Abstract Although some studies have reported potential associations of dietary patterns with depression risk, a consistent perspective hasn’t been estimated to date. Therefore, we conducted this ...meta-analysis to evaluate the relation between dietary patterns and the risk of depression. A literature research was conducted searching MEDLINE and EMBASE databases up to September 2016. In total, 21 studies from ten countries met the inclusion criteria and were included in the present meta-analysis. A dietary pattern characterized by a high intakes of fruit, vegetables, whole grain, fish, olive oil, low-fat dairy and antioxidants and low intakes of animal foods was apparently associated with a decreased risk of depression.A dietary pattern characterized by a high consumption of red and/or processed meat, refined grains, sweets, high-fat dairy products, butter, potatoes and high-fat gravy, and low intakes of fruits and vegetables is associated with an increased risk of depression. The results of this meta-analysis suggest that healthy pattern may decrease the risk of depression, whereas western-style may increase the risk of depression. However, more randomized controlled trails and cohort studies are urgently required to confirm this findings.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is a highly vascularized solid tumor. Angiopoietin-2 (ANGPT2) has been described as an attractive target for antiangiogenic ...therapy. Exosomes are small extracellular vesicles secreted by most cell types and contribute to cell-to-cell communication by delivering functional cargo to recipient cells. The expression of ANGPT2 in tumor-derived exosomes remains unknown.
We detected the ANGPT2 expression in HCC-derived exosomes by immunoblotting, enzyme-linked immunosorbent assay and immunogold labeling, then observed exosomal ANGPT2 internalization and recycling by confocal laser scanning microscopy, co-immunoprecipitation and immunoblotting. We used two HCC cell lines (Hep3B and MHCC97H) to overexpress ANGPT2 by lentivirus infection or knockdown ANGPT2 by the CRISPR/Cas system, then isolated exosomes to coculture with human umbilical vein endothelial cells (HUVECs) and observed the angiogenesis by Matrigel microtubule formation assay, transwell migration assay, wound healing assay, cell counting kit-8 assay, immunoblotting and in vivo tumorigenesis assay.
We found that HCC-derived exosomes carried ANGPT2 and delivered it into HUVECs by exosome endocytosis, this delivery led to a notable increase in angiogenesis by a Tie2-independent pathway. Concomitantly, we observed that HCC cell-secreted exosomal ANGPT2 was recycled by recipient HUVECs and might be reused. In addition, the CRISPR-Cas systems to knock down ANGPT2 significantly inhibited the angiogenesis induced by HCC cell-secreted exosomal ANGPT2, and obviously suppressed the epithelial-mesenchymal transition activation in HCC.
Taken together, these results reveal a novel pathway of tumor angiogenesis induced by HCC cell-secreted exosomal ANGPT2 that is different from the classic ANGPT2/Tie2 pathway. This way may be a potential therapeutic target for antiangiogenic therapy. Video Abstract.
Hematuria is the most typical presentation of immunoglobulin A nephropathy (IgAN); however, its role in disease progression is still controversial. This study aimed to evaluate the association of ...hematuria and progression of IgAN.
Retrospective cohort study.
A cohort of 1,333 patients with IgAN treated at a Chinese referral hospital with a median follow-up of 45 months.
Microhematuria was evaluated in fresh urine using a fully automated urine particle analyzer (automated method) and urine sediment examination by a skilled examiner (manual method). Hematuria was characterized as a time-varying attribute; namely, average hematuria level was calculated for every 6-month period for each patient during follow-up. Remission was defined as average red blood cell count ≤5/high-power field (manual method) or ≤28 red blood cells/μL (automated method) during the first 6 months of follow-up.
Composite event of 50% decline in estimated glomerular filtration rate or development of kidney failure.
Multivariable cause-specific hazards models to analyze the relationship between hematuria and the composite kidney disease progression event.
Time-varying hematuria during follow-up was an independent risk factor for the composite kidney disease progression event (HR, 1.46; 95% CI, 1.13-1.87; P = 0.003). Hematuria remission during the 6 months after diagnosis was associated with a significantly lower rate of the composite kidney disease progression event (HR, 0.41; 95% CI, 0.28-0.61; P < 0.001). A significant interaction was detected between remission of proteinuria and remission of hematuria during the first 6 months (P < 0.001). The association between remission of hematuria and kidney disease progression was detectable (HR, 0.46; 95% CI, 0.32-0.68) within the subpopulation with persistent proteinuria (protein excretion > 1.0 g/d during the first 6 months), but not among patients whose proteinuria had remitted (HR, 0.64; 95% CI, 0.31-1.29; P = 0.2). The 2 techniques for hematuria evaluation were strongly and significantly linearly correlated (r = 0.948; P < 0.001), and results using these 2 methods were consistent.
A single-center retrospective study. Proportional hazards regression incorporating time-varying covariates may create time-varying confounding. The predictive value of reductions in hematuria was not directly evaluated.
Level of hematuria was independently associated with kidney disease progression, whereas hematuria remission was associated with improved kidney outcomes in IgAN among patients with persistent proteinuria. Additionally, to monitor IgAN progression, automated methods to evaluate hematuria hold promise as a replacement for manual evaluation of urinary sediment.
The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular ...carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell–derived exosomes. Next, coculture experiments indicated that HCC cell–derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down‐regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A‐associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol‐3‐kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol‐3‐kinase/Akt pathway was inactivated by Vps4A overexpression. Conclusion: Exosome‐mediated miRNA transfer is an important mechanism of self‐modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC. (Hepatology 2015;61:1284–1294)
A novel nickel‐catalyzed practical and simple synthesis of thioesters from amides and disulfides has been developed. Diverse substituted aromatic amides are capable of coupling with diaryl or dialkyl ...disulfides via C−N/S−S bonds cleavage to produce the desirable thioesters in moderate to good yields. This procedure features cheap metals, novel and easily preparative substrates, providing a simple and practical access to a variety of thioesters without toxic thiols or CO gas.
A novel nickel‐catalyzed practical and simple synthesis of thioesters from amides and disulfides has been developed. Diverse substituted aromatic amides are capable of coupling with diaryl or dialkyl disulfides via C−N/S−S cleavage to produce the desirable thioesters in moderate to good yields. This procedure features cheap metals, novel and easily preparative substrates, providing a simple and practical access to a variety of thioesters without toxic thiols or CO gas.
The metabolic disorders are becoming an epidemic disease endangering public health in countries. Environmental factors are mainly reason for the growth of metabolic disorders. Previous research ...suggests that DNA methylation is a potential mechanism. Recently, it has been reported that DNA hydroxymethylation is also a stable marker of epigenetic reprogramming. Hence, the study aims to investigate whether DNA hydroxymehylation mediates early-life environmental stress-evoked metabolic disorder in adulthood. Mice were orally administered with arsenic (As), an environmental stressor, throughout pregnancy. We show that early-life As exposure induces glucose intolerance and hepatic lipid accumulation in adulthood. Early-life As exposure alters epigenetic reprogramming and expression of lipid metabolism-related genes including β-oxidation-specific genes in adulthood. Of interest, early-life As exposure alters epigenetic reprogramming of hepatic lipid metabolism partially through reducing DNA hydroxymethylation modification of β-oxidation-related genes in developing liver. Mechanistically, early-life As exposure suppresses ten-eleven translocation (TET) activity through downregulating isocitrate dehydrogenases (Idh) and reducing alpha-ketoglutarate (α-KG) content in the developing liver. In addition, early-life As exposure inhibits TET1 binding to CpG-rich fragments of β-oxidation-related genes in developing liver. This study provide novel evidence that early-life environmental stress leads to later life metabolic disorders by altering hepatic DNA hydroxymethylation reprogramming.
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•Early-life As exposure alone induces hepatic lipid accumulation in adulthood.•Early-life As exposure causes epigenetic reprogramming of hepatic β-oxidative-related genes in adulthood.•As-altered epigenetic reprogramming of hepatic β-oxidation-related genes begins with changes in 5hmC at fetal period.•Early-life As exposure inhibits TET activity by reducing α-KG contents in the developing liver.•Early-life As exposure suppresses TET1 binding to CpG-rich sites of β-oxidative-related genes in the developing liver.
Abstract
Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that ...the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.
The objective of this study was to explore the neuroprotective molecular mechanisms of erythropoietin (EPO) in rats following spinal cord injury (SCI). First, a standard SCI model was established. ...After drug or saline treatment was administered, locomotor function was evaluated in rats using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. H&E, Nissl, and TUNEL staining were performed to assess the ratio of cavities, number of motor neurons, and apoptotic cells in the damaged area. The relative protein and mRNA expressions were examined using western blot and qRT-PCR analyses, and the inflammatory markers, axon special protein, and neuromuscular junctions (NMJs) were detected by immunofluorescence. Both doses of EPO notably improved locomotor function, but high-dose EPO was more effective than low-dose EPO. Moreover, EPO reduced the cavity ratio, cell apoptosis, and motor neuron loss in the damaged area, but enhanced the autophagy level and extracellular-regulated protein kinase (ERK) activity. Treatment with an ERK inhibitor significantly prevented the effect of EPO on SCI, and an activator mimicked the benefits of EPO. Further investigation revealed that EPO promoted SCI-induced autophagy via the ERK signaling pathway. EPO activates autophagy to promote locomotor function recovery in rats with SCI via the ERK signaling pathway.
Several studies found that reduction of 5-hydroxymethylcytosine (5hmC), a marker of DNA hydroxymethylation highly enriched in developing brain, is associated with anxiety-like behaviors. This study ...aimed to investigate whether gestational arsenic (As) exposure induces anxiety-like behaviors in adult offspring by reducing DNA hydroxymethylation in the developing brain. The dams drank ultrapure water containing NaAsO2 (15 mg/L) throughout pregnancy. Anxiety-like behaviors were evaluated and developing brain 5hmC was detected. Results showed that anxiety-like behaviors were observed in As-exposed adult offspring. In addition, 5hmC content was reduced in As-exposed fetal brain. Despite no difference on Tet1, Tet2 and Tet3 expression, TET activity was suppressed in As-exposed fetal brain. Mechanistically, alpha-ketoglutarate (α-KG), a cofactor for TET dioxygenases, was reduced and Idh2, a key enzymatic gene for mitochondrial α-KG synthesis, was downregulated in As-exposed fetal brain. Of interest, ascorbic acid, a cofactor for TET dioxygenases, reversed As-induced suppression of TET activity. Moreover, ascorbic acid attenuated As-induced reduction of 5hmC in fetal brain. In addition, ascorbic acid alleviated As-induced anxiety-like behaviors in adult offspring. Taken together, these results suggest that gestational As exposure induces anxiety-like behaviors in adult offspring, possibly at part, by inhibiting DNA hydroxymethylation in developing brain.
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•Gestational As exposure induces anxiety-like behaviors in adult offspring.•Gestational As exposure reduces 5hmC in fetal brain.•Gestational As exposure inhibits TET activity by reducing α-KG content in fetal brain.•AA attenuates As-induced reduction of 5hmC and TET activity in fetal brain.•AA alleviated As-induced anxiety-like behaviors in adult offspring.
•Coxsackievirus A4 (CV-A4) is one of re-emerging pathogens that causes by multiple diseases including hand, foot and mouth disease (HFMD).•The study on antigenicity is important for development of ...diagnostic reagents and vaccine candidates. Here, mAbs specific for CV-A4 and more broadly binding to CV-A4/CV-A2/CV-A5, were obtained.•The mAbs target the first 15 amino acids at the N-terminus of VP1, a newly discovered epitope.•This is an important step to understand the function of these epitopes.•The mAbs are suitable for the development of rapid detection of enteroviruses causing HFMD, herpangina and other diseases.
Hand, foot and mouth disease (HFMD) is caused by a variety of serotypes in species A of the Enterovirus genus, including recently re-emerged Coxsackievirus A2 (CV-A2), CV-A4 and CV-A5. For development of diagnostic reagents, for surveillance, and the development of multivalent vaccines against HFMD, the antigenicity of HFMD-associated enteroviruses warrants investigation. The purified virions of CV-A4 were inoculated into Balb/c mice and hybridomas were obtained secreting monoclonal antibodies (mAbs) directed against CV-A4 and cross-reacting with other closely related species A enteroviruses. The mAbs were characterized by ELISA, Western blotting and in vitro neutralizing assays. The majority of mAbs was non-neutralizing, with only 2% of the mAbs neutralizing CV-A4 specifically. Most of mAbs bound to linear VP1 epitopes of CV-A4. Interestingly, four types of mAbs were obtained which bound specifically to CV-A4 or were broadly to CV-A4/-A2, CV-A4/-A5 and CV-A4/-A2/-A5, respectively. Mapping with overlapping or single-amino-acid mutant peptides revealed that the four types of mAbs all bound to the first 15 amino acids at the N-terminus of the VP1. This region of picornaviruses is functionally important as it is involved in uncoating and releasing of viral RNA into the cytosol. The binding footprints of four type mAbs are composed of conserved and variable residues and are different from each other. The newly discovered broadly cross-reactive mAbs reflect the high homology of CV-A4/ CV-A2/CV-A5. The results also demonstrate that it is possible and beneficial to develop the diagnostic reagents to detect rapidly the main pathogens of enteroviruses associated with HFMD cause by CV-A4/CV-A2/CV-A5.
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