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Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by extensive membrane destruction in the vascular wall that is closely associated with vascular smooth muscle cell (VSMC) phenotypic switching. A thorough understanding of the changes in regulatory factors during VSMC phenotypic switching is essential for managing AAA therapy. In this study, we revealed the impact of NRF2 on the modulation of VSMC phenotype and the development of AAA based on single-cell RNA sequencing analysis. By utilizing a murine model of VSMC-specific knockout of nuclear factor E2-related factor 2 (NRF2), we observed that the absence of NRF2 in VSMCs exacerbated AAA formation in an angiotensin II-induced AAA model. The downregulation of NRF2 promoted VSMC phenotypic switching, leading to an enhanced inflammatory response. Through genome-wide transcriptome analysis and loss- or gain-of-function experiments, we discovered that NRF2 upregulated the expression of VSMC contractile phenotype-specific genes by facilitating microRNA-145 (miR-145) expression. Our data identified NRF2 as a novel regulator involved in maintaining the VSMC contractile phenotype while also influencing AAA formation through an miR-145-dependent regulatory mechanism.
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Aneurisma da Aorta Abdominal , MicroRNAs , Músculo Liso Vascular , Miócitos de Músculo Liso , Fator 2 Relacionado a NF-E2 , Fenótipo , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Masculino , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Camundongos Knockout , Análise de Célula Única , Camundongos Endogâmicos C57BL , Angiotensina II/farmacologia , Análise de Sequência de RNA , Modelos Animais de DoençasRESUMO
Senescence of vascular smooth muscle cells (VSMCs) contributes to the formation of abdominal aortic aneurysm (AAA). Although mesenchymal stem cell exosomes (MSC-EXO) have been confirmed to restrict the development of AAA, their biological activity depends largely on the physiological state of the MSCs. This study aimed to compare the effects of adipose-derived MSC-EXO from healthy donors (HMEXO) and AAA patients (AMEXO) on senescence of VSMCs in AAA and explore the underlying mechanisms. An ApoE-/- mouse model of AAA was used to investigate the therapeutic effects of HMEXO, AMEXO or miR-19b-3p-AMEXO on AAA development. This in vitro model of AAA was established by treating VSMCs with Ang II (Angiotensin II). The senescence of VSMCs was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The morphology of mitochondria in VSMCs was examined by MitoTracker staining. HMEXO exhibited superior capacity compared with AMEXO to inhibit VSMC senescence and attenuate AAA formation in Ang II-treated ApoE-/- mice. In vitro, both AMEXO and HMEXO inhibited Ang II-induced VSMC senescence via downregulation of mitochondrial fission. Notably, compared with HMEXO, the ability of AMEXO to inhibit VSMC senescence was significantly decreased. miRNA sequencing and the expression of miR-19b-3p was significantly decreased in AMEXO compared with HMEXO. Luciferase assay suggested that MST4 (Mammalian sterile-20-like kinase 4) is a potential target of miR-19b-3p. Mechanistically, miR-19b-3p in HMEXO ameliorated VSMC senescence by inhibiting mitochondrial fission via regulation of the MST4/ERK/Drp1 signaling pathway. Overexpression of miR-19b-3p in AMEXO improved their beneficial effect on AAA formation. Our study reveals that MSC-exosomal miR-19b-3p exerts protective effects against Ang II-induced AAA and VSMC senescence via regulation of the MST4/ERK/Drp1 pathway. The pathological state of AAA patients alters the miRNA components of AMEXO and impairs their therapeutic benefits.
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Aneurisma da Aorta Abdominal , Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Animais , Camundongos , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Exossomos/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos Knockout para ApoE , MicroRNAs/genética , MicroRNAs/metabolismo , HumanosRESUMO
Vascular smooth muscle cells (VSMCs) senescence contributes to abdominal aortic aneurysm (AAA) formation although the underlying mechanisms remain unclear. This study aimed to investigate the role of miR-199a-5p in regulating VSMC senescence in AAA. VSMC senescence was determined by a senescence-associated ß-galactosidase (SA-ß-gal) assay. RT-PCR and Western blotting were performed to measure miRNA and protein level, respectively. The generation of reactive oxygen species (ROS) was evaluated by H2DCFDA staining. Dual-luciferase reporter assay was used to validate the target gene of miR-199a-5p. VSMCs exhibited increased senescence in AAA tissue relative to healthy aortic tissue from control donors. Compared with VSMCs isolated from control donors (control-VSMCs), those derived from patients with AAA (AAA-VSMCs) exhibited increased cellular senescence and ROS production. Angiotensin II (Ang II) induced VSMC senescence by promoting ROS generation. The level of miR-199a-5p expression was upregulated in the plasma from AAA patients and Ang II-treated VSMCs. Mechanistically, Ang II treatment significantly elevated miR-199a-5p level, thereby stimulating ROS generation by repressing Sirt1 and consequent VSMC senescence. Nevertheless, Ang II-induced VSMC senescence was partially attenuated by a miR-199a-5p inhibitor or Sirt1 activator. Our study revealed that miR-199a-5p aggravates Ang II-induced VSMC senescence by targeting Sirt1 and that miR-199a-5p is a potential therapeutic target for AAA.
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AIMS: Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS: Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a â¼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS: ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.
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Dissecção Aórtica , MicroRNAs , Aldeído-Desidrogenase Mitocondrial/genética , Dissecção Aórtica/genética , Dissecção Aórtica/prevenção & controle , Animais , Proliferação de Células , Células Cultivadas , China , Humanos , Camundongos , Músculo Liso Vascular , Miócitos de Músculo Liso , FenótipoRESUMO
BACKGROUND & AIMS: De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. METHODS: FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). RESULTS: Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. CONCLUSIONS: In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.
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Adenocarcinoma/etiologia , Carboidratos Epimerases/deficiência , Colite/etiologia , Colite/metabolismo , Colo/metabolismo , Neoplasias do Colo/etiologia , Mucosa Intestinal/metabolismo , Cetona Oxirredutases/deficiência , Adenocarcinoma/química , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Transplante de Medula Óssea , Carboidratos Epimerases/genética , Carcinogênese , Ceco/patologia , Proliferação de Células , Colite/patologia , Colite/prevenção & controle , Colo/patologia , Neoplasias do Colo/química , Neoplasias do Colo/patologia , Citocinas/genética , Citocinas/metabolismo , Fezes/microbiologia , Feminino , Fucose/administração & dosagem , Microbioma Gastrointestinal , Guanosina Difosfato Fucose/biossíntese , Guanosina Difosfato Fucose/deficiência , Humanos , Cetona Oxirredutases/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Permeabilidade , RNA Mensageiro/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/análise , Fatores de Transcrição HES-1/metabolismo , Adulto JovemRESUMO
Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK -mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK -independent HSPC egress and enhanced HSPC mobilization. We, therefore, conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.
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Células-Tronco Hematopoéticas/metabolismo , Receptores Notch/metabolismo , Nicho de Células-Tronco/genética , Células Estromais/metabolismo , Animais , Humanos , Camundongos , Transdução de SinaisRESUMO
Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-ß-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-ß-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-ß-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.
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Proteínas Quinases Ativadas por AMP , Angiotensina II , Dissecção Aórtica , Senescência Celular , Ciprofloxacina , Músculo Liso Vascular , Miócitos de Músculo Liso , Espécies Reativas de Oxigênio , Transdução de Sinais , Humanos , Senescência Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/enzimologia , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/patologia , Dissecção Aórtica/enzimologia , Dissecção Aórtica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/metabolismo , Angiotensina II/toxicidade , Células Cultivadas , Ciprofloxacina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Estudos de Casos e Controles , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/patologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/enzimologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacosRESUMO
Notch signaling is essential for lymphocyte development and is also implicated in myelopoiesis. Notch receptors are modified by O-fucosylation catalyzed by protein O-fucosyltransferase 1 (Pofut1). Fringe enzymes add N-acetylglucosamine to O-fucose and modify Notch signaling by altering the sensitivity of Notch receptors to Notch ligands. To address physiologic functions in hematopoiesis of Notch modified by O-fucose glycans, we examined mice with inducible inactivation of Pofut1 using Mx-Cre. These mice exhibited a reduction in T lymphopoiesis and in the production of marginal-zone B cells, in addition to myeloid hyperplasia. Restoration of Notch1 signaling rescued T lymphopoiesis and the marrow myeloid hyperplasia. After marrow transfer, both cell-autonomous and environmental cues were found to contribute to lymphoid developmental defects and myeloid hyperplasia in Pofut1-deleted mice. Although Pofut1 deficiency slightly decreased cell surface expression of Notch1 and Notch2, it completely abrogated the binding of Notch receptors with Delta-like Notch ligands and suppressed downstream Notch target activation, indicating that O-fucose glycans are critical for efficient Notch-ligand binding that transduce Notch signals. The combined data support a key role for the O-fucose glycans generated by Pofut1 in Notch regulation of hematopoietic homeostasis through modulation of Notch-ligand interactions.
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Fucosiltransferases/fisiologia , Homeostase/fisiologia , Linfopoese/fisiologia , Mielopoese/fisiologia , Receptores Notch/metabolismo , Animais , Transplante de Medula Óssea , Diferenciação Celular , Células Cultivadas , Citometria de Fluxo , Fucose/metabolismo , Humanos , Hidroliases/metabolismo , Hiperplasia/enzimologia , Hiperplasia/patologia , Integrases/metabolismo , Ligantes , Camundongos , Camundongos Knockout , Camundongos Transgênicos , RNA Mensageiro/genética , Receptores Notch/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Linfócitos T/enzimologia , Linfócitos T/patologiaRESUMO
The Omicron variant of COVID-19, which emerged at the end of 2021, has caused a new wave of infections around the world and is causing a new wave of the crisis due to the extreme variability of the pathogen. In response to public health emergencies such as SARS and COVID-19, the first task is to identify the vulnerabilities of regional health systems and perform a comprehensive assessment of the region's resilience. In this paper, we take the carrying capacity of medical resources as the focus; evaluate the medical, human, and financial resources of various regions; and construct an epidemic safety index based on the actual situation or future trend of the epidemic outbreak to evaluate and predict the risk level of each region in response to the epidemic. The study firstly evaluates the epidemic safety index for each province and city in China and 150 countries around the world, using the first wave of the COVID-19 epidemic in 2020 and the Omicron variant virus in 2022 as the background, respectively, and justifies the index through the actual performance in terms of epidemic prevention and control, based on which the epidemic safety index for 150 countries in the next year is predicted. The conclusions show that Europe, the Americas, and parts of Asia will face a significant risk of epidemic shocks in the coming period and that countries need to formulate policies in response to the actual situation of the epidemic.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Saúde Pública , Emergências , Conservação dos Recursos Naturais , Surtos de Doenças , China/epidemiologiaRESUMO
The accessibility of rail transit station areas is an important factor affecting the efficiency of rail transit. Taking the Beijing rail transit station area as our research object, this paper took a 15 min walking distance as the index of station area accessibility, and investigated the status quo and influencing factors of the unbalanced distribution of rail transit station area accessibility in Beijing. In this paper, the data of Beijing rail transit stations were obtained from the Amap open platform, and the accessibility of the station area was calculated using the path planning service provided by the Amap API. The Getis-Ord Gi* method was used to analyze the overall distribution characteristics of the accessibility of the Beijing rail transit station area, then the high accessibility area and the low accessibility area were determined. To explore the factors influencing domain accessibility, multi-source data were obtained, a total of 11 indicators were constructed, and the random forest model was used to identify feature importance. Using the eight selected influencing factors, the OLS regression model, GWR model, and MGWR model were used to study the spatial heterogeneity of influencing factors. By comparison, it was concluded that the MGWR model can not only effectively analyze the spatial heterogeneity of rail transit station accessibility, which can automatically mediate the bandwidth of different influencing factors, and then reflect the spatial changes of the influencing factors of rail transit station accessibility more truly. The results show that (1) the accessibility of the Beijing rail transit station area shows obvious spatial agglomeration characteristics in space. The accessibility of the station area in the fourth ring is higher than that outside of the fourth ring road, and the accessibility near the south and north fifth ring road is higher than that of the east fifth ring road and the west fifth ring road. (2) The basic influencing factors of rail transit station accessibility include road density and functional mixing degree.
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Meios de Transporte , PequimRESUMO
The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.
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Moderate altitude exposure has shown beneficial effects on diabetes incidence but the underlying mechanisms are not understood. Our study aimed to investigate how the human gut microbiome impacted the serum metabolome and associated with glucose homeostasis in healthy Chinese individuals upon moderate-altitude exposure. Faecal microbiome composition was assessed using shotgun metagenomic sequencing. Serum metabolome was acquired by untargeted metabolomics technology, and amino acids (AAs) and propionic acid in serum were quantified by targeted metabolomics technology. The results indicated that the moderate-altitude exposed individuals presented lowered fasting blood glucose (FBG) and propionic acid, increased circulating L-Glutamine but decreased L-Glutamate and L-Valine, which correlated with enriched Bacteroidetes and decreased Proteobacteria. Additionally, the silico causality associations among gut microbiota, serum metabolome and host FBG were analyzed by mediation analysis. It showed that increased Bacteroides ovatus (B. ovatus) and decreased Escherichia coli (E. coli) were identified as the main antagonistic species driving the association between L-Glutamate and FBG in silico causality. Furthermore, the high-fat diet (HFD) fed mice subjected to faecal microbiota transplantation (FMT) were applied to validate the cause-in-fact effects of gut microbiota on the beneficial glucose response. We found that microbiome in the moderate-altitude exposed donor could predict the extent of the FBG response in recipient mice, which showed lowered FBG, L-Glutamate and Firmicutes/Bacteroidetes ratio. Our findings suggest that moderate-altitude exposure targeting gut microbiota and circulating metabolome, may pave novel avenues to counter dysglycemia.
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Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Glicemia , Propionatos , Ácido Glutâmico , Altitude , Escherichia coli , Metaboloma , Glucose , JejumRESUMO
As people's levels of stress increase with the complexity of contemporary urban life, the stress healing agenda in built environments has become more critical than ever. Previous research has demonstrated that linear and nonlinear shapes in the environment have an impact on human stress recovery. However, to date, most studies have focused on indoor and outdoor spaces, while research on transitional spaces is still limited. Transitional spaces connect the interior with the exterior and are ubiquitous in the city, such as plazas, open cafes, and urban corridors. We hypothesize that curved and linear environments affect human stress recovery differently in transitional spaces. To test this hypothesis, virtual reality (VR) technology and experiments were conducted with 40 participants. At the end of the Trier Social Stress Test (TSST), participants were randomly assigned to four VR environments to test which environment is more effective in stress recovery for humans. Participants' physiological data, including heart rate and blood pressure, were measured by bio-monitoring sensors. The psychological data were tested by the State-Trait Anxiety Inventory (STAI). In general, the resulting data indicate that the curved environment is more effective than the linear environment for the recovery of human stress in transitional spaces.
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Estresse Psicológico , Realidade Virtual , Humanos , Estresse Psicológico/psicologia , Frequência Cardíaca/fisiologia , Testes Psicológicos , Pressão SanguíneaRESUMO
With the growing challenge of aging populations around the world, the study of the care services for older adults is an essential initiative to accommodate the particular needs of the disadvantaged communities and promote social equity. Based on open-source data and the geographic information system (GIS), this paper quantifies and visualizes the imbalance in the spatial distribution of elderly care facilities in 14,578 neighborhoods in downtown (seven districts) Shanghai, China. Eight types of elderly care facilities were obtained from Shanghai elderly care service platform, divided into two categories according to their service scale. With the introduction of the improved Gaussian 2-step floating catchment area method, the accessibility of two category facilities was calculated. Through the global autocorrelation analysis, it is found that the accessibility of elderly care facilities has the characteristics of spatial agglomeration. Local autocorrelation analysis indicates the cold and hot spots in the accessibility agglomeration state of the two types of facilities, by which we summarized the characteristics of their spatial heterogeneity. It is found that for Category-I, there is a large range of hot spots in Huangpu District. For Category-II, the hot-spot and cold-spot areas show staggered distribution, and the two categories of hot spot distribution show a negative correlation. We conclude that the two categories are not evenly distributed in the urban area, which will lead to the low efficiency of resource allocation of elderly care facilities and have a negative impact on social fairness. This research offers a systematic method to study urban access to care services for older adults as well as a new perspective on improving social fairness.
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Sistemas de Informação Geográfica , Acessibilidade aos Serviços de Saúde , Idoso , Área Programática de Saúde , China , Serviços de Saúde , Humanos , Análise EspacialRESUMO
Ovarian juvenile granulosa cell tumor (JGCT) is an extremely rare sex cord-stromal tumor that is most commonly encountered in prepubertal girls and young women. In this study, 3 cases of childhood JGCT are reported. The main causes of hospitalization were abnormal abdominal signs and syndromes. Imaging findings indicated masses with multiple cysts and solid components in the abdominal cavities. Diagnosis was confirmed by histopathology. Tumors were excised completely, and all cases have a good outcome in the follow-up (2 to 13 y) without any adjuvant chemotherapy or radiotherapy. This data suggests that children with JGCT might have a variety of initial clinical manifestations. Pathologic examination especially immunohistochemical staining could help to diagnose JGCT. For children, adjuvant treatment may not be necessary if the tumor can be excised completely in early stage.
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Tumor de Células da Granulosa , Antígeno 12E7 , Antígenos CD/análise , Moléculas de Adesão Celular/análise , Pré-Escolar , Estradiol/sangue , Feminino , Tumor de Células da Granulosa/diagnóstico , Tumor de Células da Granulosa/patologia , Tumor de Células da Granulosa/terapia , Humanos , Lactente , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
BACKGROUND: Emergency medical service system (EMSS) in China is becoming more important. However, studies on mortality of emergency departments (EDs) patients in tertiary hospitals and on the trends in mortality of ED patients all over China are stagnant. The objective of this study was to quantify and describe the trends in mortality of ED patients in China. METHODS: Nine tertiary teaching hospitals were selected from tertiary teaching hospitals in different regions. The annual numbers of ED visits and deaths of these hospitals in 2004, 2009 and 2014 were recorded and analyzed. Chi-square test was used to compare the mortality of the EDs' visits. Moreover, data on the mortality of ED patients in China from 2005 to 2015 were summarized and analyzed from the China Health and Family Planning Statistical Yearbooks (2006-2016). RESULTS: From 2004 to 2014, the overall annual mortalities in EDs increased among the tertiary hospitals (P<0.001). However, the overall annual mortality in EDs all over China decreased from 0.12% in 2005 to 0.08% in 2015. And the mortalities of EDs patients in the eastern, central and western regions of China all decreased. In addition, the average mortality of EDs patients in northern China was obviously higher than that in southern China (P<0.05). CONCLUSION: The ED mortality was increased in tertiary hospitals while decreased all over China during the past decade, which may be partly caused by some critical challenges faced by China's EMSS, such as overcrowding and long length of stay in EDs of tertiary hospitals.
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Formation of aortic aneurysms as a consequence of augmented transforming growth factor ß (TGF-ß) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-ß. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated ß-galactosidase (SA-ß-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-ß-gal activity and mitochondrial reactive oxygen species (ROS). In addition, TGF-ß1 levels were much higher in MFS- than control-VSMCs. TGF-ß1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo, a mitochondria-targeted antioxidant, or SC-514, a NF-κB inhibitor. This suggests TGF-ß1 induces VSMC senescence through ROS-mediated activation of NF-κB signaling. It thus appears that a TGF-ß1/ROS/NF-κB axis may mediate VSMC senescence and aneurysm formation in MFS patients. This finding could serve as the basis for a novel strategy for treating aortic aneurysm in MFS.
Assuntos
Aorta/metabolismo , Senescência Celular/fisiologia , Síndrome de Marfan/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Aneurisma Aórtico/metabolismo , Humanos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , beta-Galactosidase/metabolismoRESUMO
Mesenchymal stem cells (MSCs) have shown beneficial effects in the treatment of abdominal aortic aneurysm (AAA). Nonetheless, the biological properties of adipose-derived MSCs (ASCs) from patients with AAA (AAA-ASCs) remain unclear. This study is aimed at investigating the properties of cell phenotype and function of AAA-ASCs compared with ASCs from age-matched healthy donors (H-ASCs). H-ASCs and AAA-ASCs were studied for cell phenotype, differentiation capacity, senescence, and mitochondrial and autophagic functions. Cellular senescence was examined by senescence-associated ß-galactosidase (SA-ß-gal) staining. Mitochondrial morphology was determined by MitoTracker staining. Despite the similar surface markers of AAA-ASCs and H-ASCs, AAA-ASCs exhibited altered multidifferentiation potential. Compared with H-ASCs, AAA-ASCs displayed enhanced senescence manifested by increased SA-ß-gal activity and decreased proliferation and migration ability. Furthermore, AAA-ASCs showed increased mitochondrial fusion, reactive oxygen species (ROS) production, and decreased mitochondrial membrane potential. In addition, AAA-ASCs exhibited decreased autophagy level, upregulation of IL-6 and TNF-α secretion, and downregulation of IL-10 secretion compared with H-ASCs. Nonetheless, treatment of AAA-ASCs with rapamycin (an autophagy activator) dramatically reduced secretion of IL-6 and TNF-α and enhanced secretion of IL-10. In conclusion, our study showed that AAA-ASCs exhibit senescence phenomena and decreased cell function. Understanding the specific alterations in AAA-ASCs will help explore novel strategies to restore cell function for AAA treatment.
Assuntos
Aneurisma da Aorta Abdominal/patologia , Senescência Celular , Tecido Adiposo/citologia , Idoso , Aneurisma da Aorta Abdominal/metabolismo , Autofagia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Dano ao DNA , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aß-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Proteínas de Drosophila/metabolismo , Azul de Metileno/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Corantes Azur/farmacologia , Células HEK293 , Humanos , Larva , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Sinapses/efeitos dos fármacos , Sinapses/patologia , Proteínas tau/genéticaRESUMO
More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients.