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1.
Aging (Albany NY) ; 12(3): 2453-2470, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019902

RESUMO

Recently, mitochondrial-nuclear interaction in aging has been widely studied. However, the nuclear genome controlled by natural mitochondrial variations that influence aging has not been comprehensively understood so far. We hypothesized that mitochondrial polymorphisms could play critical roles in the aging process, probably by regulation of the whole-transcriptome expression. Our results showed that mitochondria polymorphisms not only decreased the mitochondrial mass but also miRNA, lncRNA, mRNA, circRNA and metabolite profiles. Furthermore, most genes that are associated with mitochondria show age-related expression features (P = 3.58E-35). We also constructed a differentially expressed circRNA-lncRNA-miRNA-mRNA regulatory network and a ceRNA network affected by the mitochondrial variations. In addition, Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the genes affected by the mitochondrial variation were enriched in metabolic activity. We finally constructed a multi-level regulatory network with aging which affected by the mitochondrial variation in Caenorhabditis elegans. The interactions between these genes and metabolites have great values for further aging research. In sum, our findings provide new evidence for understanding the molecular mechanisms of how mitochondria influence aging.

2.
Cell Death Dis ; 11(1): 75, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001672

RESUMO

The bivalent domain (BD) at promoter region is an unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of BDs in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA (vascular endothelial growth factor A) stimulation, we discovered that BDs are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The BDs responsive to VEGFA have more permissive chromatin environment comparing to other BDs. The initial activation of bivalent genes depends on RNAPII pausing release induced by EZH1 rather than removal of H3K27me3. The later suppression of bivalent gene expression depended on KDM5A recruitment by its interaction with PRC2. Importantly, EZH1 promoted both in vitro and in vivo angiogenesis by upregulating EGR3, whereas KDM5A dampened angiogenesis. Collectively, this study demonstrates a novel dual function of BDs in endothelial cells to control VEGF responsiveness and angiogenesis.

3.
Diabetologia ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008054

RESUMO

AIMS/HYPOTHESIS: Although obesity is a predisposing factor for pancreatic beta cell dysfunction, the mechanisms underlying its negative effect on insulin-secreting cells is still poorly understood. The aim of this study was to identify islet long non-coding RNAs (lncRNAs) involved in obesity-mediated beta cell dysfunction. METHODS: RNA sequencing was performed to analyse the islets of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). The function in beta cells of the selected lncRNA 1810019D21Rik (referred to in this paper as ROIT [regulator of insulin transcription]) was assessed after its overexpression or knockdown in MIN6 cells and primary islet cells, as well as in siRNA-treated mice. Then, RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation and bisulphite sequencing were performed to investigate the mechanism of ROIT regulation of islet function. RESULTS: ROIT was dramatically downregulated in the islets of the obese mice, as well as in the sera of obese donors with type 2 diabetes, and was suppressed by HNF1B. Overexpression of ROIT in MIN6 cells and islets led to improved glucose homeostasis and insulin transcription. Investigation of the mechanism involved showed that ROIT bound to DNA methyltransferase 3a and caused its degradation through the ubiquitin proteasome pathway, which blocked the methylation of the Nkx6.1 promoter. CONCLUSIONS/INTERPRETATION: These findings functionally suggest a novel link between obesity and beta cell dysfunction via ROIT. Elucidating a precise mechanism for the effect of obesity on lncRNA expression will broaden our understanding of the pathophysiological development of diabetes and facilitate the design of better tools for diabetes prevention and treatment. DATA AVAILABILITY: The raw RNA sequencing data are available from the NCBI Gene Expression Omnibus (GEO series accession number GSE139991).

4.
Proc Natl Acad Sci U S A ; 117(7): 3427-3432, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32015109

RESUMO

High levels of ultrafine particles (UFPs; diameter of less than 50 nm) are frequently produced from new particle formation under urban conditions, with profound implications on human health, weather, and climate. However, the fundamental mechanisms of new particle formation remain elusive, and few experimental studies have realistically replicated the relevant atmospheric conditions. Previous experimental studies simulated oxidation of one compound or a mixture of a few compounds, and extrapolation of the laboratory results to chemically complex air was uncertain. Here, we show striking formation of UFPs in urban air from combining ambient and chamber measurements. By capturing the ambient conditions (i.e., temperature, relative humidity, sunlight, and the types and abundances of chemical species), we elucidate the roles of existing particles, photochemistry, and synergy of multipollutants in new particle formation. Aerosol nucleation in urban air is limited by existing particles but negligibly by nitrogen oxides. Photooxidation of vehicular exhaust yields abundant precursors, and organics, rather than sulfuric acid or base species, dominate formation of UFPs under urban conditions. Recognition of this source of UFPs is essential to assessing their impacts and developing mitigation policies. Our results imply that reduction of primary particles or removal of existing particles without simultaneously limiting organics from automobile emissions is ineffective and can even exacerbate this problem.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32041887

RESUMO

Although regional haze adversely affects human health and possibly counteracts global warming from increasing levels of greenhouse gases, the formation and radiative forcing of regional haze on climate remain uncertain. By combining field measurements, laboratory experiments, and model simulations, we show a remarkable role of black carbon (BC) particles in driving the formation and trend of regional haze. Our analysis of long-term measurements in China indicates declined frequency of heavy haze events along with significantly reduced SO2, but negligibly alleviated haze severity. Also, no improving trend exists for moderate haze events. Our complementary laboratory experiments demonstrate that SO2 oxidation is efficiently catalyzed on BC particles in the presence of NO2 and NH3, even at low SO2 and intermediate relative humidity levels. Inclusion of the BC reaction accounts for about 90-100% and 30-50% of the sulfate production during moderate and heavy haze events, respectively. Calculations using a radiative transfer model and accounting for the sulfate formation on BC yield an invariant radiative forcing of nearly zero W m-2 on the top of the atmosphere throughout haze development, indicating small net climatic cooling/warming but large surface cooling, atmospheric heating, and air stagnation. This BC catalytic chemistry facilitates haze development and explains the observed trends of regional haze in China. Our results imply that reduction of SO2 alone is insufficient in mitigating haze occurrence and highlight the necessity of accurate representation of the BC chemical and radiative properties in predicting the formation and assessing the impacts of regional haze.

6.
Bioorg Chem ; 96: 103614, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-32007725

RESUMO

Phytochemical investigation into the calyx of Physalis alkekengi L. var franchetii (Mast) Makino resulted in the isolation of ten cytotoxic withanolides, including five new withanolides, 1-5. Compounds 2-4 were obtained as epimeric withaphysalins. The new structures were elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. The withanolides were evaluated for their cytotoxic activities against the A549 and K562 cell lines. Compounds 1 and 8 exhibited potent cytotoxic activity against both cell lines with IC50 values of 1.9-4.3 µM and induced typical apoptosis as evaluated by flow cytometric analysis. Further studies indicated that 1 and 8 displayed antitumour effects by suppressing the PI3K-Akt-mTOR signalling pathway.

7.
Gene Expr Patterns ; 35: 119096, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32027977

RESUMO

Glomerular capillary formation is one of the fundamental mysteries in renal developmental biology. However, there are still debates on this issue, and its detailed formation process has not been clarified. To resolve this problem, we performed antibody staining with ultra-thick section on embryonic and postnatal mouse kidneys. We obtained the expression patterns of several genes that play an important role in the development of glomerular capillaries. We found that blood vessel of the fetal kidneys expanded through proliferation and sprouting. During the comma-stage and S-shaped stage, 3-4 capillaries began to bud and migrate into the glomerular cleft, forming a capillary bed in the Bowman's capsule. Then, the capillary bed expanded into mature glomerular capillary by intussusceptive angiogenesis. The afferent and efferent arterioles were formed through pruning. The distribution of VEGFA in the nephron epithelial cells but not only in podocytes, induced multiple capillaries sprouted into the glomerular cleft. And CXCR4 played an important role in the differentiation and expansion of capillary bed into glomerular capillary. Immunofluorescence performed with ultra-thick section allowed us to investigate the development of complex structure tissues systematically and comprehensively.

8.
Food Res Int ; 128: 108869, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31955777

RESUMO

China is the largest planting country of asparagus (Asparagus officinalis L.) in the world. Caoxian, as the famous asparagus township in China, enjoys a reputation for producing asparagus with high yield and good quality, due to its unique geological characteristic. In this study, a method of reverse-phase ultraperformance liquid chromatography coupled with electrospray tandem mass spectrometry (RP-UPLC-ESI-MS/MS) was established for profiling metabolites from three segments (tip, mid, and base) of 'Caoxian white and green Asparagus'. A total of 114 metabolites were identified, among them, 43 were found for the first time in this vegetable. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to provide an overview of the metabolite profiles of Caoxian asparagus and to separate different segments of spears. The variables most decisive to discriminate among segments included 9 of the metabolites tentatively identified. This study will help to improve the protection of Caoxian asparagus geographical indication.

9.
Sci Transl Med ; 12(526)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941827

RESUMO

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting ß-amyloid (Aß) and tau, two key pathological components of AD pathogenesis. Our results show that Aß oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3ß (GSK3ß) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3ß/tau activation in response to nanomolar accumulations of extracellular Aß, which is 50- to 100-fold lower than the amount required to activate GSK3ß by Aß alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aß proteotoxicity, which might have strong implications for the interpretation of Aß clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

10.
Mol Oncol ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31944556

RESUMO

Exosomes released by tumor cells have been recently identified as important determinants of tumor progression. They often carry circular RNAs (circRNAs) that are differentially-expressed in tumors and may regulate tumorigenesis and metastasis. Here, we showed that supernatant of 97H HCC cell line could promote metastasis in L02 human liver cells and HCC cell lines. Moreover, we determined that circ_MMP2 (has_circ_0039411) could be delivered by 97H- or LM3-cell derived exosomes to L02 and HepG2 cell cultures. High expression of circ_MMP2 led to the upregulation of its host gene matrix metallopeptidase 2 (MMP2) via the sponging of miR-136-5p. Rescue assays demonstrated that miR-136-5p and MMP2 were two essential participants in HCC metastasis. Finally, high level of circ_MMP2 or MMP2, as well as low level of miR-136-5p, were correlated with low overall survival of HCC patients. Our study highlights a novel molecular pathway in HCC cell-derived exosomes.

11.
J Diabetes Investig ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981444

RESUMO

AIM: To analyze the strength of association between fasting plasma glucose (FPG), 2h-postprandial glucose (2hPPG), hemoglobin A1c (HbA1c), disposition index (DI) and nine anthropometrics measures, to explore the best indicator for hyperglycemia. MATERIALS AND METHODS: Analyses were based on the cross-sectional data of 3 572 adults from the Pinggu Metabolic Disease study. Anthropometrics were measured, visceral fat area (VFA) and subcutaneous fat area (SFA) were calculated using abdominal CT scan. Linear regression was used to analyze the association between FPG, 2hPPG, HbA1c, DI and nine anthropometrics measures (height, weight, waist circumference (WC), body mass index (BMI) and waist to hip ratio (WHR), waist to height ratio, VFA, SFA, and visceral to subcutaneous ratio (VSR)). Logistic regression was further performed to understand the association between per standard increase and risk for hyperglycemia. RESULTS: Higher VFA and SFA were associated with higher FPG, 2hPPG, HbA1c and DI after adjusting for other covariates. The strongest association observed after adjustment was WC for FPG, with one standard deviation (SD) greater WC associated with 1.70 increased odds; WHR for 2h PPG, with one SD greater WHR associated with 1.83 increased odds. The strength of association between VFA and FPG, 2h PPG, HbA1c and DI was less than WHR and WC, but slightly stronger than BMI. Stratified analyses showed that VFA perform better as an anthropometrics indicator in predicting hyperglycaemic risk in female than male. CONCLUSION: WHR and WC remains the best indicators for hyperglycemic risk among healthy Chinese population.

12.
Cell Death Dis ; 11(1): 15, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907356

RESUMO

Oral lichen planus (OLP) is a kind of oral epithelial disorder featured with keratinocyte apoptosis and inflammatory reaction. The pathogenesis of OLP remains an enigma. Herein, we showed that the levels of miR-26a/b were robustly down-regulated in oral mucosal biopsies, serum and saliva in OLP patients compared with healthy control. Moreover, we found the binding sites of vitamin D receptor (VDR) in the promoter regions of miR-26a/b genes and proved that the induction of miR-26a/b was VDR dependent. The reduction of miR-26a/b expression was also detected in the oral epithelium of vitamin D deficient or VDR knockout mice. miR-26a/b inhibitors enhanced apoptosis and Type 1T helper (Th1) cells-related cytokines production in oral keratinocytes, whereas miR-26a/b mimics were protective. Mechanistically, we analyzed miRNA target genes and confirmed that miR-26a/b blocked apoptosis by directly targeting Protein Kinase C δ (PKCδ) which promotes cellular apoptotic processes. Meanwhile, miR-26a/b suppressed Th1-related cytokines secretion through targeting cluster of the differentiation 38 (CD38). In accordant with miR-26a/b decreases, PKCδ and CD38 levels were highly elevated in OLP patients' samples. Taken together, our present investigations suggest that vitamin D/VDR-induced miR-26a/b take protective functions in OLP via both inhibiting apoptosis and impeding inflammatory response in oral keratinocytes.

13.
Medicine (Baltimore) ; 99(2): e18697, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914072

RESUMO

RATIONALE: Giant porokeratosis is considered to be a variant of porokeratosis of Mibelli (PM) by some medical scholars. Porokeratosis can develop into several epidermal malignant tumors, such as Bowen disease and basal cell carcinoma, among which squamous cell carcinoma (SCC) is the most common. PATIENT CONCERNS: The patient was a 53-year-old man who was admitted to our hospital due to postoperative recurrence and metastasis as SCC arising from giant PM in his left leg and foot. DIAGNOSES: The pathological results are porokeratosis and well-differentiated squamous cell carcinoma. Positron emission tomography and computed tomography results show the local recurrence of the tumor with multiple lymph node metastasis. INTERVENTIONS: This patient was transferred to orthopedic surgery for amputation of the middle and lower left thigh. OUTCOMES: Follow-up for 3 months has shown no recurrence after the surgery. LESSONS: This report reminds us to pay close attention to the likelihood of giant porokeratosis. The physicians should explore all clinical possibilities to avoid misdiagnosis of this rare disease.Although the recurrence rate of SCC arising from giant PM is very low, the surgical resection region should be expanded appropriately such as the en-block resection.


Assuntos
Carcinoma de Células Escamosas/secundário , Poroceratose/patologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Poroceratose/cirurgia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
14.
Sci Rep ; 10(1): 301, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942011

RESUMO

MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that miR-27b is down-regulated in the oral specimens of patients suffering with oral lichen planus (OLP), the molecular mechanism of miR-27b decrease remains a large mystery, and the expression of miR-27a in OLP is not well explored. Here, we demonstrated both miR-27a and miR-27b, compared with healthy controls, were reduced in the oral biopsies, serum and saliva samples derived from OLP patients. The reductions of miR-27a/b were also confirmed in the lipopolysaccharide (LPS)- or activated CD4+ T cell-treated human oral keratinocytes (HOKs). Furthermore, we found vitamin D receptor (VDR) binding sites in the promoters of miR-27a/b genes and verified this finding. We also tested miR-27a/b levels in the oral epithelium from paricalcitol-treated, vitamin D deficient or VDR knockout mice. In the rescue experiments, we confirmed vitamin D and VDR inhibited LPS- or activated CD4+ T cell-induced miR-27a/b reductions in HOKs. In sum, our results show that vitamin D/VDR signaling induces miR-27a/b in oral lichen planus.

15.
J Am Chem Soc ; 142(5): 2204-2207, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31927964

RESUMO

The ability of the doublet excited state of perylene diimide anion radical 2(PDI-•)* to reduce aromatic electron acceptors was probed by picosecond time-resolved transient absorption (TA) spectroscopy. Excitation of PDI-• produces visible TA due to 2(PDI-•)* that decays with τ = 160 ps. Aromatic electron acceptors with varying reduction potential quench 2(PDI-•)* and, in some cases, give a new visible region absorption that is attributed to the products of bimolecular photoinduced electron transfer, 2(PDI-•)* + Ar-X → PDI + Ar-X-•. Stern-Volmer quenching of 2(PDI-•)* accomplished with a series of acceptors provides bimolecular quenching rate constants as a function of acceptor reduction potential. Rehm-Weller analysis of the electron transfer quenching data affords the potential for the (*PDI-•/PDI) electrochemical half-reaction as -1.87 V vs SCE.

16.
Int Immunopharmacol ; 80: 106207, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31958742

RESUMO

BACKGROUNDS: Myocardial ischemia-reperfusion injury (MI-RI) has many adverse complications with high mortality rate. It has been demonstrated that the induced cardiospheres (iCS), generated from adult skin fibroblasts via somatic reprogramming, represents a novel source for cell therapy in myocardial infarction. However, whether the iCS could also be applied to treat MI-RI remains unclear. Thus, we investigated the therapeutic application of iCS in the mice model MI-RI. METHODS: The mice model of MI-RI was established and the iCS cells were transplanted to the mice via tail-vein injection. Left ventricular (LV) dimensions and LV pressure-volume measurements were assessed by parasternal long-axis echocardiography. The infarct size was determined by histology analysis. And the inflammatory responses were analyzed by using enzyme-linked immunosorbent assay (ELISA). RESULTS: The LV function was significantly improved after the iCS transplantation when compared to the vehicle control group, including the end-systolic pressure and dP/dtMax. Furthermore, the infarct size was significantly decreased after the iCS transplantation. The protein levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), were down-regulated by the iCS transplantation while the IL-10 was up-regulated. The anti-inflammatory factor IL-10 was found to be expressed and secreted by the iCS cells and knocking down the IL-10 in iCS would significantly impair the therapeutic effects of iCS in the mice model of MI-RI. CONCLUSION: The present study indicated that the iCS had therapeutic effects on the mice model of MI-RI through secreting the IL-10.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31944958

RESUMO

This paper proposes an approach to content-preserving image stitching with regular boundary constraints, which aims to stitch multiple images to generate a panoramic image with a piecewise rectangular boundary. Existing methods treat image stitching and rectangling as two separate steps, which may result in suboptimal results as the stitching process is not aware of the further warping needs for rectangling. We address these limitations by formulating image stitching with regular boundaries in a unified optimization. Starting from the initial stitching results produced by the traditional warping-based optimization, we obtain the irregular boundary from the warped meshes by polygon Boolean operations which robustly handle arbitrary mesh compositions. By analyzing the irregular boundary, we construct a piecewise rectangular boundary. Based on this, we further incorporate line and regular boundary preservation constraints into the image stitching framework, and conduct iterative optimization to obtain an optimal piecewise rectangular boundary. Thus we can make the boundary of the stitching results as close as possible to a rectangle, while reducing unwanted distortions. We further extend our method to video stitching, by integrating the temporal coherence into the optimization. Experiments show that our method efficiently produces visually pleasing panoramas with regular boundaries and unnoticeable distortions.

18.
Nanotechnology ; 31(19): 195503, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31978920

RESUMO

We herein report a DNA hairpin structure containing a polycytosine loop region, and this hairpin can operate like a nanomachine allowing independently controlled stability of the i-motif loop and duplex stem region. This was made possible by the opposite salt-dependent stability of DNA duplex and hairpin, thus providing a new method for designing molecular devices or switches design. A singly-labeled fluorescent method was used to measure the stability of an i-motif DNA in the presence of various metal ions. Salt in general destabilizes the i-motif but stabilizes duplex DNA, allowing us to engineer an i-motif containing hairpin for modulating the stability of each secondary structure independently.

19.
Anticancer Drugs ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913196

RESUMO

Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data showed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.

20.
Anal Chim Acta ; 1099: 1-15, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-31986265

RESUMO

Nucleic acid-based techniques could achieve highly sensitive detection by amplifying template molecules to millions of folds. It has been one of the most valued analytical methods and is applied in many detection fields, such as diagnosis of infectious diseases, food safety assurance and so on. Nucleic acid-based techniques consist of three steps: nucleic acid extraction, amplification, and product detection. Among them, the detection step plays a vital role because it shows the results directly. As the trend of detection is simple, rapid and instrument-free, it is of necessity to carry out visual detection, where the result read-out could be visible and distinguished by the naked eye. In this critical review, advanced visual detection methods are summarized and discussed in detail, aiming to promote the potential application in on-site detection.

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