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Synthesis of the C19-truncated maltepolide E has been accomplished via a diene–ene RCM strategy without damage to the C11–C14 alkenyl epoxy unit. Upon release of the C17-OH group, it attacked at the C14 position with double bond migration and epoxide ring-opening to furnish the C19-truncated maltepolide A and B as proposed for the biosynthesis of maltepolides. Preliminary cytotoxicity data of the synthesized C19-truncated maltepolides against L929 mouse fibroblast cell line suggest irrelevance of the vinyl epoxide and importance of the conjugated dienyl keto unit for the observed anticancer activity.

Two-dimensional (2D) IV–VI nanomaterials have been important candidates for energy conversion and storage. However, there is still lack of a simple method of realizing control synthesis of IV–VI na...

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth in vivo. Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated., Graphical abstract LW-218-induced cholesterol accumulation on lysosomes via NPC1 binding can elicit lysosomal damage followed by lysophagy and lysosome-dependent cell death in hematological malignancies cells.Image 1

Promoted by K2CO3 (2.0 equiv), the 1,3-dipolar [3+3] cy­cloaddition between 1, 4-benzodiazepinone-based nitrones and α-halohydroxamates processed smoothly under the mild reaction conditions and delivered structurally novel and complex cis- or trans-configured d-edge heterocycle-fused 1,4-benzodiazepinones in up to >99% isolated yield with >20:1 dr. The relative configuration of the title chemical entities was clearly identified with the use of single-crystal X-ray structure analysis. The reaction mechanism was assumed to interpret the diastereoselective production of the obtained cis- or trans-configured d-edge heterocycle-fused 1,4-benzodiazepinones.

Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) is one of the diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available about the possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependent manner in the ACC in C57/BL6 mice. The enhancement was long-lasting, and persisted for at least 3 h. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC.

A successful pregnancy requires sufficient decidualization of endometrial stromal cells (ESCs). CD82, a metastasis suppressor, is a critical regulator for trophoblast invasion but the effect in decidualization was largely unknown. Here we reported that there was a high level of CD82 in DSC by the immunohistochemistry staining and flow cytometer analysis. Stimulation with prostaglandin E2 (PGE2) elevated the expression of CD82 in ESCs. In contrast, celecoxib, a selective COX-2 inhibitor, significantly downregulated the expression of CD82 in decidual stromal cells (DSCs). Bioinformatics analysis and further research showed that recombinant human interleukin (IL)-1β protein (rhIL-1β) upregulated CD82 in ESCs. Of note, blocking IL-1β signaling with anti-human IL-1β neutralizing antibody could reverse the stimulatory effect of PGE2 on CD82 in ESCs. Silencing CD82 resulted in the decease of the decidualization markers PRL and IGFBP1 mRNA levels in DSCs. More importantly, we observed rhIL-1β also upregulated the expression of COX-2, and the upregulation of PRL and IGFBP1 induced by rhIL-1β could be abolished by celecoxib in ESCs or CD82 deficiency in DSCs. This study suggests that CD82 should be a novel promotor for decidualization under a positive regulation of the COX-2/PGE2/IL-1β positive feedback loop.

Cu2O as a new heterogeneous green nanocatalyst is biosynthesized from Cressa leaf extract and characterized by some techniques including XRD, FTIR, UV–Vis, SEM, and TEM. Then, the prepared nanocatalyst was applied in the synthesis of some chromeno[4,3-b]chromenes under aerobic conditions. Reusability studies warrant acceptable reproducibility of the nanomaterial. Low reaction time, easy workup, cost-effectiveness, wide substrate scope, good to excellent yield, and complete atom economy are significant features of this new method. At the final part of this study, the in vitro cellular toxicity of Cu2O nanoparticles is examined on SKOV3 human ovarian carcinoma cell line via an MTT assay. The reduction in cell viability proved the cytotoxicity of the nanoparticles toward the performed ovarian cancer cell line.

Summary LncRNA PVT1 has been demonstrated to be upregulated in acute myeloid leukaemia (AML) patients and indicates a poor prognosis. Nevertheless, its role in AML remains obscure. This study investigated the regulatory role and potential mechanisms of PVT1 in the progression of AML. Expression of PVT1, miR-29 family and WAVE1 was detected by quantitative real-time polymerase chain reaction. CCK8 and EdU assays were performed to assess the proliferation of AML cells. Cell cycle and apoptosis were determined by propidium iodide (PI) staining and Annexin V/PI staining on a flow cytometer. Transwell assay was carried out to evaluate the migration and invasion abilities. The interaction between miR-29 family and PVT1/WAVE1 was confirmed by dual luciferase reporter assay and RNA immunoprecipitation assay. The protein levels of WAVE1, Bcl-2, Bax, cleaved Caspase 3, cyclin D1, and p21 were detected by western blotting. Xenograft transplantation was performed to determine the tumourigenicity of AML cell in vivo. PVT1 expression was significantly increased in AML patient samples and cells, which positively correlated with WAVE1 expression. Silencing of PVT1 restrained growth, migration and invasion, while inducing apoptosis of AML cells. Moreover, PVT1 acted as a sponge for miR-29 family to increase WAVE1 expression in AML cells. Overexpression of WAVE1 partly counteracted PVT1 knockdown-induced anti-tumour effects on AML cells in vitro and xenograft tumour in vivo. PVT1 facilitated the progression of AML via regulating miR-29 family/WAVE1 axis, which supported the conclusion that PVT1 may be a promising therapeutic target for AML.

The association of triglyceride-rich lipoprotein-cholesterol (TRL-C) with recurrent cardiovascular events (RCVEs) has not been studied. Moreover, whether inflammation can affect TRL-C-associated cardiovascular risk is unknown. This study sought to examine the association between TRL-C and RCVEs, and whether this relationship is modulated by systemic inflammation in statin-treated patients with coronary artery disease (CAD) and nearly normal triglyceride.In this study, 6723 CAD patients were consecutively enrolled, following a first CVE with triglyceride2.3 mmol/L. Baseline lipid profile and high-sensitivity C-reactive protein (hsCRP) levels were determined. All patients were searched for RCVEs. The risk of RCVEs was assessed across quartiles (Q) of baseline TRL-C and further stratified by the median of hsCRP.Over a mean follow-up of 58.91 ± 17.79 months, 538 RCVEs were recorded. After adjustment for potential confounders, Q4 of TRL-C was significantly associated with the risk of RCVEs, which remained unchanged after hsCRP stratification. When subjects were grouped according to both TRL-C and hsCRP levels, patients with Q4 of TRL-C and hsCRP had the highest increase of the risk of RCVEs compared with the reference group (TRL-C Q1-3 and hsCRP Q1-3; HR, 1.90; 95%CI: 1.27-2.87). Furthermore, adding TRL-C to the original predicting model led to a slight but significant improvement.The present analysis firstly showed that elevated TRL-C was associated with an increased RCVEs risk in statin-treated patients with CAD independent of systemic inflammation, suggesting that it might be a useful marker for risk stratification and a treatment target in this patient population.

Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.

SOmega-3 polyunsaturated fatty acids (PUFAs) possess anti-inflammatory properties. There is a lack of consensus regarding the effects of omega-3 PUFAs on C-reactive protein (CRP), a marker of systemic inflammation, in cancer patients. Herein, a meta-analysis of randomized controlled trials was conducted to evaluate the effects of omega-3 PUFAs on CRP levels in patients with cancer. PubMed and EMBASE were searched until May 2020 to identify randomized controlled trials that examined the effects of omega-3 PUFA administration on CRP levels in cancer patients. Standardized mean differences (SMDs) with their 95% confidence intervals (CIs) were calculated to determine the differences in omega-3 PUFA administration and control conditions. Seventeen eligible studies involving 916 cancer patients were included in this meta-analysis. Significant heterogeneity was present among individual studies (Pheterogeneity = 0.000; I2 = 74.5%). The overall SMDs of CRP levels between omega-3 PUFA administration and control conditions were 0.628 (95% CI: 0.342-0.914) and 0.456 (95% CI: 0.322-0.590) by the random-effect and fixed-effect models, respectively. Sources of heterogeneity were not found through subgroup and meta-regression analyses. Existing publication bias contributed slightly to the effect size. Omega-3 PUFAs can reduce systemic inflammation, as indicated by CRP levels in cancer patients. The use of omega-3 PUFAs is recommended for cancer patients due to their anti-inflammatory properties.

A comparative study on the effects of SiO2 modification and mesoporous structures on catalytic performances over ZSM-5 zeolites in MTA conversion both theoretically and experimentally was done. Experimental results showed that hierarchical pores increased the production of aromatics. However, DFT calculation proved that energy barriers for producing aromatics over mesoporous ZSM-5 were larger than that of parent ZSM-5 due to decreasing acid strength after alkali treatment which significantly influenced rate-determining step. Furthermore, diffusion behaviors of toluene were studied by Molecular Dynamics. Larger pores led to the improvement of diffusion behaviors over hierarchical ZSM-5 owing to the decrease of collision frequency between molecules. Therefore, the formation of aromatics was mainly determined by diffusion limitation over hierarchical ZSM-5. The lowest BTX selectivity was obtained over SiO2 deposited mesoporous ZSM-5 due to decreasing acid strength and blockage of pore mouth. Additionally, the deactivation of ZSM-5 serial catalysts in MTA was attributed the formation of insoluble coke. Moreover, the introduction of mesopores and silylation on external surface alleviated the deactivation of catalysts.

Two dammarane glycosides (1-2) were isolated from the leaves of Cyclocarya paliurus. The structures of new compounds were established by application of spectroscopic methods, including one-dimensional and two-dimensional NMR, HRESIMS, and chemical hydrolysis. When evaluated against seven human cancer cell lines, the two compounds exhibited selective cytotoxicity to MCF-7 cells.

In the presence of Na2CO3, conjugate addition of α-halo hydrazones to nitroso compounds proceeded readily to give polyfunctionalized nitrones in reasonable chemical yields and excellent stereoselectivities. The chemical structure and the stereochemical configuration of the products were unambiguously identified by an X-ray single-crystal structural analysis.

Under the catalysis of PhCO2H, the 1,3-dipolar [3+2] cyclo­addition between pyrazolone-based olefins and N,N′-cyclic azomethine imines proceeded readily, thus delivering structurally novel spiropyrazolones with up to 98% yield and >20:1 dr. The relative stereochemical configuration of the obtained spiropyrazolones was unambiguously ­assigned by X-ray single-crystal structure analysis. The diastereoselective formation of the title spiropyrazolones was interpreted by the hypothesized reaction mechanism.

Aquaporins (AQPs) involved in water and small molecule transport respond to environmental stress, while it is not clear how arbuscular mycorrhizal fungi (AMF) regulate AQP expression. Here, we investigated the change in leaf water potential and expression level of four tonoplast intrinsic proteins (TIPs), six plasma membrane intrinsic proteins (PIPs), and four nodin-26 like intrinsic proteins (NIPs) genes in trifoliate orange (Poncirus trifoliata) inoculated with Funneliformis mosseae under well-watered (WW), salt stress (SS), and waterlogging stress (WS). Root AMF colonization and soil hyphal length collectively were reduced by SS and WS. Under WW, inoculation with AMF gave diverse responses of AQPs: six AQPs up-regulated, three AQPs down-regulated, and five AQPs did not change. Such up-regulation of more AQPs under mycorrhization and WW partly accelerated water absorption, thereby, maintaining higher leaf water potential. However, under SS, all the fourteen AQPs were dramatically induced by AMF inoculation, which improved water permeability of membranes and stimulated water transport of the host. Under WS, AMF colonization almost did not induce or even down-regulated these AQPs expressions with three exceptions (PtTIP2;2, PtPIP1;1, and PtNIP1;2), thus, no change in leaf water potential. As a result, mycorrhizal plants under flooding may have an escape mechanism to reduce water absorption. It is concluded that AMF had different strategies in response to environmental stresses (e.g. SS and WS) by regulating leaf AQP expression in the host (e.g. trifoliate orange).

Background Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis. Methods Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFβ1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected. Results After Ang II stimulation, TGFβ1, TGFβ1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFβ1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFβ1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFβ1/MAPK signaling pathway. Conclusions This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFβ1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis.

A novel Gram-negative, rod-shaped, aerobic, oxidase-positive and catalase-negative bacterium, designated strain SM1970T, was isolated from a seawater sample collected from the Mariana Trench. Strain SM1970T grew at 15-37 oC and with 1–5% (w/v) NaCl. It hydrolyzed colloidal chitin, agar and casein but did not reduce nitrate to nitrite. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain SM1970T formed a distinct lineage close to the genus Catenovulum within the family Alteromonadaceae, sharing the highest sequence similarity (93.6%) with type strain of Catenovulum maritimum but < 93.0% sequence similarity with those of other known species in the class Gammaproteobacteria. The major fatty acids of strain SM1970T were summed feature 3 (C16: 1 ω7c and/or C16: 1 ω6c), C16: 0 and summed feature 8 (C18: 1 ω7c and/or C18: 1 ω6c). The major polar lipids of the strain included phosphatidylethanolamine and phosphatidylglycerol and its main respiratory quinone was ubiquinone 8. The draft genome of strain SM1970T consisted of 77 scaffolds and was 4,172,146 bp in length, containing a complete set of genes for chitin degradation. The average amino acid identity (AAI) values between SM1970T and type strains of known Catenovulum species were 56.6–57.1% while the percentage of conserved proteins (POCP) values between them were 28.5–31.5%. The genomic DNA G + C content of strain SM1970T was 40.1 mol%. On the basis of the polyphasic analysis, strain SM1970T is considered to represent a novel species in a novel genus of the family Alteromonadaceae, for which the name Marinifaba aquimaris is proposed with the type strain being SM1970T (= MCCC 1K04323T = KCTC 72844T).

Objectives In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound. Methods The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry. Results SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters. Conclusions Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.

In this work, a high-performance liquid chromatography-diode array detection (HPLC-DAD) method combined with chemometrics was developed for differentiating geographical origins of Chinese red wines. Phenolic compounds were firstly detected and quantified by direct injection HPLC-DAD method in thirty red wines originated from two famous wine-growing regions in China. Given the high complexity of the wine samples and the co-elution problems during chromatographic separation, multivariate curve resolution-alternating least squares (MCR-ALS) was utilized to extract pure chromatographic and spectral profiles of each co-eluted compound. Quantification of phenolic compounds was thus achieved even in the presence of overlapping peaks and uncalibrated interferents. The quantitative data of the phenolic compounds in wines provided by the MCR-ALS algorithm were afterwards analyzed by unsupervised principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods and supervised orthogonal partial least squares-discrimination analysis (OPLS-DA) method. Both PCA and HCA results showed that the thirty red wines from different geographical origins could be obviously distinguished, and the OPLS-DA could successfully predict the geographical origins of red wines. This study demonstrated that the HPLC-DAD method combined with chemometrics can be used as an effective tool for differentiating geographical origins of Chinese red wines on the basis of phenolic compounds.

Under the reaction conditions of Pd(PPh3)4 (2.5 mol %) and PPh3 (10 mol %) in EtOAc at 60 °C, the formal (5 + 6) cycloaddition of vinylethylene carbonates with isatoic anhydrides proceeded smoothly and furnished medium-sized N,O-containing heterocycles in reasonable chemical yields. The chemical structures of the title products were clearly identified by X-ray diffraction analysis.

Background Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P P Conclusion This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.

The interaction between ovalbumin (OVA) and high methoxyl pectin (PEC) was explored according to turbidity and coacervate yield measurements. Coacervation could occur between the two polyelectrolytes in pHs ranging from 2.5 to 4.0 and peaked in pH 2.5. The presence of NaCl suppressed the interaction, and their mass ratio determined the solubility of resultant coacervates. The association between OVA and PEC was highly temperature dependent and hydrophobic interaction played an important role in their complexation. Atomic force microscope observation revealed that serious aggregation occurred to the coacervates separated in pH 2.5, and circular dichroism analysis indicated that coacervation with PEC induced structural changes in OVA, which was positively related to the degree of coacervation. Thermogravimetry analysis demonstrated increased thermal stability of OVA in the coacervates, and quartz crystal microbalance analysis confirmed that the association between OVA and PEC was pH dependent and a rigid layer could be formed between them.

Aberrant DNA methylation is closely associated with the pathogenesis of Parkinson's disease (PD). DNA methyltransferases (DNMTs) are the enzymes for establishment and maintenance of DNA methylation patterns. It has not been clearly defined how DNMTs respond in PD and what mechanisms are associated. Models of PD were established by treatment of five different neurotoxins in cells and intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Plasma samples of PD patients were also used. Western blot, real-time PCR, immunostaining, and/or luciferase reporter were employed. DNA methylation was analyzed by the bisulfite sequencing analysis. Protein expression of DNMT1, but not of DNMT3A and DNMT3B, was reduced in the cellular and mouse models of PD. Paradoxically, mRNA levels of DNMT1 were increased in these models. After ruling out the possibility of protein degradation, we screened a set of miRNAs that potentially targeted DNMT1 3'-UTR by luciferase reporters and expression abundancies. miR-17 was identified for further investigation with miR-19a of low expression as a parallel comparison. Although exogenous transfection of either miR-17 or miR-19a mimics could inhibit DNMT1 expression, results of miRNA inhibitors showed that miR-17, but not miR-19a, endogenously regulated DNMT1 and the subsequent DNA methylation. Furthermore, levels of miR-17 were elevated in the neurotoxin-induced PD models and the plasma of PD patients. This study demonstrates that the miR-17-mediated DNMT1 downregulation underlies the aberrant DNA methylation in PD. Our results provide a link bridging environmental insults and epigenetic changes and implicate miR-17 in therapeutical modulation of DNA methylation in PD.

Three tetrahydroquinoline alkaloids, lycibarbarines A-C (1-3), possessing a unique tetracyclic tetrahydroquinoline-oxazine-ketohexoside fused motif, were isolated from the fruits of Lycium barbarum. Their structures were determined by spectroscopic analysis and quantum-chemical calculations. Compounds 1 and 3 exhibited neuroprotective activity when evaluated for corticosterone-induced injury by reducing the apoptosis of PC12 cells through the inhibition of caspase-3 and caspase-9.

Methylation pattern of gene modification is essential for the differentiation of T regulatory cells (Tregs) and 5-Aza-2ʹ-deoxycytidine is a common inhibitor of methylation. This study aimed to inve...

Objective: Clinically, low-dose aspirin and progesterone are frequently used to prevent pregnancy loss. We investigated the effect of these drugs on the biological behavior of human extravillous trophoblasts in vitro. Methods: HTR-8/SVneo cells were cultured in vitro and treated with different concentrations of aspirin and progesterone. The proliferation, invasion, and apoptosis of HTR-8/SVneo cells were assessed using a cell counting Kit-8 assay, Matrigel Transwell assay, and Hoechst staining, respectively. Reverse transcriptase polymerase chain reaction was used to verify the expression of related genes. Reactive oxygen species (ROS) levels were detected using the 2,7-dichlorofluorescin diacetate assay. Results: Low-dose aspirin alone, progesterone alone, or aspirin plus progesterone upregulated the proliferation and invasion and decreased the apoptosis of HTR-8/SVneo cells. Moreover, the expression of marker of proliferation Ki-67 (MKI67), matrix metalloproteinases 2 (MMP2), and MMP9 was increased. In addition, low-dose aspirin plus progesterone exerted stronger anti-apoptosis effects than low-dose aspirin and progesterone alone. Interestingly, aspirin upregulated the expression of progesterone receptor (PGR). Treatment with hydrogen peroxide (H2O2) promoted ROS production in HTR-8/SVneo cells; however, low-dose aspirin plus progesterone significantly restricted H2O2-mediated ROS production and apoptosis in HTR-8/SVneo cells. Conclusions: These data suggest that low-dose aspirin and progesterone promote proliferation and invasion and cooperatively reduce oxidative stress and apoptosis in trophoblasts in vitro. These results may provide an experimental basis for the combined application of aspirin and progesterone to prevent unexplained recurrent spontaneous miscarriage, especially in patients with trophoblast dysfunction.

Three mononuclear tetrakis(pseudohalido)-cobalt(II) complexes (Ph4P)2[Co(E)4] (E = N3−, 1; NCO−, 2; NCS−, 3) have been synthesized and structurally characterized. Each compound contains a distorted tetrahedral Co2+ ion coordinated by four pseudohalide ligands. The magnetic properties of 1–3 have been studied using direct-current magnetic measurements and high-frequency and -field EPR spectroscopy (HFEPR), suggesting easy-axis magnetic anisotropy for 1 and 2 and easy-plane anisotropy for 3. Analysis of the HFEPR spectra yielded D values of −5.23 and +3.63 cm−1 for 2 and 3, respectively. The absence of the EPR signal in 1 is consistent with a large, negative value of the zero-field splitting (ZFS) parameter D in 1. The nature of magnetic anisotropies of 1–3 has also been confirmed by ab initio calculations. The calculated D values are consistent with those determined using magnetometry and HFEPR studies. Alternating current (AC) magnetic susceptibilities reveal slow magnetic relaxation under an applied magnetic field, thus indicating that 1–3 are field-induced single-ion magnets (SIMs).

It is widely accepted that lysosomes are essential for cell homeostasis, and autophagy plays an important role in tumor development. Here, we found FV-429, a synthetic flavonoid compound, inhibited autophagy flux, promoted autophagosomes accumulation, and inhibited lysosomal degradation in T-cell malignancies. These effects were likely to be achieved by lysosomal dysregulation. The destructive effects of FV-429 on lysosomes resulted in blockage of lysosome-associated membrane fusion, lysosomal membrane permeabilization (LMP), and cathepsin-mediated caspase-independent cell death (CICD). Moreover, we initially investigated the effects of autophagy inhibition by FV-429 on the therapeutic efficacy of chemotherapy and found that FV-429 sensitized cancer cells to chemotherapy agents. Our findings suggest that FV-429 could be a potential novel autophagy inhibitor with notable antitumor efficacy as a single agent.

In the ongoing efforts to discover natural cholesterol-lowering compounds, dihydrocucurbitacin B, isolated from Trichosanthes cucumeroides roots, was found to promote LDL uptake by upregulating LDLR protein in a PCSK9-dependent process. In this study, an in-depth investigation of T. cucumeroides roots afforded 27 cucurbitacins (1-27), including seven new cucurbitacins (1-7), and their structures were elucidated by spectroscopic data analyses. In order to gain insight into their structure-activity relationship, cucurbitacin derivatives (B1-11 and DB1-11) were synthesized. Evaluation of lipid-lowering activities of these cucurbitacins by an LDL uptake assay in HepG2 cells revealed that most of the compounds improved the LDL uptake rate, among which hexanorisocucurbitacin D (6) and isocucurbitacin D (21) exhibited the highest activities (rates of 2.53 and 2.47, respectively), which were comparable to that of the positive control, nagilactone B (rate of 2.07). According to a mechanistic study by Western blot analysis, compounds 6 and 21 dose-dependently increased LDLR protein levels and reduced PCSK9 protein levels, representing promising new lipid-lowering drug candidates.

Introduction: Diabetes mellitus is one of the most important health issues worldwide. The rising incidence of the disease has resulted in a parallel increase of complications such as diabetic foot ulcers (DFU). It is estimated that 25% of patients with diabetes will develop foot ulcers over a lifetime. In Mexico, this lifetime incidence is about 40% to 50%, and 20% of the cases will require amputations. DFU can result in staggering financial burdens for the healthcare system and the patient. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. Methods: Cu/TiO2–SiO2 nanoparticles were synthesized by T. López et al. sol-gel patented method. After synthesis, they were characterized using transmission electron microscopy (TEM) and X-ray diffraction. Then, they were embedded in a polymeric gel matrix. The Cu/TiO2–SiO2 nanogel was used as conservative therapy for a chronic non-healing DFU on a 62-year old female with several comorbidities and chronic complications of diabetes. Wound debridement was performed prior to nanogel administration. The nanogel was applied over the ulcer on alternate days for an initial period of 2 weeks and then continued for 10 months. Results: Significant improvement was observed in the wound healing process since the first applications. The infection was limited and tissue regeneration was enhanced until complete healing of the ulcer. Conclusion: Cu/TiO2–SiO2 nanogel therapy enhanced reepithelialization and healing of the DFU. The successful outcome allowed to avoid the amputation that was proposed for the patient.

Biomass is an important resource of functional carbonaceous materials for a wide range of applications. Herein, we introduce a self-supporting three-dimensional carbon felt derived from loofah spon...

Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT;Lpin1−/− mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy., Altered lipid metabolism has been associated with tumour malignancy, but underlying mechanisms are not clear. Here the authors show that proto-oncogene Src interacts and phosphorylates metabolic enzyme phosphatidic acid phosphatase LPIN1 (lipin-1) to promote growth and metastasis in breast cancer.

In the presence of Pd2(dba)3·CHCl3 (2.5 mol%), PPh3 (10 mol%), and 60% NaH (1.5 equiv), the formal [5+3] cycloaddition between isatin-based α-(trifluoromethyl)imines and vinyloxiranes proceeded readily in 1,2-DCE at 40 ℃ and afforded cis-configured medium-heterocycle-fused spirooxindoles in the reasonable chemical yields with >20:1 dr. The relative stereochemical configuration of the title products was identified by X-ray diffraction analysis.

Whether allicin can suppress the angiogenesis via inhibiting the activity of vascular endothelial cells (VECs) in preventing epidural hypertrophic scars remains unknown. VECs were treated by allicin at a gradient of concentrations. Cell activity was measured by CCK-8 assay, scratch assay and flow cytometry. Reverse-transcription PCR and Western Blot were used to measure the expression levels of relevant genes and proteins. After treated with allicin at concentrations of 0, 25, 50 and 100 mg/L, the viability of VECs significantly decreased at 24 h (p

Background Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status. Methods A total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs. Results During a median of 5.1 (interquartile range 3.9 to 5.9) years’ follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149–2.955), 1.828 (1.165–2.867), 2.212 (1.396–3.507), all p Conclusions In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC(50) values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP(3)R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP(3)R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Reactive oxygen species (ROS) have already been demonstrated to impede the migratory ability in non-melanocytic cell lines by depleting mitochondrial ATP production. Therefore, understanding the mitochondrial metabolic response to migration in the presence of ROS should be a key to understanding repigmentation in vitiligo. This study aimed to investigate the energy mechanism associated with the ROS-mediated attenuation of melanocyte migration. After melanocytes were pretreated with H2 O2 , their ATP production, migratory ability, ultrastructural changes and Mitochondrial Permeability Potential were analysed. The results showed that, in parallel with the decreased ATP production, the migratory ability of melanocytes was significantly inhibited by oxidative stress. Supplementation with exogenous ATP reversed the suppressed ATP-dependent migration of melanocytes. Melanocytes were then stressed with H2 O2 and Agilent Whole Human Genome microarray analysis identified 763 up-regulated mRNAs and 1117 down-regulated mRNAs. Among them, 11 of the encoded proteins were involved in mitochondrial ATP production and their expression levels were verified. The decreased expression of NADH dehydrogenase 2(ND2) , cytochrome c oxidase 1(COX1) and cytochrome c oxidase 3(COX3) was shown to be involved in the depletion of mitochondrial ATP production, which was coupled with the impaired migratory potential. These results indicate that the migration of melanocytes relies heavily on an inexhaustible supply of ATP from mitochondria.

A facile, cost-effective, and eco-friendly method was proposed to synthesize Fe3O4@tannic acid@Au nanocomposites (Fe3O4@TA@Au). First, Fe3O4 nanoparticles with diameters of 20 and 200 nm were synthesized by co-precipitation and solvothermal methods, respectively. Gold nanoparticles were deposited on magnetic Fe3O4 through tannic acid-metal-polymer intermediate-layer-mediated reductions. The catalytic activities of the as-prepared Fe3O4@TA@Au were investigated by spectroscopically monitoring the reduction of 4-nitrophenol (4-NP) and methylene blue (MB), which could be achieved within several minutes with an excess of NaBH4. The impact of the Fe3O4 size on the overall catalytic ability of the Fe3O4@TA@Au was systematically studied. The reaction rate constants of the Fe3O4-20 nm@TA@Au for 4-NP and MB reduction were 0.432 and 0.543 min–1, respectively. For the Fe3O4-200 nm@TA@Au nanocomposite, the optimized reaction rate constants for 4-NP and MB reduction were 3.09 and 0.441 min–1, respectively. Due to magnetic separation, the Fe3O4@TA@Au could be easily harvested and recycled. After five recycling cycles, the catalytic ability remained over 90%, and the recycling process could be completed in several minutes, highlighting its potential as a catalyst for 4-NP and MB removal.

Resveratrol has been extensively studied as the anti-cancer agent. A variety of resveratrol analogues have been developed with structural modification to improve its bioactivity. In this work, resveratrol analogues, compound 1-4, were designed and synthesized with the Stille–Heck reaction. These results showed compound 1–4 had better anticancer effect than that of parent resveratrol. Especially compound 1 ((E)-4,4′-(ethene-1,2-diyl)bis(3-methylphenol)) displayed the excellent cytotoxicity and high selectivity. The mechanism research indicated compound 1 inhibited cell proliferation by binary paths of cell cycle arrest in S phase regulated by cyclin A1/A2 and apoptosis induction mediated by Bax/Bcl2 in a prooxidant manner.

Xian-Ling-Gu-Bao (XLGB), a famous traditional Chinese medicine prescription consisted of six herbal medicines, was used for prevention and treatment of osteoporosis in China. As an oral formulation, the multiple components contained in XLGB were inevitably biotransformed by the intestinal microflora before absorption via the gastrointestinal tract. However, the dynamic profiles of biotransformation products of XLGB remain unknown. In this paper, a rapid and sensitive ultra-performance liquid chromatography tandem triple quadrupole mass spectrometry method was developed for the simultaneous quantitative analysis of multiple biotransformation products of XLGB with rat intestinal microflora. For 10 selected quantitative compounds, all calibration curves revealed good linearity (r2 > 0.99) within the sampling ranges considered. The whole intra- and inter-day precisions (as relative standard deviation) of all analytes were