MicroRNAs (MiRNAs, MiRs) represent a class of conserved small non‐coding RNAs that affect post‐transcriptional gene regulation and play a vital role in angiogenesis, proliferation, apoptosis, ...migration and invasion. They are essential for a wide range of physiological and pathological processes, especially for vascular diseases. However, data concerning miRNAs in endothelial progenitor cells (EPCs) and deep vein thrombosis (DVT) remain incomplete. We explored miRNAs that modulate angiogenesis in EPCs and thrombolysis, and analysed their underlying mechanisms using a DVT model, dual‐luciferase reporter assay, qRT‐PCR, Western blot, immunofluorescence staining, flow cytometry analysis, CCK‐8 assay, angiogenesis assay, wound healing and Transwell assay. We found that miR‐205 enhanced the homing ability of EPCs to DVT sites and promoted thrombosis resolution and recanalization, which significantly reduced venous thrombus. Additionally, we demonstrated that miR‐205 overexpression significantly enhanced angiogenesis in vivo and in vitro, migration, invasion, F‐actin filaments and proliferation in EPCs, and inhibited cell apoptosis. Conversely, down‐regulation of miR‐205 played the opposite role in EPCs. Importantly, this study demonstrated that miR‐205 directly targeted PTEN to modulate the Akt/autophagy pathway and MMP2 expression, subsequently playing a key role in EPC function and DVT recanalization and resolution. These results elucidated the pro‐angiogenesis effects of miR‐205 in EPCs and established it as a potential target for DVT treatment.
Efficient recruitment and angiogenesis of endothelial progenitor cells (EPCs) are critical during a thrombus event. However, the details of EPC recruitment and the regulation of angiogenesis have not ...been fully determined. The aim of this study was to determine the role of the long noncoding (lnc)RNA Wilms tumor 1 associated protein pseudogene 1 (WTAPP1) in regulation of the migration and angiogenesis of EPCs. EPCs were isolated from human peripheral blood and characterized by flow cytometry, after which lentivirus‐mediated lncRNA WTAPP1 overexpression and knockdown were performed. Scratch assay, Transwell assay, and in vitro and in vivo tube formation assays were performed to measure cell migration, invasion, and angiogenic abilities, respectively. Moreover, a microarray screen, bioinformatic prediction, and quantitative PCR and Western blot of miRNAs interacting with lncRNA WTAPP1 were conducted. Western blot was carried out to elucidate the relationship among WTAPP1, miR‐3120‐5P, and MMP‐1 in the autophagy pathway. WTAPP1 positively regulated migration, invasion, and in vitro and in vivo tube formation in EPCs by increasing MMP‐1 expression and activating PI3K/Akt/mTOR signaling. Furthermore, WTAPP1 contains a putative miR‐3120‐5P binding site. Suppression of WTAPP1 by miR‐3120‐5P decreased the level of MMP‐1. In addition, we demonstrated that suppression of the autophagy pathway is involved in the effects of WTAPP1 on EPC migration and angiogenesis. The lncRNA WTAPP1, a molecular decoy for miR‐3120‐5p, regulates MMP‐1 expression via the PI3K/Akt and autophagy pathways, thereby mediating cell migration and angiogenesis in EPCs. Acting as a potential therapeutic target, the lncRNA WTAPP1 may play an important role in the pathogenesis of DVT. Stem Cells 2018;36:1863–12
The long noncoding RNA Wilms tumor 1 associated protein pseudogene 1, a molecular decoy for miR‐3120‐5p, regulates MMP‐1 expression via the PI3K/Akt and autophagy pathways, thereby mediating cell migration and angiogenesis in endothelial progenitor cells.
Metal chalcogenophosphates are receiving increasing interest, specifically as promising infrared nonlinear optical (NLO) candidates. Here, a rare‐earth chalcogenophosphate Eu2P2S6 crystallizing in ...the monoclinic noncentrosymmetric space group Pn was synthesized using a high‐temperature solid‐state method. Its structure features isolated P2S64− dimer, and two types of EuS8 bicapped triangular prisms. Eu2P2S6 exhibits a phase‐matchable second‐harmonic generation (SHG) response ≈0.9×AgGaS2@2.1 μm, and high laser‐induced damage threshold of 3.4×AgGaS2, representing the first rare‐earth NLO chalcogenophosphate. The theoretical calculation result suggests that the SHG response is ascribed to the synergetic contribution of P2S64− dimers and EuS8 bicapped triangular prisms. This work provides not only a promising high‐performance infrared NLO material, but also opens the avenue for exploring rare‐earth chalcogenophosphates as potential IR NLO materials.
Eu2P2S6 exhibits excellent NLO properties, including a phase‐matchable second‐harmonic generation (SHG) response ≈0.9×AgGaS2@2.1 μm, and a high laser‐induced damage threshold of 3.4×AgGaS2. Eu2P2S6 is the first NLO‐active rare‐earth‐based chalcogenophosphate.
Abstract
Computational prediction of drug–target interactions (DTIs) has become an essential task in the drug discovery process. It narrows down the search space for interactions by suggesting ...potential interaction candidates for validation via wet-lab experiments that are well known to be expensive and time-consuming. In this article, we aim to provide a comprehensive overview and empirical evaluation on the computational DTI prediction techniques, to act as a guide and reference for our fellow researchers. Specifically, we first describe the data used in such computational DTI prediction efforts. We then categorize and elaborate the state-of-the-art methods for predicting DTIs. Next, an empirical comparison is performed to demonstrate the prediction performance of some representative methods under different scenarios. We also present interesting findings from our evaluation study, discussing the advantages and disadvantages of each method. Finally, we highlight potential avenues for further enhancement of DTI prediction performance as well as related research directions.
Diminished ovarian reserve (DOR) is defined as a reduction in ovarian reserve and oocyte quality. The pathophysiology of DOR has not been completely explained as of yet. Scholars have uncovered a ...large number of exosomes that have been detected in follicular fluid, and exosomal miRNAs have been proven to play a critical role in controlling ovarian disorders and follicle formation. We focused on the expression profile of follicular fluid-derived exosomal microRNAs (miRNAs) and attempted to understand if their role is connected to the pathomechanism of DOR.
The follicular fluid-derived differentially expressed exosomal miRNAs (DEmiRs) between patients with DOR and those with normal ovarian function were investigated using the next-generation sequencing (NGS) method. The main metabolic and signaling pathways of DEmiRs were identified using the KEGG pathway database, disease ontology (DO) analysis, and gene ontology (GO) analysis. In the end, a Protein-Protein Interaction (PPI) network was built to search for exosomal miRNAs and their target genes that were potentially strongly connected with DOR.
In comparison to normal controls, 52 DEmiRs were discovered in follicular fluid-derived exosomes of DOR patients, of which 19 were up-regulated and 33 were down-regulated (|log2(fold change) |>2, P < 0.05). GO, DO analysis, and the KEGG pathway database revealed that many of these DEmiRs have broad biological roles that are connected to ovarian function and disorders. The top ten DEmiRs in terms of expression were then chosen for miRNA-mRNA interaction analysis. Totally, 8 experimentally supported miRNAs (hsa-miR-1246, hsa-miR-483-3p, hsa-miR-122-5p, hsa-miR-130b-3p, hsa-miR-342-3p, hsa-miR-625-3p, hsa-miR-675-3p, and hsa-miR-134-5p) and 126 target genes were filtrated by utilizing Cytoscape software. The module analysis findings of the PPI network showed that the main module cluster with a score > 6.0 (MCODE score = 15) had six hub genes, including IGFR, VEGFA, KRAS, ERBB2, RHOA, and PTEN (MCODE score = 11.472).
Our data suggested a special expression profile of follicular fluid-derived exosomal miRNAs in patients with DOR, which was probably correlated to ovarian dysfunction and follicle formation. These results may give a unique insight into a better understanding of the molecular process in the pathogenesis of DOR or other ovarian diseases.
Two new antimicrobial bisabolane-type sesquiterpenoid derivatives,
-aspergoterpenin C (compound
) and 7-
-methylhydroxysydonic acid (
), and two new butyrolactone-type monoterpenoids, ...pestalotiolactones C (
) and D (
), along with a known monoterpenoid pestalotiolactone A (
) and four known bisabolane sesquiterpenoids (
-
), were isolated and identified from the deep-sea sediment-derived fungus
SD-330. The structures of these compounds were elucidated on the basis of spectroscopic analysis, and the absolute configurations of the new compounds
-
were determined by the combination of NOESY and TDDFT-ECD calculations and X-ray crystallographic analysis. Additionally, we first determined and reported the absolute configuration of the known monoterpenoid pestalotiolactone A (
) through the X-ray crystallographic experiment. All of these isolated compounds were evaluated for antimicrobial activities against human and aquatic pathogenic bacteria. Compounds
,
,
and
exhibited selective inhibitory activities against zoonotic pathogenic bacteria such as
,
,
and
, with MIC values ranging from 1.0 to 8.0 μg/mL.
Background
Handelin is a bioactive compound from Chrysanthemum indicum L. that improves motor function and muscle integrity during aging in Caenorhabditis elegans. This study aimed to further ...evaluate the protective effects and molecular mechanisms of handelin in a mouse muscle atrophy model induced by cachexia and aging.
Methods
A tumour necrosis factor (TNF)‐α‐induced atrophy model was used to examine handelin activity in cultured C2C12 myotubes in vitro. Lipopolysaccharide (LPS)‐treated 8‐week‐old model mice and 23‐month‐old (aged) mice were used to examine the therapeutic effects of handelin on cachexia‐ and aging‐induced muscle atrophy, respectively, in vivo. Protein and mRNA expressions were analysed by Western blotting, ELISA and quantitative PCR, respectively. Skeletal muscle mass was measured by histological analysis.
Results
Handelin treatment resulted in an upregulation of protein levels of early (MyoD and myogenin) and late (myosin heavy chain, MyHC) differentiation markers in C2C12 myotubes (P < 0.05), and enhanced mitochondrial respiratory (P < 0.05). In TNF‐α‐induced myotube atrophy model, handelin maintained MyHC protein levels, increased insulin‐like growth factor (Igf1) mRNA expression and phosphorylated protein kinase B protein levels (P < 0.05). Handelin also reduced atrogin‐1 expression, inhibited nuclear factor‐κB activation and reduced mRNA levels of interleukin (Il)6, Il1b and chemokine ligand 1 (Cxcl1) (P < 0.05). In LPS‐treated mice, handelin increased body weight (P < 0.05), the weight (P < 0.01) and cross‐sectional area (CSA) of the soleus muscle (P < 0.0001) and improved motor function (P < 0.05). In aged mice, handelin slightly increased the weight of the tibialis anterior muscle (P = 0.06) and CSA of the tibialis anterior and gastrocnemius muscles (P < 0.0001). In the tibialis anterior muscle of aged mice, handelin upregulated mRNA levels of Igf1 (P < 0.01), anti‐inflammatory cytokine Il10 (P < 0.01), mitochondrial biogenesis genes (P < 0.05) and antioxidant‐related enzymes (P < 0.05) and strengthened Sod and Cat enzyme activity (P < 0.05). Handelin also reduced lipid peroxidation and protein carbonylation, downregulated mRNA levels of Fbxo32, Mstn, Cxcl1, Il1b and Tnf (P < 0.05), and decreased IL‐1β levels in serum (P < 0.05). Knockdown of Hsp70 or using an Hsp70 inhibitor abolished the ameliorating effects of handelin on myotube atrophy.
Conclusions
Handelin ameliorated cachexia‐ and aging‐induced skeletal muscle atrophy in vitro and in vivo, by maintaining homeostasis of protein synthesis and degradation, possibly by inhibiting inflammation. Handelin is a potentially promising drug candidate for the treatment of muscle wasting.
Coronavirus disease 2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to an unprecedented setback for global economy and health. Vaccination is ...one of the most effective interventions to substantially reduce severe disease and death due to SARS‐CoV‐2 infection. Vaccination programmes are being rolled out globally, but most of these vaccines have been approved without extensive studies on their side‐effects and efficacy. Recently, new‐onset autoimmune phenomena after COVID‐19 vaccination have been reported increasingly (e.g. immune thrombotic thrombocytopenia, autoimmune liver diseases, Guillain–Barré syndrome, IgA nephropathy, rheumatoid arthritis and systemic lupus erythematosus). Molecular mimicry, the production of particular autoantibodies and the role of certain vaccine adjuvants seem to be substantial contributors to autoimmune phenomena. However, whether the association between COVID‐19 vaccine and autoimmune manifestations is coincidental or causal remains to be elucidated. Here, we summarize the emerging evidence about autoimmune manifestations occurring in response to certain COVID‐19 vaccines. Although information pertaining to the risk of autoimmune disease as a consequence of vaccination is controversial, we merely propose our current understanding of autoimmune manifestations associated with COVID‐19 vaccine. In fact, we do not aim to disavow the overwhelming benefits of mass COVID‐19 vaccination in preventing COVID‐19 morbidity and mortality. These reports could help guide clinical assessment and management of autoimmune manifestations after COVID‐19 vaccination.
As vaccination programmes are being rolled out globally, new‐onset autoimmune phenomena are emerging after COVID‐19 vaccination (e.g. immune thrombotic thrombocytopenia, autoimmune liver diseases, Guillain–Barré syndrome, IgA nephropathy, rheumatoid arthritis and systemic lupus erythematosus).
Our purpose was to compare toxicity and biochemical control in postprostatectomy patients treated with conventional (66 Gy) or dose-intensified (72 Gy) radiation therapy.
Patients who had stage ...pT3-4, positive surgical margins, or rising prostate-specific antigen ≥ 0.2 ng/mL after radical prostatectomy were randomly assigned to receive either 66 Gy in 33 fractions or 72 Gy in 36 fractions. A primary endpoint was to assess the difference in biochemical progression-free survival (bPFS) between these 2 cohorts, and secondary endpoints were to assess differences in genitourinary (GU), gastrointestinal (GI), and hematologic toxicities between these 2 cohorts. bPFS was estimated by the Kaplan–Meier method and toxicities were compared using the χ2 test.
Between September 2011 and November 2016, 144 patients were enrolled: 71 patients to the 66 Gy cohort and 73 patients to the 72 Gy cohort. The median follow-up time was 48.5 months (range, 14-79 months). There was no difference in 4-year bPFS between the 66 Gy and 72 Gy cohorts (75.9% vs 82.6%; P = .299). However, in patients with a higher Gleason score (8-10), the 72 Gy cohort had statistically significant improvement in bPFS compared with the 66 Gy cohort (79.7% vs 55.7%; P = .049). Toxicity analysis showed no difference in ≥2 acute or late GI or GU toxicities between these 2 cohorts. A total of 48 patients were scored as urinary incontinence before radiation therapy, of which 39 (81.3%) reported incontinence recovery or stable at 1-year follow-up, and only 9 (18.8%) patients reported worsening. There was no difference between the 2 cohorts in urinary incontinence either at baseline or at 1-year follow-up.
Dose escalation (72 Gy) demonstrated no improvement in 4-year bPFS compared with the 66 Gy regimen. However, the dose escalation was not associated with greater acute or late GU or GI toxicities and did not increase urinary incontinence.
•Gelation with alginate can rapidly remove heavy metal ions from wastewater.•Pb2+ can be selectively removed by alginate when Cu2+ and Cd2+ are present.•FTIR and XPS analyses indicate the role of OH ...and COO− in metal gelation.•Calcination of the gels can obtain PbO, CuO, and CdO nanopowders for metal recovery.
A novel method that uses the aqueous sodium alginate solution for direct gelation with metal ions is developed for effective removal and recovery of heavy metals from industrial wastewater. The experimental study was conducted on Pb2+, Cu2+, and Cd2+ as the model heavy metals. The results show that gels can be formed rapidly between the metals and alginate in less than 10min and the gelation rates fit well with the pseudo second-order kinetic model. The optimum dosing ratio of alginate to the metal ions was found to be between 2:1 and 3:1 for removing Pb2+ and around 4:1 for removing Cu2+ and Cd2+ from wastewater, and the metal removal efficiency by gelation increased as the solution pH increased. Alginate exhibited a higher gelation affinity toward Pb2+ than Cu2+ and Cd2+, which allowed a selective removal of Pb2+ from the wastewater in the presence of Cu2+ and Cd2+ ions. Chemical analysis of the gels suggests that the gelation mainly occurred between the metal ions and the COO− and OH groups on alginate. By simple calcination of the metal-laden gels at 700°C for 1h, the heavy metals can be well recovered as valuable resources. The metals obtained after the thermal treatment are in the form of PbO, CuO, and CdO nanopowders with crystal sizes of around 150, 50, and 100nm, respectively.
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