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1.
Micron ; 145: 103060, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33799086

RESUMO

Quantification of immuno-gold labeling can provide valuable information on the quantity and localization of a target within a region of interest (ROI). Background subtraction usually requires preparation of material with a deliberately reduced amount of target component often by gene knockout/knockdown. This paper reports a modified method without the need for gene knockout/knockdown, by using a region outside the ROI as a background and non-immune serum to verify the reliability of the data. An optimized parameter for use in image processing was also developed to improve semi-automatic segmentation of gold particles, by using the standard deviation of pixel intensity together with default parameters (size and intensity) to improve specificity. The modified methods were used to quantify the gold labeling of various components within chloroplasts and their 3 sub-organelle compartments (thylakoid, stroma and starch). Rubisco, actin, myosin, ß-tubulin, Endoplasmic reticulum-retention signal HDEL, Sterol methyltransferase 1, and double stranded RNA were all effectively and consistently quantified at the level of the different sub-chloroplast compartments. The approach should be applicable more widely for high resolution labelling of samples in which a background requiring gene knockout/knockdown is not a realistic option.

2.
J Immunol Res ; 2021: 6693542, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816637

RESUMO

Increasing evidence has suggested that T helper 17 (Th17) cells play a central role in the pathogenesis of ocular immune disease. The association between pathogenic Th17 cells and the development of uveitis has been confirmed in experimental and clinical studies. Several cytokines affect the initiation and stabilization of the differentiation of Th17 cells. Therefore, understanding the mechanism of related cytokines in the differentiation of Th17 cells is important for exploring the pathogenesis and the potential therapeutic targets of uveitis. This article briefly describes the structures, mechanisms, and targeted drugs of cytokines-including interleukin (IL)-6, transforming growth factor-ß1 (TGF-ß1), IL-1ß, IL-23, IL-27, IL-35, IL-2, IL-4, IL-21, and interferon (IFN)-γ-which have an important influence on the differentiation of Th17 cells and discusses their potential as therapeutic targets for treating autoimmune uveitis.

3.
J Mol Med (Berl) ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33770188

RESUMO

Reactive oxygen species (ROS), a by-product of oxygen metabolism mainly originating from mitochondria, participate in many pathological processes related to ophthalmopathy. Excessive production of ROS leads to oxidative stress, which influences the permeability, proliferation, migration, and tube formation of human retinal microcapillary endothelial cells (HRMECs). The molecular mechanisms underlying the effects of ROS are not clear. In Vldlr-/- mice, we used fundus fluorescein angiography and retinal flat mount staining to observe the effect of polypyrimidine tract-binding protein-associated splicing factor (PSF) on pathological retinal neovascularization in vivo. Additionally, in human retinal microvascular endothelial cells treated with 4-HNE, cell viability, tube formation, wound healing, and Transwell assays were performed to study the effect of PSF on the proliferation, migration, and tube formation of retinal vascular endothelial cells in vitro. Moreover, reactive oxygen species assay, real-time PCR, and Western blot were included to analyze the potential mechanism of PSF in the above series of effects. PSF ameliorated intraretinal neovascularization (IRNV) in vivo in Vldlr-/- mice. Under 4-hydroxynonenal (4-HNE) conditions in vitro, PSF reprogrammed mitochondrial bioenergetic and glycolytic profiles. It also reduced ROS levels and inhibited 4-HNE-induced angiogenesis, which involves the proliferation, migration, and tube formation of HRMECs. These results suggest that PSF participates in the regulation of HRMECs proliferation and migration during the development of pathological angiogenesis. We demonstrated that PSF enhanced Nrf2 activation and heme oxygenase-1 (HO-1) expression via extracellular signal-regulated kinase (ERK) and Akt signaling in HRMECs, which subsequently resulted in intracellular ROS scavenging. PSF restored endoplasmic reticulum (ER) redox homeostasis, which was indicated by an increase in protein disulfide isomerase (PDI) and Ero-1α and a reduction in GRP78 and C/EBP homologous protein (CHOP). PSF also attenuated ER stress via regulation of the protein kinase R (PKR)-like endoplasmic reticulum kinase PERK/eukaryotic translation factor 2 alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway in 4-HNE-treated HRMECs. Our research shows that PSF may be a potential antioxidant that regulates pathological angiogenesis through ERK-AKT/Nrf2/HO-1 and PERK/eIF2α/ATF4 signal regulation. KEY MESSAGES: Reactive oxygen species (ROS) mainly originating from mitochondria is a by-product of oxygen metabolism in the body and participates in the pathological process related to multiple blindness-related ophthalmopathy. Moreover , excessive production of ROS will lead to oxidative stress. Consequently, oxidative stress influences the permeability, proliferation, migration, and tube formation of human retinal microcapillary endothelial cells (HRMECs). The molecular mechanisms underlying the effects of ROS remain unclear. Here, we reveal that Polypyrimidine tract-binding protein-associated splicing factor (PSF) ameliorates intraretinal neovascularization (IRNV) in vivo in Vldlr-/- mice. Furthermore, under 4-HNE conditions in vitro, PSF reprograms mitochondrial bioenergetic and glycolytic profiles, reduces ROS levels, and inhibits 4-HNE-induced angiogenesis, which involves the proliferation, migration, and tube formation of HRMECs, suggesting that it participates in regulating the proliferation and migration of HRMECs during the development of pathological angiogenesis. Furthermore, PSF enhances Nrf2 activation and HO-1 expression through ERK and AKT signaling in HRMECs, resulting in intracellular ROS scavenging. PSF restores endoplasmic reticulum (ER) redox homeostasis, as indicated by an increase in PDI and Ero-1α and a reduction in GRP78 and CHOP. PSF also attenuates ER stress by regulating the PERK/eIF2α/ATF4 pathway in 4-HNE-treated HRMECs.

4.
J Am Heart Assoc ; 10(6): e018999, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33719498

RESUMO

Background Mounting evidence suggests that circulating microRNAs (miRNAs) are critical indicators of cardiovascular disease. However, prospective studies linking circulating miRNAs to incident acute coronary syndrome (ACS) are limited, and the underlying effect of associated miRNA on incident ACS remains unknown. Methods and Results Based on a 2-stage prospective nested case-control design within the Dongfeng-Tongji cohort, we profiled plasma miRNAs from 23 pairs of incident ACS cases and controls by microarray and validated the candidate miRNAs in 572 incident ACS case-control pairs using quantitative real-time polymerase chain reaction. We observed that plasma miR-4286 was associated with higher risk of ACS (adjusted odds ratio according to an interquartile range increase, 1.26 [95% CI, 1.07-1.48]). Further association analysis revealed that triglyceride was positively associated with plasma miR-4286, and an interquartile range increase in triglyceride was associated with an 11.04% (95% CI, 3.77%-18.83%) increase in plasma miR-4286. In addition, the Mendelian randomization analysis suggested a potential causal effect of triglyceride on plasma miR-4286 (ß coefficients: 0.27 [95% CI, 0.01-0.53] and 0.27 [95% CI, 0.07-0.47] separately by inverse variance-weighted and Mendelian randomization-pleiotropy residual sum and outlier tests). Moreover, the causal mediation analysis indicated that plasma miR-4286 explained 5.5% (95% CI, 0.7%-17.0%) of the association of triglyceride with incident ACS. Conclusions Higher level of plasma miR-4286 was associated with an increased risk of ACS. The upregulated miR-4286 in plasma can be attributed to higher triglyceride level and may mediate the effect of triglyceride on incident ACS.

5.
Am J Epidemiol ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33728442

RESUMO

Present shift work has been associated with coronary heart disease (CHD) among employed workers, but it remains unclear whether shift work in the past is still associated with CHD in retired workers. We recruited 21,802 retired workers in Shiyan, China in 2008-2010 and 2013, and followed them up for CHD events to December 31, 2018. Retired workers with longer duration of past shift work had higher CHD risks (hazard ratios for those with ≤5.0, 5.25 to 10.0, 10.5 to 20.0, and >20.0 years of past shift work were 1.05 (95% confidence interval: 0.94, 1.16), 1.08 (0.94, 1.25), 1.23 (1.07, 1.42), and 1.28 (1.08, 1.51)). The association was substantially higher among services or sales workers than among manufacturing or manual labor workers (hazard ratio for every 5-year increase in past shift work, 1.11 (95% confidence interval: 1.05, 1.16) versus 1.02 (0.98, 1.06)). Moreover, the risk was lower among those who were physically active than their inactive counterparts (P for interaction, 0.019). Longer duration of past shift work was associated with higher risk of incident CHD among retired workers, especially those from services or sales sectors. Physical exercise might be beneficial in reducing the excess risk.

6.
J Hazard Mater ; 414: 125519, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33676251

RESUMO

Mosaic loss of chromosome Y (mLOY) is an indicator of genome instability, but the environmental stressors of mLOY remained largely unknown. In this study, we detected the internal exposure levels of 11 polycyclic aromatic hydrocarbon (PAH) metabolites and 22 metals among 888 coke-oven workers, and calculated their blood mLOY based on genome-wide SNP genotyping data and presented as median log R ratio (mLRR-Y). The generalized linear model (GLM), LASSO, and Bayesian kernel machine regression (BKMR), were used to select mLOY-relevant chemicals. The results of these models consistently suggested the negative dose-response relationships of urinary 1-hydroxynaphthalene (1-OHNa), antimony (Sb), and molybdenum (Mo) with mLRR-Y. There were no pairwise interactions between these three chemicals (Pinteraction > 0.05), but subjects with high exposure to ≥ 2 kinds of these chemicals showed reducing mLRR-Y [ß(95%CI) = - 0.015(- 0.023, - 0.008)], increasing oxidative DNA damage (marked by 8-hydroxydeoxyguanosine) [ß(95%CI) = 0.625(0.454, 0.796)] and chromosome damage (marked by micronucleus frequency in lymphocytes) [frequency ratio (FR) and 95%CI = 1.146(1.047, 1.225)] than those with low exposure to all these chemicals. The combined effects of 1-OHNa, Sb, and Mo on elevating DNA damage may partly explain their joint effects on increased blood mLOY. These results provided a new insight into environmental hazards co-exposure on chromosome-Y deletions.

7.
Sleep Breath ; 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33738752

RESUMO

PURPOSE: To investigate the associations between sleep duration and atherosclerotic cardiovascular disease (ASCVD) risk and the potential mechanism. METHODS: Overall, 24,471 subjects without ASCVD were included from Dongfeng-Tongji (DFTJ) cohort. Data collection included questionnaires and general medical examinations. We used logistic regression models and generalized linear models to examine the associations between sleep duration, peripheral white blood cell (WBC) counts, and 10-year ASCVD risk. Mediation analyses were further performed to assess the potential role of peripheral WBC counts in the associations between sleep duration and 10-year ASCVD risk. RESULTS: Increased risk of 10-year ASCVD was observed as sleep duration extended. After adjusting for potential confounders, the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of 10-year ASCVD were 1.24 (1.11-1.38), 1.12 (1.03-1.22), and 1.21(1.08-1.36) for individuals with nighttime sleeping duration of ≥ 9 h, daytime napping duration of > 30 min, and daily sleep duration of ≥ 9 h, respectively. Peripheral WBC counts mediated 14.1%, 14.5%, and 12.6% in the associations of nighttime sleep duration of ≥ 9 h, daytime napping duration of > 30 min and daily sleep duration of ≥ 9 h with 10-year ASCVD risk, respectively. CONCLUSIONS: Extended sleep durations are associated with the increased 10-year ASCVD risk, and the associations are partially mediated by peripheral WBC counts.

8.
J Neurosci Methods ; : 109125, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33711356

RESUMO

BACKGROUND: To understand information coding in single neurons, it is necessary to analyze subthreshold synaptic events, action potentials (APs), and their interrelation in different behavioral states. However, detecting excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) in behaving animals remains challenging, because of unfavorable signal-to-noise ratio, high frequency, fluctuating amplitude, and variable time course of synaptic events. NEW METHOD: We developed a method for synaptic event detection, termed MOD (Machine-learning Optimal-filtering Detection-procedure), which combines concepts of supervised machine learning and optimal Wiener filtering. Experts were asked to manually score short epochs of data. The algorithm was trained to obtain the optimal filter coefficients of a Wiener filter and the optimal detection threshold. Scored and unscored data were then processed with the optimal filter, and events were detected as peaks above threshold. RESULTS: We challenged MOD with EPSP traces in vivo in mice during spatial navigation and EPSC traces in vitro in slices under conditions of enhanced transmitter release. The area under the curve (AUC) of the receiver operating characteristics (ROC) curve was, on average, 0.894 for in vivo and 0.969 for in vitro data sets, indicating high detection accuracy and efficiency. COMPARISON WITH EXISTING METHODS: When benchmarked using a (1 - AUC)-1 metric, MOD outperformed previous methods (template-fit, deconvolution, and Bayesian methods) by an average factor of 3.13 for in vivo and 6.42 for in vitro data sets, but showed comparable (template-fit, deconvolution) or higher (Bayesian) computational efficacy. CONCLUSIONS: MOD may become an important new tool for large-scale, real-time analysis of synaptic activity.

9.
Life Sci ; 274: 119313, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667511

RESUMO

AIMS: To design and evaluate a novel AWRK6 peptide-based long-acting GLP-1 receptor agonist (GLP-1RA) conjugated a recombinant polyethylene glycol mimetic (XTEN protein) with significant therapeutic potential on type 2 diabetes mellitus (T2DM) alone as well as Herpes simplex virus type 2 (HSV-2) infection in combination with double shRNA. MAIN METHODS: First, four AWRK6 analogs (termed XA-1 to XA-4) were designed and produced by solid phase synthesis strategy. Further surface plasmon resonance (SPR) measurement and in vitro cAMP accumulation assay were performed to detect the GLP-1R binding affinities and GLP-1R activation, respectively. The in vivo efficacy evaluation including pharmacokinetic test, oral glucose tolerance test (OGTT), hypoglycemic duration test and chronic pharmacodynamics study in rodent animals were all carefully performed. KEY FINDINGS: Four XA peptides were synthesized with purity >99%. High binding affinity as well as activation potency of XA-4 for GLP-1R were demonstrated by SPR and cell-based luciferase reporter assay, respectively. Additionally, XA-4 exhibited the long-lasting antidiabetic effects in the multiple OGTTs, hypoglycemic duration test and chronic study in mice. Furthermore, combined treatment of XA-4 and double shRNA (D-shRNA) achieved potent antiviral effects in HSV-2 infected HEK293 cells. SIGNIFICANCE: XA-4 exhibited promising pharmaceutical potential to be a therapeutic drug for treating T2D, and also held potential to against the HSV-2 infection, which is really an accidental discovery. The strategy of recombinant XTENylation can also be applied to other peptides or small molecules for the development of long-acting therapeutic drugs.

10.
Sci Total Environ ; 771: 145401, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545483

RESUMO

Associations of bisphenol A (BPA) levels with renal disease are inconsistent. The present prospective study aims to evaluate the association of serum BPA levels with chronic kidney disease (CKD) in a Chinese middle-aged and elderly population. At baseline 1370 participants (mean age 61.7 years, 58.8% females) free of kidney disease and cancer were followed up nearly 10 years. Baseline serum BPA concentration was measured with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Multivariable logistic regression model was used to investigate relationship between serum BPA levels and incident CKD risk. During a 10-year follow-up, 246 individuals developed CKD. Baseline serum BPA concentration was 2.92 (1.00, 5.27) ng/mL. At baseline, after adjustment for multiple covariates serum BPA levels were negatively correlated with eGFR levels (ß = -0.068, P = 0.009). Compared to those with low levels of serum BPA, participants with high levels had a significant negative association with CKD [ORs (95% CI) = 0.35 (0.25, 0.50), P < 0.001], and this association was not modified by conventional risk factors. The negative associations remained in females but not in males (P for interaction = 0.016). Significant interaction between baseline eGFR and serum BPA levels on CKD risk was also found (P for interaction = 0.027), Except subjects with 60-70 mL/min/1.73 m2 eGFR at baseline, inverse association robustly existed between serum BPA levels and incident CKD risk in the other eGFR subgroups. Further studies are needed to validate our findings.


Assuntos
Compostos Benzidrílicos , Insuficiência Renal Crônica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenóis , Estudos Prospectivos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco
11.
Mar Drugs ; 19(2)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540563

RESUMO

Six undescribed polyhydroxy p-terphenyls, namely asperterphenyllins A-F, were isolated from an endophytic fungus Aspergillus candidus LDJ-5. Their structures were determined by NMR and MS data. Differing from the previously reported p-terphenyls, asperterphenyllin A represents the first p-terphenyl dimer connected by a C-C bond. Asperterphenyllin A displayed anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 53 µM and 21 µM, respectively. The anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity of p-terphenyls are reported for the first time. Asperterphenyllin G exhibited cytotoxicity against nine cell lines with IC50 values ranging from 0.4 to 1.7 µM. Asperterphenyllin C showed antimicrobial activity against Proteus species with a MIC value of 19 µg/mL.

12.
J Cell Mol Med ; 25(6): 3063-3079, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33599104

RESUMO

Primary open-angle glaucoma (POAG) is characterized by irreversible neurodegeneration accompanied by visual field defects and high intraocular pressure. Currently, an effective treatment is not available to prevent the progression of POAG, other than treatments to decrease the high intraocular pressure. We performed proteomic analysis of aqueous humour (AH) samples from patients with POAG combined with cataract and patients with cataract to obtain a better understanding of the pathogenesis of POAG and explore potential treatment targets for this condition. Samples were collected from 10 patients with POAG combined with cataract and 10 patients with cataract. Samples from each group were pooled. A high-resolution, label-free, liquid chromatography-tandem mass spectrometry-based quantitative proteomic analysis was performed. In total, 610 proteins were identified in human AH samples from the two groups. A total of 48 up-regulated proteins and 49 down-regulated proteins were identified in the POAG combined with cataract group compared with the control group. Gene Ontology (GO) analysis revealed key roles for these proteins in inflammation, immune responses, growth and development, cellular movement and vesicle-mediated transport in the biological process category. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated the down-regulated expression of glutathione S-transferase P (GSTP1) in the glutathione metabolism signalling pathway in the POAG combined with cataract group. Additionally, certain significantly differentially expressed proteins in the proteomic profile were verified by enzyme-linked immunosorbent assay (ELISA). GSTP1 levels were reduced in the human AH samples from the POAG combined with cataract group, based on the results of ELISA and proteomic profiling. Therefore, GSTP1, a redox-related marker, may be involved in the pathological process of POAG and may become a treatment target in the future.

13.
Biomed Res Int ; 2021: 8109134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33575344

RESUMO

Bone morphogenetic proteins (BMPs), a member of the transforming growth factor ß (TGF-ß) superfamily, are abundant in human ocular tissues and play an important role in lens development. Targeted deletion of BMP-4 in mice results in failure of lens placode formation. Following lens maturation, the formation of senile cataracts is demonstrably associated with free radical-related oxidative stress. Previous studies reported that BMPs play an antiapoptotic role in cells under oxidative stress, and the BMP-4 signal is important in inflammation regulation and homeostasis. BMP-4 evidently suppressed the apoptosis of human lens epithelial cells (HLECS) under oxidative stress induced by H2O2. This protective antiapoptotic effect is partly due to a decrease in caspase-3 activity and reactive oxygen species (ROS) level. Furthermore, the expression of activating transcription factor- (ATF-) 6 and Krüppel-like factor- (KLF-) 6 increased under oxidative stress and decreased after BMP-4 treatment.

14.
Int Immunopharmacol ; 93: 107402, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540246

RESUMO

Aberrant expression of long non-coding RNA (lncRNA) H19 is tightly linked to multiple steps of tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of lncRNA H19 in macrophages remain obscure. To investigate whether lncRNA H19 modulates macrophage activation in rheumatoid arthritis (RA), lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced arthritis mouse model. The level of lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of lncRNA H19 altered lipopolysaccharide plus interferon-induced M1 macrophage polarization and decreased IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients. LncRNA H19 overexpression markedly induced IL-6, CD80, HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated arthritis in mice by promoting M1 macrophage polarization along with iNOS, IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle. GSK-J4, an inhibitor of KDM6A, suppressed the activity of lncRNA H19 in macrophages and ameliorated lncRNA H19-aggravated arthritis. In summary, the current study demonstrated that lncRNA H19 is upregulated in RA patients and arthritic mice. LncRNA H19 promotes M1 macrophage polarization and aggravates arthritis by upregulating KDM6A expression.

15.
J Proteome Res ; 20(3): 1770-1782, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33594895

RESUMO

Small extracellular vesicles (sEVs) derived from the plasma have been increasingly recognized as important vehicles of intercellular communication and potential sources of new biomarkers for multiple diseases. In this study, proteomic profiles of plasma sEVs from normal subjects and diabetic patients with or without diabetic retinopathy (DR) were systematically compared using iTRAQ-based quantitative proteomics. Among a total of 901 identified proteins in plasma sEVs (false discovery rate (FDR) < 1%), 90 proteins were found to have significantly changed levels in DR. Based on the findings from the proteomic analysis, the role of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in promoting human retinal microvascular endothelial cell (HRMEC) proliferation was investigated. The enzyme-linked immunosorbent assay (ELISA) showed that TNFAIP8 levels in plasma sEVs and vitreous are elevated in DR, whereas not statistically different in large EVs (lEVs) and plasma. In addition, in vitro experiments demonstrated that 4-hydroxynonenal (4-HNE) increased the expression of TNFAIP8 in HRMECs. TNFAIP8 significantly increased HRMECs cell viability and promote cell migration and tube formation, and the depletion of TNFAIP8 impaired HRMEC proliferation. We demonstrated that TNFAIP8 in plasma sEVs could be used as a potential biomarker of DR. Functional studies suggested that TNFAIP8 might be an important mediator of angiogenesis in DR.

16.
J Physiol Sci ; 71(1): 6, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546583

RESUMO

Our previous research has shown that galanin plays an antinociceptive effect via binding to galanin receptors (GalRs) in nucleus accumbens (NAc). This study focused on the involvement of GalR2 in galanin-induced antinociceptive effect in NAc of neuropathic pain rats. The chronic constriction injury of sciatic nerve (CCI) was used to mimic neuropathic pain model. The hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation were measured as the indicators of pain threshold. The results showed that 14 and 28 days after CCI, the expression of GalR2 was up-regulated in bilateral NAc of rats, and intra-NAc injection of GalR2 antagonist M871 reversed galanin-induced increases in HWL and HWT of CCI rats. Furthermore, intra-NAc injection of GalR2 agonist M1145 induced increases in HWL and HWT at day 14 and day 28 after CCI, which could also be reversed by M871. Finally, we found that M1145-induced antinociceptive effect in NAc of CCI rats was stronger than that in intact rats. These results imply that the GalR2 is activated in the NAc from day 14 to day 28 after CCI and GalR2 is involved in the galanin-induced antinociceptive effect in NAc of CCI rats.

17.
Cell Commun Signal ; 19(1): 14, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33573690

RESUMO

BACKGROUND: Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1α, the transcriptional activator of VEGF, has intricate mechanisms of nuclear translocation and activation, but its signal termination mechanisms remain unclear. METHODS: We investigated the role of polypyrimidine tract-binding protein-associated splicing factor (PSF) in cellular energy production, migration, and proliferation by targeting HIF-1α in vivo and in vitro PSF plasmids were transfected with liposome 2000 transfection reagent. Young C57/BL6J mice were kept in a hyperoxia environment, followed by indoor air, resulting in oxygen-induced retinopathy. Oxygen-induced retinopathy (OIR) animals were randomly divided into three groups: OIR group, OIR + vector group (OIR cubs treated with rAAV vector) and OIR + PSF group (OIR cubs treated with rAAV-PSF). Age-matched C57/BL6J mice were used as controls and exposed to constant normoxic conditions. The animals were executed and their pupils were subjected to subsequent experiments. The metabolic spectrum was analyzed by Seahorse XFe96 flux analyzer, and OCR and extracellular acidification rate were quantified at the same time. RESULTS: PSF ameliorated retinal neovascularization and corrected abnormal VEGF expression in mice with oxygen-induced retinopathy and reduced intra-retinal neovascularization in Vldlr - / - mice. PSF reprogrammed mitochondrial bioenergetics and inhibited the transition of endothelial cells after hypoxia, suggesting its involvement in pathological angiogenesis.Ectopic PSF expression inhibited hypoxia-induced HIF-1α activation in the nucleus by recruiting Hakai to the PSF/HIF-1α complex, causing HIF-1α inhibition. PSF knockdown increased hypoxia-stimulated HIF-1α reactions. These hypoxia-dependent processes may play a vital role in cell metabolism, migration, and proliferation. Thus, PSF is a potential treatment target in neovascularization-associated ophthalmopathy. CONCLUSION: This is the first study showing that PSF inhibits HIF-1α via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 α/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy. PSF-Hakai-HIF-1α signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai-HIF-1α signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1α signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually. Video Abstract: Detailed information of Materials and Methods.

18.
Clin Epigenetics ; 13(1): 19, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33499918

RESUMO

BACKGROUND: Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. METHODS: We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. RESULTS: We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02-1.48; P = 0.03). CONCLUSIONS: We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

19.
Biomed Res Int ; 2021: 8197936, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33506034

RESUMO

Aim: Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) has been acknowledged as a tumor-suppressive gene in several cancers; however, there are few reports on the clinical significance of CPEB3 in melanoma. The aim of this study was to investigate the role of CPEB3 in predicting the prognosis of melanoma patients. Methods: The association of CPEB3 expression and clinical pathologic features was performed using The Cancer Genome Atlas (TCGA) data set. The role of CPEB3 expression in prognosis was also analyzed. In addition, CPEB3 expression-related pathways were enriched by gene set enrichment analysis (GSEA). Association analysis of CPEB3 gene expression and immune infiltration was performed by ssGSEA. Results: The mRNA was significantly less in melanoma than in normal tissues (p < 0.001). The decrease in CPEB3 expression in melanoma was significantly correlated with T staging (p < 0.001), clinical staging (p = 0.029), melanoma Clark level (p = 0.014), and melanoma ulceration (p = 0.003), while it was marginally significant in N staging (p = 0.089). Melanoma with low CPEB3 expression was associated with worse OS (overall survival), progression-free survival (PFS), and disease-specific survival (DSS) than in that with high expression. In the univariate analysis, expression of CPEB3, melanoma ulceration, Clark level of melanoma, age, clinical stage, T stage, and N stage were correlated with OS (p < 0.05). Further analysis by multivariate Cox regression showed that N stage (p = 0.029), melanoma ulceration (p = 0.004), and CPEB3 expression (p < 0.001) were independent prognostic factors of OS in melanoma. Moreover, GSEA showed that several pathways were enriched in CPEB3, such as PD1 signaling, CTLA4 pathway, CTCF pathway, CHEMOKIN signaling, VEGF signaling, and JAK-STAT pathway. CPEB3 was significantly correlated with the infiltration level of B cells (p < 0.001), T cells (p < 0.001), T helper cells (p < 0.001), and central memory T (Tcm) cells (p < 0.001). Conclusion: CPEB3 may be a potential prognostic marker in melanoma with poor survival. Moreover, PD1 signaling, CTLA4 pathway, CTCF pathway, CHEMOKIN signaling, VEGF signaling, and JAK-STAT pathway may be the key pathway regulated by CPEB3. Moreover, the expression of CPEB3 in melanoma is related to the level of immune infiltration.

20.
Anal Chim Acta ; 1143: 45-52, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33384129

RESUMO

Copper ions (Cu2+) pollution in the water environment poses a great threat to the health function of life-sustaining metabolic activities. However, the current detection methods need relatively expensive instruments, complex operation procedures and long time, so a facile and direct detection method is desired to be developed. In this work, the Ni-based composite wires with p-n junction (the Ni/NiO/ZnO/Chitosan wire) and Schottky junction (the Ni/NiO/Au/Chitosan wire) were fabricated, and the barrier driven electrochemical sensing mechanism was studied. The direct and facile detection of Cu2+ was achieved with a wide linear range (0-6000 nM) and a low LOD (0.81 nM). The excellent stability and recovery in real water samples made the Ni-based composite wires a promising candidate for the practical application. The interfacial barriers of semiconductor can be used as a special sensing factor to develop novel sensors.

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