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1.
BMC Nephrol ; 21(1): 97, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169051

RESUMO

BACKGROUND: Growing evidence has shown that the gut-renal connection and gut microbiota dysbiosis play a critical role in immunoglobulin A nephropathy (IgAN). However, the fecal microbiome profile in Chinese patients with IgAN remains unknown. A cross-sectional study was designed for the first time to investigate the fecal microbiota compositions in patients with primary IgAN in China and to evaluate the relationship between the fecal microbiome and IgAN clinical presentation. METHODS: Fecal samples were collected from 17 IgAN patients and 18 age-, sex-, and body mass index-matched healthy controls, and bacterial DNA was extracted for 16S ribosomal RNA gene sequencing targeting the V3-V4 region. RESULTS: Fecal samples from the IgAN patients and healthy controls showed differences in gut microbiota community richness and compositions. Compared to the healthy controls, IgAN patients at the phylum level had an increased abundance of Fusobacteria, but a decreased abundance of Synergistetes. The significantly increased genera in the IgAN group were Escherichia-Shigella, Hungatella, and Eggerthella, all of which possess pathogenic potential. Furthermore, the genus Escherichia-Shigella was negatively associated with the estimated glomerular filtration rate (eGFR) but was positively associated with the urinary albumin-to-creatinine ratio (uACR). However, the genus rectale_group was present in the IgAN group with a low abundance and was negatively associated with the uACR. Functional analysis disclosed that infection-related pathways were enriched in the IgAN group. CONCLUSIONS: We demonstrate that gut microbiota dysbiosis occurs in patients with IgAN, and that changes in gut bacterial populations are closely related to IgAN clinical features, suggesting that certain specific gut microbiota may be a potential therapeutic target for IgAN.

2.
Cardiovasc Res ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065618

RESUMO

AIM: Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels, but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action. METHODS AND RESULTS: We found that ADK expression was higher in the neointima of injured vessels and in PDGF-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisulfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimal VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance. CONCLUSIONS: Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby downregulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury. TRANSLATIONAL PERSPECTIVE: Abnormal proliferation of vascular smooth muscle cell (VSMC) is key to abundant occlusive vascular diseases in humans, such as atherosclerosis and intimal hyperplasia associated with restenosis. Adenosine has been shown to combat abnormal smooth muscle proliferation. Here, we demonstrate that increased catabolism of adenosine by adenosine kinase (ADK) promotes abnormal VSMC proliferation. The pathological ADK overexpression in both mice and humans with vascular disease promotes VSMC proliferation via inducing aberrant DNA hypermethylation and KLF4 downregulation. Our study suggests that pharmacological augmentation of endogenous adenosine by targeting ADK represents a promising therapeutic strategy for occlusive vascular diseases.

3.
Cancer Sci ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31977138

RESUMO

Anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein, is one of the receptors that facilitates the entrance of anthrax toxin into cells. Previous studies have confirmed the pivotal role of ANTXR1 in progression and tumorigenesis of diverse cancer types. However, the biological function of ANTXR1 in gastric cancer (GC) is still unknown. The present study aimed to investigate the role of ANTXR1 in GC and illuminate the potential molecular mechanisms. Bioinformatics analysis found that ANTXR1 expression was significantly upregulated in GC tissue and its overexpression was associated with poor prognosis of GC patients. Moreover, we confirmed the upregulation of ANTXR1 in GC cell lines and GC tissue by quantitative PCR, western blot analysis, and immunohistochemical analysis. Additionally, high protein expression level of ANTXR1 was positively associated with several clinicopathological parameters in GC patients. In our study, a series of in vitro and in vivo assays were undertaken through strategies of loss/gain-of-function and rescue assays. Consequently, our results indicated that ANTXR1 induced proliferation, cell cycle progression, invasion and migration, and tumorigenicity and induced suppressed apoptosis in GC. Mechanistic investigation indicated that ANTXR1 exerted its promoting effects on GC through activation of the PI3K/AKT/mTOR signaling pathway. In conclusion, our findings suggested that ANTXR1 plays a crucial role in the development and progression of GC and could serve as a novel prognostic biomarker and potential therapeutic target for GC.

4.
Int J Mol Sci ; 20(21)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671668

RESUMO

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a glycolytic enzyme highly expressed in cancer cells, has been reported to participate in regulating metabolism, angiogenesis, and autophagy. Although anti-cancer drug oxaliplatin (Oxa) effectively inhibits cell proliferation and induces apoptosis, the growing resistance and side-effects make it urgent to improve the therapeutic strategy of Oxa. Although Oxa induces the autophagy process, the role of PFKFB3 in this process remains unknown. In addition, whether PFKFB3 affects the cytotoxicity of Oxa has not been investigated. Here, we show that Oxa-inhibited cell proliferation and migration concomitant with the induction of apoptosis and autophagy in SW480 cells. Both inhibition of autophagy by small molecule inhibitors and siRNA modification decreased the cell viability loss and apoptosis induced by Oxa. Utilizing quantitative PCR and immunoblotting, we observed that Oxa increased PFKFB3 expression in a time- and dose-dependent manner. Meanwhile, suppression of PFKFB3 attenuated both the basal and Oxa-induced autophagy, by monitoring the autophagic flux and phosphorylated-Ulk1, which play essential roles in autophagy initiation. Moreover, PFKFB3 inhibition further inhibited the cell proliferation/migration, and cell viability decreased by Oxa. Collectively, the presented data demonstrated that PFKFB3 inhibition attenuated Oxa-induced autophagy and enhanced its cytotoxicity in colorectal cancer cells.

5.
Exp Ther Med ; 18(5): 3484-3492, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602224

RESUMO

Atmospheric particulate matter with a diameter <2.5 µm (PM2.5) and pollution are worldwide environmental problems and may have negative effects on cardiovascular disease through the lung and gut. The dynamics of intestinal microflora in response to particulate pollutants is unclear. The present study investigated changes in the gut microbiota related to pollutant exposure using spontaneously hypertensive rats (SHR). DNA was extracted from fecal samples. Amplicon Generation and the quality control of PCR products were performed. PCR products was sequenced on an Illumina HiSeq 2500 platform. Data analysis included: operational taxonomic unit (OTU) clustering and species annotation, alpha diversity, beta diversity, principal coordinates analysis (PCoA), and the use of PICRUSt bioinformatics software. The microbial diversity of the SHR rats was inversely associated with exposure to pollutants. In terms of relative abundance, 24 bacterial genera and 2 genera in particular (Actinobacillus and Fusobacterium) significantly declined, and one genus (Treponema) increased. Moreover, pollutant exposure was associated with the accumulation of genes from the gut microbiota that are implicated in cardiovascular diseases. From the long-term exposure experiment, rats appeared to respond to pollutant injury. In conclusion, these results suggest that the effects of atmospheric pollutants on organisms are not limited to the respiratory tract, but also include the gastrointestinal tract. Pollutants are likely to influence the intestinal microbiota and promote the progression of cardiovascular disease.

6.
Cell Res ; 29(10): 787-803, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31488882

RESUMO

Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

7.
Immunobiology ; 224(3): 339-346, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30975435

RESUMO

A deficiency of complement factor H may lead to excessive consumption of C3 and an increase in C3b deposition, which are important pathological characteristics of lupus nephritis. Complement factor H-related proteins (CFHRs), comprising CFHR1 to CFHR5 (CFHR1-5), are members of the wider factor H/CFHR family. Their role in lupus nephritis remains unclear. In this study, we compared circulating levels of CFHR1-5 in 152 patients diagnosed with lupus nephritis and 20 unrelated healthy individuals to explore the relationship between the expression of CFHR1-5 and development of the disease. We found that plasma levels of CFHR3 and CFHR5 were higher in patients with lupus nephritis than in healthy individuals; also, CFHR3 and CFHR5 concentrations increased with increasing systemic lupus erythematosus disease activity index (SLEDAI) values (P < 0.05). Pearson's and Spearman's correlation test results confirmed that plasma CFHR3 and CFHR5 levels in lupus nephritis patients were positively correlated with proteinuria and levels of creatinine (Cr) and anti-dsDNA (correlation coefficients = 0.491-0.717, P < 0.05), while they were negatively correlated with plasma C3 levels and eGFR [correlation coefficients = -(0.706-0.788), P < 0.05]. Receiver operating characteristic (ROC) curve analysis results confirmed that plasma CFHR3 and CFHR5 levels were predictive of SLEDAI values and disease end points (area under the curve = 0.664-0.884, P < 0.05), with patients with both high CFHR3 and high CFHR5 exhibiting the shortest progression-free survival. Thus, both CFHR3 and CFHR5 are of prognostic value in lupus nephritis status.


Assuntos
Proteínas Sanguíneas/metabolismo , Proteínas do Sistema Complemento/metabolismo , Nefrite Lúpica/metabolismo , Adolescente , Adulto , Anticorpos Antinucleares/sangue , Apolipoproteínas/metabolismo , Circulação Sanguínea , Estudos de Casos e Controles , Criança , Complemento C3/metabolismo , Proteínas Inativadoras do Complemento C3b/metabolismo , Creatinina/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria , Adulto Jovem
8.
Sensors (Basel) ; 18(11)2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30366434

RESUMO

Leaves account for the largest proportion of all organ areas for most kinds of plants, and are comprise the main part of the photosynthetically active material in a plant. Observation of individual leaves can help to recognize their growth status and measure complex phenotypic traits. Current image-based leaf segmentation methods have problems due to highly restricted species and vulnerability toward canopy occlusion. In this work, we propose an individual leaf segmentation approach for dense plant point clouds using facet over-segmentation and facet region growing. The approach can be divided into three steps: (1) point cloud pre-processing, (2) facet over-segmentation, and (3) facet region growing for individual leaf segmentation. The experimental results show that the proposed method is effective and efficient in segmenting individual leaves from 3D point clouds of greenhouse ornamentals such as Epipremnum aureum, Monstera deliciosa, and Calathea makoyana, and the average precision and recall are both above 90%. The results also reveal the wide applicability of the proposed methodology for point clouds scanned from different kinds of 3D imaging systems, such as stereo vision and Kinect v2. Moreover, our method is potentially applicable in a broad range of applications that aim at segmenting regular surfaces and objects from a point cloud.


Assuntos
Folhas de Planta/metabolismo , Imagem Tridimensional , Fotossíntese/fisiologia , Folhas de Planta/anatomia & histologia , Folhas de Planta/crescimento & desenvolvimento
9.
Int J Mol Med ; 42(1): 359-367, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29620138

RESUMO

Due to the high-level of metastatic and relapsed rates, rhabdomyosarcoma (RD) patients have a poor prognosis, and novel treatment strategies are required. Thereby, the present study evaluated the efficacy of PFK15, a PFKFB3 inhibitor, in RD cells to explore its potential underlying mechanism on the regulation of autophagy and proliferation in these cells. The effects of PFK15 on cell viability loss and cell death in different treatment groups, were evaluated by MTS assay, colony growth assay and immunoblotting, respectively. In addition, the autophagy levels were detected by electron microscopy, fluorescence microscopy and immunoblotting following PFK15 treatment, and the autophagic flux was analyzed with the addition of chloroquine diphosphate salt or by monitoring the level of p62. PFK15 was observed to evidently decrease the viability of RD cells, inhibit the colony growth and cause abnormal nuclear morphology. Furthermore, PFK15 inhibited the autophagic flux and cell proliferation, as well as induced apoptotic cell death in RD cells through downregulation of the adenosine monophosphate­activated protein kinase (AMPK) signaling pathway. An AMPK agonist rescued the inhibited cell proliferation and autophagy induced by PFK15. In conclusion, PFK15 inhibits autophagy and cell proliferation via downregulating the AMPK signaling pathway in RD cells.


Assuntos
Autofagia , Fosfofrutoquinase-2/antagonistas & inibidores , Piridinas/farmacologia , Quinolinas/farmacologia , Rabdomiossarcoma/patologia , Adenilato Quinase/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Regulação para Baixo/efeitos dos fármacos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfofrutoquinase-2/metabolismo , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/ultraestrutura , Ribonucleotídeos/farmacologia
10.
Oncotarget ; 8(46): 80909-80922, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-29113354

RESUMO

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), is a critical enzyme for glycolysis and highly expressed in cancer cells. It plays an essential role in regulating metabolism, angiogenesis, and inflammation. Although PFKFB3 is involved in modulating autophagy, its regulatory role appears to be either positive or negative, which remains to be clarified. Unlike other PFK-2/FBPase isoforms, PFKFB3 can localize in both nucleus and cytoplasm, leading to the speculation that subcellular localization of PFKFB3 may play a regulatory role in autophagy. Here, we found that either a PFKFB3 inhibitor or PFKFB3 silencing by siRNA, suppressed the basal and the H2O2-induced autophagy concomitantly with the inhibition of AMPK activity. While overexpression of the wild type PFKFB3 promoted the H2O2-induced autophagy, the K472/473A mutated PFKFB3, which lost nuclear localizing property, inhibited the autophagic process. Although the K472/473A mutated PFKFB3 stimulated more lactate production, it decreased the activity of AMPK compared to the wild type PFKFB3. Moreover, PFKFB3 similarly regulates the autophagy induced by rasfonin, a fungal secondary metabolite that downregulates the activity of AMPK. Compound C, a widely used AMPK inhibitor, induced the autophagic process but reduced the H2O2-dependent autophagy. Collectively, the data demonstrated that PFKFB3 localizing in nucleus is essential for its regulatory role in autophagy, and PFKFB3 at least positively regulated the H2O2-induced autophagy through the AMPK signaling pathway, which likely played dual roles in the process.

11.
Nat Commun ; 8(1): 943, 2017 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-29038540

RESUMO

The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play important roles in vascular inflammation. Pro-inflammatory stimuli lead to endothelial inflammation by increasing endothelial ADK expression, reducing the level of intracellular adenosine in endothelial cells, and activating the transmethylation pathway through increasing the association of ADK with S-adenosylhomocysteine (SAH) hydrolase (SAHH). Increasing intracellular adenosine by genetic ADK knockdown or exogenous adenosine reduces activation of the transmethylation pathway and attenuates the endothelial inflammatory response. In addition, loss of endothelial ADK in mice leads to reduced atherosclerosis and affords protection against ischemia/reperfusion injury of the cerebral cortex. Taken together, these results demonstrate that intracellular adenosine, which is controlled by the key molecular regulator ADK, influences endothelial inflammation and vascular inflammatory diseases.The molecular mechanisms underlying vascular inflammation are unclear. Here the authors show that pro-inflammatory stimuli lead to endothelial inflammation by increasing adenosine kinase expression, and that its knockdown in endothelial cells inhibits atherosclerosis and cerebral ischemic injury in mice.


Assuntos
Adenosina Quinase/imunologia , Adenosina/imunologia , Aterosclerose/imunologia , Vasos Sanguíneos/imunologia , Células Endoteliais/imunologia , Epigênese Genética/imunologia , Regulação da Expressão Gênica/imunologia , Adenosina Quinase/genética , Adenosil-Homocisteinase/metabolismo , Animais , Aterosclerose/genética , Córtex Cerebral/irrigação sanguínea , Epigênese Genética/genética , Técnicas de Silenciamento de Genes , Inflamação/genética , Inflamação/imunologia , Camundongos , Camundongos Knockout para ApoE , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia
12.
Nat Commun ; 8(1): 584, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28928465

RESUMO

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.


Assuntos
Células Endoteliais/metabolismo , Receptor A2A de Adenosina/metabolismo , Doenças Retinianas/metabolismo , Neovascularização Retiniana/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor A2A de Adenosina/genética , Retina/metabolismo , Retina/patologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia
13.
Cell Death Dis ; 8(8): e2988, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28796254

RESUMO

Deficiency of autophagy has been linked to increase in nuclear instability, but the role of autophagy in regulating the formation and elimination of micronuclei, a diagnostic marker for genomic instability, is limited in mammalian cells. Utilizing immunostaining and subcellular fractionation, we found that either LC3-II or the phosphorylated Ulk1 localized in nuclei, and immunoprecipitation results showed that both LC3 and Unc-51-like kinase 1 (Ulk1) interacted with γ-H2AX, a marker for the DNA double-strand breaks (DSB). Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, was found to enhance the autophagic flux concurring with increase in the frequency of micronuclei accrued upon inhibition of autophagy, and similar results were also obtained in the rasfonin-treated cells. Moreover, the punctate LC3 staining colocalized with micronuclei. Unexpectedly, deprivation of SQSTM1/p62 alone accumulated micronuclei, which was not further increased upon challenge with ST. Rad51 is a protein central to repairing DSB by homologous recombination and treatment with ST or rasfonin decreased its expression. In several cell lines, p62 appeared in the immunoprecipites of Rad51, whereas LC3, Ulk1 and p62 interacted with PARP-1, another protein involved in DNA repair and genomic stability. In addition, knockdown of either Rad51 or PARP-1 completely inhibited the ST-induced autophagic flux. Taken together, the data presented here demonstrated that both LC3-II and the phosphorylated Ulk1 localized in nuclei and interacted with the proteins essential for nuclear stability, thereby revealing a more intimate relationship between autophagy and genomic stability.


Assuntos
Instabilidade Genômica/ética , Indóis/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Pirróis/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Imunoprecipitação , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Poli(ADP-Ribose) Polimerase-1/genética , Ligação Proteica/efeitos dos fármacos , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Sunitinibe
14.
EMBO Mol Med ; 9(9): 1263-1278, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28751580

RESUMO

The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro-angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation-specific PCR, bisulfite sequencing, and methylated DNA immunoprecipitation further confirmed hypomethylation in the promoter region of VEGFR2 in ADK-deficient endothelial cells. Accordingly, loss or inactivation of ADK increased VEGFR2 expression and signaling in endothelial cells. Based on these findings, we propose that ADK downregulation-induced elevation of intracellular adenosine levels in endothelial cells in the setting of hypoxia is one of the crucial intrinsic mechanisms that promote angiogenesis.


Assuntos
Adenosina/metabolismo , Epigênese Genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Fisiológica , Adenosina Quinase/genética , Adenosina Quinase/metabolismo , Animais , Aorta/metabolismo , Metilação de DNA , Humanos , Camundongos , Regiões Promotoras Genéticas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Mycology ; 7(1): 29-35, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-30123613

RESUMO

Two major protein quality control mechanisms exist in eukaryotic cells, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system. Generally, the inhibition of UPS is believed to enhance autophagic pathway; nevertheless, the crosstalk between these two degradation systems may be much more complicated. Rasfonin, a 2-pyrone derivative of fungal secondary metabolites, is demonstrated to have the antitumor effect and can function as an autophagy inducer. Here, we reported that rasfonin activated multiple cell death pathways, including caspase-dependent apoptosis. Using electroscopy and microscopy, we observed rasfonin increased the formation of autophagosome. In immunoblotting assay, rasfonin enhanced autophagic flux concomitant with the upregulation of ubiquitination. MG132, an inhibitor of proteasome, attenuated rasfonin-dependent autophagy, whereas its presentation stimulated rasfonin-induced cleavage of poly (ADP-ribose) polymerase, a marker of caspase-dependent apoptosis. Together, we demonstrated that rasfonin induced the activation of both UPS and autophagic pathway, and the inhibition of UPS attenuated rasfonin-induced autophagy and enhanced the cytotoxicity of rasonin by upregulation of caspase-dependent apoptosis.

16.
Wei Sheng Yan Jiu ; 45(4): 648-662, 2016 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-29903338

RESUMO

OBJECTIVE: To investigate the effect of PM2. 5on the respiratory tract flora in the SHR / NCrl rats. METHODS: Through the simulation of real air pollution and mixed gas exposure, the establishment of acute exposure to air pollution in low, medium and high concentration of animal models, to detect the distribution of bacterial flora before and after the dust exposure in the throat and respiratory mucosa of SHR rats. Analysis on the trend of micro ecology of respiratory tract was studied dynamically. RESULTS: The detection rate of anaerobic bacteria in SHR rats was 71. 8% and 20. 7% respectively, compared with the previous exposure to dust was high than 0. 6%, there were significant differences( P <0. 05). In the detection rate of anaerobic bacteria, the Tetanus bacillus and Clostridium in the respiratory tract of the exposed to dust rats was not detected. After the dust exposure, two kinds of bacteria respectively in 28 and 5 SHR rats were detected. The detection rate ofVeillonella in anaerobic bacteria was 53. 1%, there were significant differences( P <0. 05). The number of pathogenic bacteria in the aerobic bacteria after the dust exposure was increased, the detection rate also increased. The results showed that in the body the number and species of bacteria after the exposure to dust were changed. CONCLUSION: PM_(2. 5) as the carrier of harmful substance, when with breathing enter the human respiratory tract, will cause the normal flora in the body 's respiratory tract disorder. The pathogen bacteria is easy to be colonized and the detection rate is increased, which affecting the body healthy.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Monitoramento Ambiental/métodos , Exposição por Inalação/efeitos adversos , Doenças Respiratórias/induzido quimicamente , Poluentes Atmosféricos/química , Poluição do Ar/análise , Animais , Poeira , Humanos , Exposição por Inalação/análise , Ratos , Ratos Endogâmicos SHR , Doenças Respiratórias/etiologia
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