , Lotus/fisiologia , Oxigênio/metabolismo , Proteínas de Plantas/fisiologia , Tolerância ao Sal/fisiologia , Fatores de Transcrição/fisiologia , Núcleo Celular/metabolismo , Lotus/genética , Tolerância ao Sal/genéticaRESUMO
Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts.Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression.Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade.Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy-JAK2-STAT3 signaling pathway, thus affecting bone metabolism.
Assuntos
Ligante RANK , Fator de Transcrição STAT3 , Animais , Autofagia , Interleucina-17 , Camundongos , Osteoblastos/metabolismo , Ligante RANK/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
OBJECTIVE AND BACKGROUND: Recently, decellularized matrix (DCM) is considered as a new biomaterial for tissue regeneration. To explore the possible application of DCM in periodontal regeneration, the effect of DCM from three different cells on the proliferation and differentiation of human periodontal ligament stem cells (PDLSCs) was investigated. METHODS: DCM derived from human periodontal ligament cells (PDLCs), dental pulp cells (DPCs), and gingival fibroblasts (GFs) were fabricated using Triton X-100/NH4 OH combined with DNase I. Allogeneic PDLSCs were cultured on PDLC-DCM, DPC-DCM, and GF-DCM, respectively. The proliferative capacity of PDLSCs was evaluated by PicoGreen assay kit. The expression of alkaline phosphatase (ALP), runt-related transcription factor-2 (RUNX2), osteocalcin (OCN), collagen I (COL1), periostin (POSTN), and cementum protein 1 (CEMP1) were detected by qRT-PCR and western blotting. RESULTS: PDLC-DCM, DPC-DCM, and GF-DCM had similar and integrated networks of extracellular matrix, as well as significantly decreased DNA content. Compared with control group in which PDLSCs were directly seeded in culture plates, PDLC-DCM, DPC-DCM, and GF-DCM promoted the proliferation of re-seeded PDLSCs. Additionally, PDLSCs on DCM exhibited higher mRNA and protein expression levels of ALP, RUNX2, OCN, and COL1. The expression of POSTN in PDLC-DCM group was significantly higher than control group at both mRNA and protein levels. CONCLUSIONS: PDLC-DCM, DPC-DCM, and GF-DCM could enhance the proliferation of PDLSCs. PDLC-DCM facilitated osteogenic differentiation and periodontal ligament differentiation of PDLSCs, while DPC-DCM and GF-DCM promoted osteogenic differentiation.
Assuntos
Osteogênese , Ligamento Periodontal , Fosfatase Alcalina , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Proteínas , Células-TroncoRESUMO
AIM: To evaluate the outcomes of an apically repositioned flap (ARF) plus xenogeneic collagen matrix (XCM) in augmenting keratinized mucosa width (KMW) around dental implants when compared with ARF plus free gingival grafts (FGG). MATERIALS AND METHODS: Twenty-six participants with at least one site with KMW ≤2 mm were randomized into FGG or XCM group. Clinical examinations were performed at baseline and at 2 and 6 months after surgery, including KMW, keratinized mucosa thickness, gingival index (GI), and probing depth (PD). Post-operative pain and patient satisfaction were also evaluated. RESULTS: At 6 months, FGG attained a greater increase of KMW and thicker mucosa than XCM (4.1 ± 1.6 mm vs. 1.8 ± 1.0 mm, p < .001; 1.7 ± 0.6 mm vs. 1.2 ± 0.3 mm, p < .01). Regarding GI, PD, post-operative pain, aesthetic outcomes, and patient satisfaction, no significant difference could be detected. Moreover, the operation time of XCM group was shorter (60 ± 9 min vs. 39 ± 8 min, p < .001). CONCLUSIONS: FGG could result in greater increase of KMW than XCM, though both could increase KMW, maintain peri-implant health, and attain comparable aesthetic outcomes. The use of XCM was associated with reduced operation time.
Assuntos
Implantes Dentários , Colágeno , Estética Dentária , Gengiva , Gengivoplastia , Humanos , MucosaRESUMO
Polycomb group (PcG) proteins, which are important epigenetic regulators, play essential roles in the regulatory networks involved in plant growth, development, and environmental stress responses. Currently, as far as we know, no comprehensive and systematic study has been carried out on the PcG family in Medicago truncatula. In the present study, we identified 64 PcG genes with distinct gene structures from the M. truncatula genome. All of the PcG genes were distributed unevenly over eight chromosomes, of which 26 genes underwent gene duplication. The prediction of protein interaction network indicated that 34 M. truncatula PcG proteins exhibited protein-protein interactions, and MtMSI1;4 and MtVRN2 had the largest number of protein-protein interactions. Based on phylogenetic analysis, we divided 375 PcG proteins from 27 species into three groups and nine subgroups. Group I and Group III were composed of five components from the PRC1 complex, and Group II was composed of four components from the PRC2 complex. Additionally, we found that seven PcG proteins in M. truncatula were closely related to the corresponding proteins of Cicer arietinum. Syntenic analysis revealed that PcG proteins had evolved more conservatively in dicots than in monocots. M. truncatula had the most collinearity relationships with Glycine max (36 genes), while collinearity with three monocots was rare (eight genes). The analysis of various types of expression data suggested that PcG genes were involved in the regulation and response process of M. truncatula in multiple developmental stages, in different tissues, and for various environmental stimuli. Meanwhile, many differentially expressed genes (DEGs) were identified in the RNA-seq data, which had potential research value in further studies on gene function verification. These findings provide novel and detailed information on the M. truncatula PcG family, and in the future it would be helpful to carry out related research on the PcG family in other legumes.
Assuntos
Regulação da Expressão Gênica de Plantas , Genoma de Planta , Medicago truncatula/genética , Família Multigênica , Proteínas de Plantas/genética , Proteínas do Grupo Polycomb/genética , Estresse Fisiológico , Cromossomos de Plantas , Perfilação da Expressão Gênica , Medicago truncatula/crescimento & desenvolvimento , FilogeniaRESUMO
: To assess the () recombinant gingivalis gingipain R2 (rRgpB)-induced Ca mobilization in human gingival fibroblast (HGF) mediated by protease-activated receptor (PAR) and its downstream signal transduction pathways. : Flow cytometry was used to detect the expression of PAR in HGF. The proliferation of HGF was measured by CCK-8. The dynamic changes of intracellular Ca concentration in HGF induced by rRgpB and the blocking effect of PAR-1 antagonist were observed by laser confocal microscopy. Western blot was performed to determine the phosphorylation levels of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (p38 MAPK) and p65 in HGF. : PAR-1 and PAR-3 were expressed in HGF, and the rRgpB could promote the proliferation of HGF. rRgpB caused a transient increase in [Ca], which could be completely suppressed by vorapaxar, a PAR-1 antagonist. The phosphorylation levels of JNK, ERK1/2 and p65 were significantly up-regulated after the induction of rRgpB for and (all <0.05), which was completely inhibited by vorapaxar. However, the phosphorylation level of p38 MAPK had no significant change after rRgpB stimulation. : rRgpB causes an increase in [Ca] in HGF mediated by PAR-1. JNK, ERK1/2 and nuclear factor-κB may be involved in intracellular signal transduction after PAR-1 activation.
Assuntos
Cálcio/metabolismo , Fibroblastos , Transdução de Sinais , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Perfluorooctane sulfonate (PFOS) is a recently identified and persistent organic pollutant that becomes enriched in living organisms via bioaccumulation and the food chain. PFOS can induce various disorders, including liver toxicity, neurotoxicity and metabolic dysregulation. Most recent studies have shown a close association of the gut microbiota with the occurrence of diseases. However, few studies have explored the effects of PFOS on the gut environment, including the intestinal flora and barrier. In this study, we evaluated the effects of PFOS in C57BL/6J male mice and explored the relationship between tissue damage and the gut environment. Mice were orally exposed to PFOS for 16 days. Liver damage was assessed by examining the inflammatory reaction in the liver and serum liver enzyme concentrations. Metabolic function was assessed by the hepatic cholesterol level and the serum concentrations of glucose, high-density lipoprotein cholesterol, total cholesterol and triglycerides. Intestinal environmental disorders were assessed by evaluating the gut microbiota, SCFAs production, inflammatory reactions and intestinal tight junction protein expression. Our results indicated that PFOS affected inflammatory reactions in the liver and colon and promoted the development of metabolic disorders (especially of cholesterol and glucose metabolism). Moreover, PFOS dysregulated various populations in the gut microbiota (e.g., Firmicutes, Bacteroides, Proteobacteria, Gammaproteobacteria, Clostridiales, Enterobacteriales, Lactobacillales, Erysipelotrichaceae, Rikenellaceae, Ruminococcaceae and Blautia) and induced a loss of gut barrier integrity by reducing short-chain fatty acids (SCFAs) production and intestinal tight junction protein expression. A Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis mainly identified metabolic pathways (e.g., the adipocytokine signalling pathway), endocrine system pathways (e.g., steroid hormone biosynthesis, flavonoid biosynthesis), the latter of which is widely considered to be associated with metabolism. Overall, our results suggest that PFOS damages various aspects of the gut environment, including the microbiota, SCFAs and barrier function, and thereby exacerbates the toxicity associated with liver, gut and metabolic disorders.
Assuntos
Ácidos Alcanossulfônicos/toxicidade , Exposição Dietética/efeitos adversos , Poluentes Ambientais/toxicidade , Fluorocarbonos/toxicidade , Intestinos/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Colesterol/metabolismo , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação , Intestinos/microbiologia , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Glioblastoma (GBM) is one of the major cause of the cancer-related fatality worldwide. Several circular RNAs (circRNAs) have been observed to exert functions in GBM. The current study is aimed to explore the potential mechanism of circ_0074027 via miR-518a-5p and IL17RD in GBM progression. Circ_0074027 expression was determined in a cohort of 50 pairs of GBM specimens and five cell lines by qRT-PCR. In addition, the association between circ_0074027 expression and its clinical value was analyzed by Fisher's exact test. Cell growth, clone formation, apoptosis, migration and invasion was evaluated after overexpress or knockdown the expression of circ_0074027 in GBM cells. Dual luciferase reporter assays were conducted to evaluate the relevant intermolecular target relationships. Circ_0074027 expression was evidently upregulated in GBM tissue specimens and cells compared to the adjacent non-tumorous tissues and NHA, respectively. The upregulation of circ_0074027 is related to clinical severity and exerts oncogenic functions in GBM. Moreover, circ_0074027 could sponge miR-518a-5p to release its suppression on IL17RD. Our findings provide evidence that circ_0074027 plays an oncogenic role in GBM by regulating miR-518a-5p/IL17RD signaling.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , RNA Circular/genética , Receptores de Interleucina/genética , Adulto , Proliferação de Células , Progressão da Doença , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regulação para CimaRESUMO
Arginine-specific cysteine proteinases, such as Arg-gingipain B (RgpB), mediate inflammation by activating protease-activated receptors (PARs). Arg-gingipain B is produced by Porphyromonas gingivalis, and is implicated in the causation of periodontal disease. The purpose of the present study was to observe the influence of recombinant RgpB protein (rRgpB) on PAR activation by monitoring intracellular Ca2+ ion concentration ([Ca2+]i) and inositol-1,4,5-triphosphate (IP3) levels in human gingival fibroblasts (HGFs). Our findings showed that rRgpB could cause a transient increase in [Ca2+]i. This increase in [Ca2+]i was completely suppressed by vorapaxar, a PAR-1 antagonist. Recombinant Arg-gingipain B increased the concentration of IP3, reaching a maximum at 60 s after treatment; this was completely inhibited by vorapaxar. We therefore conclude that rRgpB-induced calcium signaling in HGFs is mainly caused by PAR-1 activation. This suggests that PAR-1 activation plays a significant role in chronic inflammatory periodontal disease induced by P. gingivalis RgpB.
Assuntos
Sinalização do Cálcio , Fibroblastos/metabolismo , Cisteína Endopeptidases Gingipaínas/farmacologia , Porphyromonas gingivalis/enzimologia , Receptor PAR-1/metabolismo , Proteínas de Bactérias/farmacologia , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Inositol 1,4,5-Trifosfato , Lactonas/farmacologia , Piridinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Proteínas Recombinantes/farmacologiaRESUMO
BACKGROUND: A common-stem origin of lenticulostriate arteries (CS-LSAs) is an anatomical variation that supplies a moderate to large section of the basal ganglia. We hypothesized that CS-LSAs with a patent orifice are located at distal positions of the acute-occluded middle cerebral artery (MCA) and that the blood flow of CS-LSAs is supplied by pail arterial anastomoses and results in hypoperfusion of CS-LSAs, similar to a deep watershed (DWS) infarction. OBJECTIVE: Our study evaluated the possibility of CS-LSAs in patients with DWS infarction and MCA occlusion and also assessed the safety of endovascular therapy (ET) in these patients. METHODS: A cohort of consecutive patients with DWS infarction and MCA occlusion and in whom full recanalization via ET was achieved were identified. Patients were divided into two groups based on the presence of CS-LSAs observed during ET. In addition, radiological and clinical data were retrospectively analyzed. RESULTS: Thirty-three patients were included, and CS-LSAs were observed in 48.5% (16/33) of patients. The possibility (72.2%, 13/18) of CS-LSAs was high in patients with DWS infarction companied with basal ganglia infarction. A good clinical outcome was similar in patients with CS-LSAs and basal ganglia infarction and in patients without CS-LSAs and basal ganglia infarction (69.2% vs. 81.8%, P = 0.649). CONCLUSIONS: The possibility of CS-LSAs was 48.5% in patients with DWS infarction and MCA occlusion, and the revascularization procedure was safe and feasible in these patients despite the moderate-to-large basal ganglia infarction.
Assuntos
Doença Cerebrovascular dos Gânglios da Base/diagnóstico por imagem , Gânglios da Base/irrigação sanguínea , Gânglios da Base/diagnóstico por imagem , Infarto Cerebral/diagnóstico por imagem , Idoso , Angiografia Digital , Doença Cerebrovascular dos Gânglios da Base/mortalidade , Infarto Cerebral/mortalidade , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: This review aims to evaluate the efficacy of xenogeneic collagen matrix (XCM) for the treatment of single or multiple gingival recessions in terms of clinical parameters and patient-related outcomes. MATERIALS AND METHODS: Various electronic databases (The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, etc.) from 1966 to April 2018 and hand literatures were searched. Quality of the included studies was assessed through the Cochrane Collaboration's Risk of Bias tool. A meta-analysis was performed to calculate risk ratios and mean differences. RESULTS: Nine randomized controlled trials were included. The results revealed a higher percentage of mean root coverage (MRC) and a greater recession reduction (RecRed) for single recessions for the combination of coronally advanced flap (CAF) with XCM compared to CAF alone (n = 3; MD = 10.00%; 95%CI [3.56%; 16.43%]; p = 0.002) (n = 3; MD = 0.35 mm; 95%CI [0.10 mm; 0.60 mm]; p = 0.005). Comparing XCM with connective tissue graft (CTG), no significant differences were detected in MRC or RecRed for single and multiple recessions. CONCLUSIONS: The addition of XCM under CAF could improve MRC and RecRed at single tooth recessions. Initial data suggest that XCM shows promising results to improve the clinical efficacy of CAF for multiple recessions. In addition, XCM could be a valid alternative to CTG in terms of MRC and RecRed at both single and multiple recessions. Based on limited evidence, XCM may decrease postoperative morbidity and operation time compared to CTG.
Assuntos
Colágeno Tipo III , Colágeno Tipo I , Retração Gengival/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Cirurgia Bucal/métodos , Tecido Conjuntivo/transplante , Ensaios Clínicos Controlados como Assunto , Gengiva , Retração Gengival/patologia , Gengivoplastia/métodos , Humanos , Retalhos Cirúrgicos , Raiz Dentária , Resultado do TratamentoRESUMO
Subgroup 4 of R2R3-MYB transcription factors consists of four members, MYB3, MYB4, MYB7, and MYB32, which possess the conserved EAR repression motif (pdLHLD/LLxiG/S) in their C termini. Here, we show that MYB3 is a newly identified repressor in Arabidopsis (Arabidopsis thaliana) phenylpropanoid biosynthesis. However, the repression mechanism of MYB3 is completely different from MYB4, MYB7, and MYB32. Yeast two-hybrid screening using MYB3 as a bait isolates NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED1 (LNK1) and LNK2, members of a small family of four LNK proteins. The repression activity of MYB3 to cinnamate 4-hydroxylase (C4H) gene expression is directly regulated by corepressors LNK1 and LNK2, which could facilitate binding of MYB3 with C4H promoter. The two conserved Asp residues in both region 1 and 2 domain of LNKs are essential to mediate protein-protein interaction. Importantly, the Extra N-terminal Tail domain plays a negative role in LNK-MYB3 transcription complex-dependent repression of the C4H gene. We conclude that LNK1 and LNK2 act as transcriptional corepressors necessary for expression of the phenylpropanoids biosynthesis gene C4H through recruitment to its promoter via interaction with MYB3.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Vias Biossintéticas , Proteínas Correpressoras/metabolismo , Propanóis/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Proteínas de Arabidopsis/química , Ácido Aspártico/metabolismo , Sequência Conservada , Redes Reguladoras de Genes , Ligação Proteica , Domínios Proteicos , Transativadores/químicaRESUMO
The natural products cyanogenic glycosides (CNglcs) are present in various forage plant species including Sorghum spp., Trifolium spp., and Lotus spp. The release of toxic hydrogen cyanide (HCN) from endogenous CNglcs, which is known as cyanogenesis, leads to a serious problem for animal consumption while as defensive secondary metabolites, CNglcs play multiple roles in plant development and responses to adverse environment. Therefore, it is highly important to fully uncover the molecular mechanisms of CNglc biosynthesis and regulation to manipulate the contents of CNglcs in forage plants for fine-tuning the balance between defensive responses and food safety. This review summarizes recent studies on the production, function, polymorphism, and regulation of CNglcs in forage plants, aiming to provide updated knowledge on the ways to manipulate CNglcs for further beneficial economic effects.