The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
This study examines the interaction between hERG and Kv4.3. The functional interaction between hERG and Kv4.3, expressed in a heterologous cell line, was studied using patch clamp techniques, western blot, immunofluorescence, and co-immunoprecipitation. Co-expression of Kv4.3 with hERG increased hERG current density (tail current after a step to +10 mV: 26 ± 3 versus 56 ± 7 pA/pF, p < 0.01). Kv4.3 co-expression also increased the protein expression and promoted the membrane localization of hERG. Western blot showed Kv4.3 increased hERG expression by Hsp70. hERG and Kv4.3 co-localized and co-immunoprecipitated in cultured 293 T cells, indicating physical interactions between hERG and Kv4.3 proteins in vitro. In addition, Hsp70 interacted with hERG and Kv4.3 respectively, and formed complexes with hERG and Kv4.3. The α subunit of Ito Kv4.3 can interact with and modify the localization of the α subunit of IKr hERG, thus providing potentially novel insights into the molecular mechanism of the malignant ventricular arrhythmia in heart failure.
Osteoporosis presents a challenge to the long-term success of osseointegration of endosseous implants. The bio-inspired 3,4-dihydroxy-L-phenylalanine (Dopa) coating is widely used as a basic layer to bind osteogenetic molecules that may improve osseointegration. To date, little attention has focused on application of Dopa alone or binding inhibitors of bone resorption in osteoporosis. Local use of a bisphosphonate such as zoledronic acid (ZA), an inhibitor of osteoclast-mediated bone resorption, has been proven to improve implant osseointegration. In this study, ovariectomized rats were divided into four groups and implanted with implants with different surface modifications: sandblasted and acid-etched (SLA), SLA modified with Dopa (SLA-Dopa), SLA modified with ZA (SLA-ZA), and SLA modified with Dopa and ZA (SLA-Dopa + ZA). Measurement of removal torque, micro-computed tomography and histology revealed a greater extent of bone formation around the three surface-modified implants than SLA-controls. No synergistic effect was observed for combined Dopa + ZA coating. Microarray analysis showed the Dopa coating inhibited expression of genes associated with osteoclast differentiation, similarly to the mechanism of action of ZA. Simple Dopa modification resulted in a similar improvement in osseointegration compared to ZA. Thus, our data suggest simple Dopa coating is promising strategy to promote osseointegration of implants in patients with osteoporosis.
One specific behavior can be synergistically modulated by different neural pathways. Medial septal (MS) cholinergic system innervates widespread cortical and subcortical regions and participates in pain modulation, but the underlying neural pathways are not fully understood. This study examined the contribution of MS cholinergic neurons and 2 neural pathways: MS-rostral anterior cingulate cortex (rACC) and MS-ventral hippocampal CA1 (vCA1), in modulating perceptual and affective pain behaviors in a mouse model of chronic inflammatory pain. We found that chronic pain activated MS cholinergic neurons and pyramidal neurons in the rACC, but suppressed pyramidal neuronal activities in the vCA1, all of which contributed to the maintenance of pathological pain. Chemogenetic inhibition of MS cholinergic neurons or the MS-rACC pathway inhibited rACC pyramidal neuronal activities and attenuated perceptual and affective dimensions of chronic pain. By contrast, chemogenetic activation of MS cholinergic neurons also produced analgesia, but by rescuing hypofunctional pyramidal neurons in vCA1. These results clearly demonstrate that the MS cholinergic system differentially modulates chronic inflammatory pain through MS-rACC or MS-vCA1 pathways. More significantly, our research provides evidence for a novel paradigm of neural circuit modulation: MS cholinergic inhibition and activation induce similar analgesia but through distinct neural pathways.
Aroma-active compounds and non-volatile substances determine the characteristic aroma and taste of yeast extract (YE). Changes in the characteristic aroma and taste of YE due to thermal reaction are rarely studied, and the relationship between aroma-active compounds and non-volatile compounds is not yet clear.
Non-volatile compounds identified by HPLC and LC/MS/MS were reduced by a rise in temperature, except for some amino acids. Peptides underwent degradation. In addition, a further rise in temperature above 120 °C resulted in a bitter and sour taste. Furans, pyrazines, thiophenes, thiazoles and some branched chain sulfur compounds were derived from GC/O/MS (SPME and SAFE). Sensory results revealed that the concentration of volatile compounds increased with an increase in temperature. The overall aroma profiles of YE at 25, 100 and 110 °C were buttery, green, nutty and meaty, while YE at 140 °C had a strong sour and sulfur odour.
The non-volatile compounds of YE were reduced and different volatile compounds were produced under different thermal treatments. There was a negative correlation between these two types of compounds. The different taste sensors and all precursors were correlated with each other. There are significant relationships between different odorants and aroma-active compounds of YE after thermal treatment. © 2018 Society of Chemical Industry.
Prostate cancer-associated non-coding RNA transcript-1(PCAT-1), which is a newly discovered long non-coding RNA, is up-regulated in various cancers. We conducted a meta-analysis to assess the clinicopathological and prognostic value of PCAT-1 in patients with malignant tumors.
A systematic literature search involved PubMed, Medline, Cochrane Library, Web of Science, EMBASE database, Ovid, Chinese CNKI, and the Chinese WanFang database. The role of PCAT-1 in cancers was evaluated by pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs).
A total of 1005 patients from nine studies were included in this meta-analysis. High expression of PCAT-1 was associated with depth of infiltration, lymph node metastasis, distant metastasis and TNM stage. However, increased PCAT-1 expression was not related to gender, tumor size and differentiation. Moreover, high PCAT-1 expression was associated with poor overall survival (OS) and disease-free survival (DFS), and the pooled results suggested that PCAT-1 expression can be an independent predictive factor for overall survival.
This meta-analysis provides evidence that PCAT-1 expression is closely correlated with depth of infiltration, lymph node metastasis, distant metastasis and TNM stage, and that increased PCAT-1 expression may be a potential prognostic biomarker in human cancers. However, more large-scale studies are warranted.
Strobilanthes A (1), a novel isocoumarin with an unusual tetrahydro-4H-pyran-4-one moiety fused isocoumarin core skeleton, together with a known compound (2) was isolated from Strobilanthes cusia. Its chemical structures were elucidated by 2D NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction analysis. The biosynthetic pathway of 1 could be supposed to be originally derived from 3-methylisocoumarin, a product of AA-MA pathway. Both of two compounds displayed anti-influenza virus activity in vitro.
Acrylamide (AA) is a high production volume chemical in industrial applications and widely found in baked or fried carbohydrate-rich foods. In this study, we unravelled that AA induced developmental toxicity associated with oxidative stress status and disordered lipid distribution in heart region of developing zebrafish. Treatment with AA caused a deficient cardiovascular system with significant heart malformation and dysfunction. We also found that AA could reduce the number of cardiomyocytes through the reduced capacity of cardiomyocyte proliferation rather than cell apoptosis. The cardiac looping and ballooning appeared abnormal though cardiac chamber-specific identity in the differentiated myocardium was maintained well after AA treatment through MF20/S46 immunofluorescence assay. Furthermore, treatment with AA disturbed the differentiation of atrioventricular canal, which was demonstrated by the disordered expressions of the atrioventricular boundary markers bmp4, tbx2b and notch1b and further confirmed by the ectopic expressions of the cardiac valve precursor markers has2, klf2a and nfatc1 through whole-mount in situ hybridization. Thus, our studies provide the evidence of cardiac developmental toxicity of AA in the cardiovascular system, and also raised health concern about the harm of trans-placental exposure to high level of AA for foetuses and the risk of high exposure to AA for the pregnant women.
Fabrication of antibacterial materials with sustained release of active components is of great importance for long-term antibacterial applications. Graphene oxide (GO) has been found to be an excellent carrier for accumulating the antibacterial peptide of G(IIKK)4I-NH2 and mediating its loading into the layer-by-layer (LBL) films for sustained release applications. G(IIKK)4I-NH2 takes random coiled conformation in monomeric state below 0.17 mM but self-assembles into supramolecular aggregates with α-helical secondary structure at higher concentrations. It can bind onto GO surface in both monomeric and aggregate states to form stable GO@G(IIKK)4I-NH2 composites. Upon binding, the local amphiphilic environment of GO surface induces a conformational transition of G(IIKK)4I-NH2 monomers from random coils to α-helix. The aggregate binding enhances the loading amount greatly. GO (1 mg) can load as high as 1.7 mg of peptide at saturation. This enables the GO@G(IIKK)4I-NH2 composites to serve as reservoirs for sustained release of active G(IIKK)4I-NH2 monomers. Moreover, G(IIKK)4I-NH2 itself shows low efficiency in LBL assembly, whereas the GO@G(IIKK)4I-NH2 composites are ideal LBL assembling units with highly enhanced loading efficiency of G(IIKK)4I-NH2. The LBL films involving degradable poly(β-amino esters) can realize sustained release of G(IIKK)4I-NH2 for bacteria killing in a well-controlled manner. This study demonstrates an efficient strategy for fabrication of long-durable antibacterial materials and surface coatings by using GO as the carrier for drug accumulation and loading.
Nonadiabatic excited-state molecular dynamics (NEXMD) has been used to study photodecomposition in a class of recently synthesized bicyclic conjugated energetic materials (CEMs) composed of fused tetrazole and tetrazine derivatives with increasing oxygen substitutions. Modification by oxygen functionalization has already been demonstrated to increase the two-photon absorption intensity in the target CEMs while simultaneously improving oxygen balance. Photodecomposition mechanisms in materials that undergo nonlinear absorption could be used to achieve controlled, direct optical initiation. Here, we use NEXMD simulations to model the nonradiative relaxation and photodecomposition in CEMs following photoexcitation by a simulated Nd:YAG laser pulse. Excess electronic energy is quickly converted into vibrational energy on a sub-100 fs time scale resulting in bond dissociation. We find that, for the studied tetrazine derivatives, the bicyclic framework is an important structural feature that enhances the photochemical quantum yield and the high atomic oxygen content increases the relaxation lifetime and opens additional photodissociation pathways targeting the oxygen-substituted sites. The presented analysis scheme based on bond orders in the swarm of NEXMD trajectories is a useful tool for determining photochemical reactions.