Electrophotocatalysis Versus Indirect Electrolysis: Electrochemical Selenocyclization of 3-Aza-1,5-dienes Facilitated by Energy Transfer, Direct Photolysis or N-Hydroxyphthalimide.

Three hybrid electrochemical protocols, which involve the energy transfer, direct photolysis and N-hydroxyphthalimide catalyst, respectively, are presented for the selenylation/cyclization of the fragile substrates of 3-aza-1,5-dienes with diorganyl diselenides to afford 3-selenomethyl-4-pyrrolin-2-ones. The two electrophotocatalytic reactions and the indirect electrolysis one are both regioselective and external-oxidant- and transition-metal-free, and are associated with a broad substrate scope and high Se-economy, and all three methods are amenable to gram-scale syntheses, late-stage functionalizations, sunlight-induced experiments and all-solar-driven syntheses.

Enhancing the Properties of Water-Soluble Copolymer Nanocomposites by Controlling the Layer Silicate Load and Exfoliated Nanolayers Adsorbed on Polymer Chains.

Novel polymer nanocomposites of methacryloyloxy ethyl dimethyl hexadecyl ammonium bromide-modified montmorillonite (O-MMt) with acrylamide/sodium p-styrene sulfonate/methacryloyloxy ethyl dimethyl hexadecyl ammonium bromide (ASD/O-MMt) were synthesized via in situ polymerization. The molecular structures of the synthesized materials were confirmed using Fourier-transform infrared and 1H-nuclear magnetic resonance spectroscopy. X-ray diffractometry and transmission electron microscopy revealed well-exfoliated and dispersed nanolayers in the polymer matrix, and scanning electron microscopy images revealed that the well-exfoliated nanolayers were strongly adsorbed on the polymer chains. The O-MMt intermediate load was optimized to 1.0%, and the exfoliated nanolayers with strongly adsorbed chains were controlled. The properties of the ASD/O-MMt copolymer nanocomposite, such as its resistance to high temperature, salt, and shear, were significantly enhanced compared with those obtained under other silicate loads. ASD/1.0 wt% O-MMt enhanced oil recovery by 10.5% because the presence of well-exfoliated and dispersed nanolayers improved the comprehensive properties of the nanocomposite. The large surface area, high aspect ratio, abundant active hydroxyl groups, and charge of the exfoliated O-MMt nanolayer also provided high reactivity and facilitated strong adsorption onto the polymer chains, thereby endowing the resulting nanocomposites with outstanding properties. Thus, the as-prepared polymer nanocomposites demonstrate significant potential for oil-recovery applications.

The nociceptin receptor promotes autophagy through NF-kB signaling and is transcriptionally regulated by E2F1 in HCC.

Opioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.

Increased dopamine and its receptor dopamine receptor D1 promote tumor growth in human hepatocellular carcinoma.

BACKGROUND: Dopamine and dopamine receptor D1 (DRD1), a member of the dopamine receptor family, have been indicated to play important roles in cancer progression, but dopamine secretion in hepatocellular carcinoma (HCC) and the effects of DRD1 on HCC remain unclear. This study was designed to explore the contribution of the dopaminergic system to HCC and determine the relationship between DRD1 and prognosis in HCC patients. METHODS: The dopamine metabolic system was monitored using enzyme-linked immunosorbent assays (ELISAs). The expression of DRD1 was detected by microarray analysis, immunohistochemistry (IHC), and quantitative real-time PCR (qRT-PCR). Stable DRD1 knockout and overexpression cell lines were established for investigation. Transwell, colony formation, and Cell Counting Kit 8 (CCK8) assays were performed to assess the malignant behaviors of cancer cells. The cAMP/PI3K/AKT/ cAMP response element-binding (CREB) signaling pathway was evaluated by Western blot. This pathway, which is agitated by DRD1 in striatal neurons, had been proven to participate in tumor progression. Xenograft HCC tumors were generated for in vivo experiments. RESULTS: Dopamine secretion increased locally in HCC due to an imbalance in dopamine metabolism, including the upregulation of dopa decarboxylase (DDC) and the downregulation of monoamine oxidase A (MAOA). Dopamine promoted the proliferation and metastasis of HCC. DRD1 was highly expressed in HCC tissues and positive DRD1 expression was related to a poor prognosis in HCC patients. The upregulation of DRD1 agitated malignant activities, including proliferation and metastasis in HCC by regulating the cAMP/PI3K/AKT/CREB pathway, and the downregulation of DRD1 had opposing effects. The effects of dopamine on HCC was reversed by depleting DRD1. SCH23390, a selective DRD1 antagonist, inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo. CONCLUSION: Dopamine secretion was locally increased in HCC and promoted HCC cell proliferation and metastasis. DRD1 was found to exert positive effects on HCC progression and play a vital role in the dopamine system, and could be a potential therapeutic target and prognostic biomarker for HCC.

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux.

Background: Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA in vitro and in vivo. Methods: The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth in vivo. Results: Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity. Conclusion: Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.

Andrographolide Prevents EV-D68 Replication by Inhibiting the Acidification of Virus-Containing Endocytic Vesicles.

Enterovirus D68 (EV-D68) has emerged as a significant respiratory pathogen that can cause severe respiratory disease and acute neurologic disease. At present, there are no approved antiviral agents or vaccines for EV-D68. In this study, we demonstrate that andrographolide (ADO), an active component of Andrographis paniculata, exerts substantial antiviral activity against EV-D68 infection. ADO treatment dramatically inhibited EV-D68 RNA replication (EC50 = 3.45 µM) and protein synthesis without producing significant cytotoxicity at virucidal concentrations. ADO-treated cells did not show any changes in host immune activation, EV-D68 attachment, or viral 5' UTR activity. Using a pH-sensitive fluorescent indicator system for endocytosis in living cells, we found that ADO prevented the acidification of endocytic vesicles after receptor-mediated endocytosis. Finally, we showed that ADO inhibited the viral replication of circulating isolated EV-D68 strains. In summary, our results demonstrate that ADO suppresses EV-D68 replication by targeting the maturation of virus-containing endosomes of EV-D68. This mechanism represents a promising strategy for drug development.

NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies.

Background: Initial observational studies and a systematic review published recently have suggested that non-steroidal anti-inflammatory drug (NSAID) use has the trend to be associated with reduced risk of Alzheimer's disease (AD), while results remain conflicting. Thus, we performed an updated meta-analysis to reevaluate the evidence on this association. Methods: Data sources from PUBMED, Embase and Cochrane Library from inception through April 2017 were searched by two independent reviewers. Eligible cohort studies were selected according to predefined keywords. We did a meta-analysis of available study data using a random-effects model to calculate overall relative risks (RRs) for associations between NSAID exposure and AD risk. Results: From 121 potentially relevant studies, 16 cohort studies including 236,022 participants, published between 1995 and 2016, were included in this systematic review. Meta-analysis demonstrated that current or former NSAID use was significantly associated with reduced risk of AD (RR, 0.81, 95% CI0.70 to 0.94) compared with those who did not use NSAIDs. This association existed in studies including all NSAID types, but not in aspirin (RR, 0.89, 95% CI 0.70 to 1.13), acetaminophen (RR, 0.87, 95% CI 0.40 to 1.91) or non-aspirin NSAID (RR, 0.84, 95% CI 0.58 to 1.23). Conclusions: Current evidence suggests that NSAID exposure might be significantly associated with reduced risk of AD. However, further large-scale prospective studies are needed to reevaluate this association, especially the associations in individual NSAID type.

The poly-proline tail of SIVmac Vpx provides gain of function for resistance to a cryptic proteasome-dependent degradation pathway.

The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion. Unlike wild-type Vpx, the poly-proline tail mutant Vpx is partly defective in enhancing viral infection in macrophages. Our findings suggest that during Vpx evolution, Vpx of the HIV-2/SIVsm/SIVmac lineage is targeted by a CRL4(DCAF1) E3 ligase-independent ubiquitination pathway, and have gained this interesting region, allowing them to maintain nuclear accumulation as part of their adaptation to host cell regulation.

Palladium-catalyzed direct C-H arylation of 3-aryl-2H-benzo[1,2,4]thiadiazine 1,1-dioxides: an efficient strategy to the synthesis of benzothiadiazine-1,1-dioxide derivatives.

A new palladium-catalyzed benzothiadiazine-1,1-dioxide direct arylation of C(sp(2))-H bonds is described. 3-Aryl-2H-benzo[1,2,4]thiadiazine 1,1-dioxides react with various aryl iodides to give the corresponding mono-arylation products 3-(biphenyl-2-yl)-2H-benzo[1,2,4]thiadiazine 1,1-dioxides with high reactivity and regioselectivity in the presence of AgOAc. Remarkedly, the addition of TFA is crucial to improve the arylation yield.