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1.
Artigo em Inglês | MEDLINE | ID: mdl-32041891

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases. The RNA binding protein, QKI, belongs to the STAR family and plays tumor-suppressive functions in NSCLC. QKI-5 is a major isoform of QKIs and is predominantly expressed in NSCLC. However, the underlying mechanisms of QKI-5 in NSCLC progression remain unclear. We found that QKI-5 regulated microRNA (miRNA), miR-196b-5p, and its expression was significantly up-regulated in NSCLC tissues. Up-regulated miR-196b-5p promotes lung cancer cell migration, proliferation, and cell cycle through directly targeting the tumor suppressors, GATA6 and TSPAN12. Both GATA6 and TSPAN12 expressions were down-regulated in NSCLC patient tissue samples and were negatively correlated with miR-196b-5p expression. Mouse xenograft models demonstrated that miR-196b-5p functions as a potent onco-miRNA, whereas TSPAN12 functions as a tumor suppressor in NSCLC in vivo. QKI-5 bound to miR-196b-5p and influenced its stability, resulting in up-regulated miR-196b-5p expression in NSCLC. Further analysis showed that hypomethylation in the promoter region enhanced miR-196b-5p expression in NSCLC. Our findings indicate that QKI-5 may exhibit novel anticancer mechanisms by regulating miRNA in NSCLC, and targeting the QKI5∼miR-196b-5p∼GATA6/TSPAN12 pathway may enable effectively treating some NSCLCs.

2.
Inorg Chem ; 59(3): 1653-1659, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31965792

RESUMO

A discrete tetrahedral indium cage, {[In12(µ3-OH)4(HCO2)24(tcma)4]} (In12-GL), was synthesized solvothermally by the reaction of indium nitrate with the tripodal tricarboxylic acid ligand N,N,N-tris{(2'-carboxy[1,1'-biphenyl]-4-yl)methyl}methylammonium chloride ([H3tcma]+Cl). This cage consists of four trimeric units [In3(µ3-OH)(µ2-CO2)3(µ2-HCO2)3] and four [tcma]2- ligands, which all perform as 3-connection nodes to bridge each other, resulting in a tetrahedral cage structure. The trimeric unit [In3(µ3-OH)(µ2-CO2)3(µ2-HCO2)3] is observed for the first time in the family of In-based metal-organic structures and can be considered as an evolution of a 6-connected [In3(µ3-O)(µ2-CO2)6] unit. Each In3+ is terminally coordinated by a µ1-HCO2 group. This cage contains potential Lewis acidic/basic active sites endowed by In3+ ions as Lewis acidic sites and the uncoordinated oxygen atoms of µ1-HCO2 moieties as Lewis basic sites and was explored as an effective heterogeneous catalyst in the cycloaddition of CO2 with epoxides and the Strecker reaction for amino nitriles. These catalytic reactions were deduced to happen on the surface of the In12-GL cage.

3.
Chem Commun (Camb) ; 56(12): 1847-1850, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31950956

RESUMO

A novel, practical and metal-free approach for the regioselective selenation of coumarins employing (bis(trifluoroacetoxy)iodo)benzene (PIFA) at room temperature is presented. The developed method is suitable for a wide substrate scope and affords 3-selenyl coumarins in good to excellent yields with high selectivity. A radical mechanism is proposed for this new transformation. Furthermore, the application of sulfenylation with coumarines and selenation with other (hetero)arenes in this transformation is successful.

4.
Sci Adv ; 6(1): eaax5819, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911943

RESUMO

Autophagy is an evolutionarily conserved catabolic process, which plays a vital role in removing misfolded proteins and clearing damaged organelles to maintain internal environment homeostasis. Here, we uncovered the checkpoint kinase 2 (CHK2)-FOXK (FOXK1 and FOXK2) axis playing an important role in DNA damage-mediated autophagy at the transcriptional regulation layer. Mechanistically, following DNA damage, CHK2 phosphorylates FOXK and creates a 14-3-3γ binding site, which, in turn, traps FOXK proteins in the cytoplasm. Because FOXK functions as the transcription suppressor of ATGs, DNA damage-mediated FOXKs' cytoplasmic trapping induces autophagy. In addition, we found that a cancer-derived FOXK mutation induces FOXK hyperphosphorylation and enhances autophagy, resulting in chemoresistance. Cotreatment with cisplatin and chloroquine overcomes the chemoresistance caused by FOXK mutation. Overall, our study highlights a mechanism whereby DNA damage triggers autophagy by increasing autophagy genes via CHK2-FOXK-mediated transcriptional control, and misregulation of this pathway contributes to chemoresistance.

5.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165683, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953218

RESUMO

Arachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of inflammatory factors, and tissue injuries. In summary, we have discovered that AA interacts with MD2 and disrupts TLR4 activation by LPS and saturated fatty acids. These findings provide experimental evidence for a direct mechanism of AA-induced regulation of inflammation.

6.
J Org Chem ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31994395

RESUMO

An unprecedented method for the palladium (II)-catalyzed direct halogenation of benzothiadiazole derivatives is reported here, which would allow the rational tuning of their electronic properties by further transformations. The key strategy is the combination of the double functions of benzothiadiazole as both an important moiety of functional materials and modifiable directing group. Various mono/polychlorinated, brominated, or iodinated benzothiadiazole products could be prepared efficiently, which can be converted into a wide range of valuable polyaromatic compounds with potential applications in material chemistry.

7.
Nat Chem Biol ; 16(3): 267-277, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31959966

RESUMO

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.

8.
Fitoterapia ; 140: 104415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704260

RESUMO

Four new sesquiterpenoids, phellinignins A-D (1-4), together with four known ones (5-8), were isolated from cultures of the fungus Phellinus igniarius. The structures were established by extensive spectroscopic methods including MS, NMR, and the single crystal X-ray diffraction. Compounds 1-3 and 5-8 are tremulane sesquiterpenoids, while compound 4 possesses a new carbon skeleton that might derive from an illudane framework. Compounds 1, 2, 4, and 5 showed certain cytotoxicities to three human cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Basidiomycota/química , Sesquiterpenos/farmacologia , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Sesquiterpenos/isolamento & purificação
10.
Nanomaterials (Basel) ; 9(12)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835756

RESUMO

Lead-free double perovskites have been considered as a potential environmentally friendly photovoltaic material for substituting the hybrid lead halide perovskites due to their high stability and nontoxicity. Here, lead-free double perovskite Cs2AgBiBr6 films are initially fabricated by single-source evaporation deposition under high vacuum condition. X-ray diffraction and scanning electron microscopy characterization show that the high crystallinity, flat, and pinhole-free double perovskite Cs2AgBiBr6 films were obtained after post-annealing at 300 °C for 15 min. By changing the annealing temperature, annealing time, and film thickness, perovskite Cs2AgBiBr6 solar cells with planar heterojunction structure of FTO/TiO2/Cs2AgBiBr6/Spiro-OMeTAD/Ag achieve an encouraging power conversion efficiency of 0.70%. Our preliminary work opens a feasible approach for preparing high-quality double perovskite Cs2AgBiBr6 films wielding considerable potential for photovoltaic application.

11.
Drug Des Devel Ther ; 13: 4161-4171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849448

RESUMO

Background: Acute lung injury (ALI) is characterized by high prevalence and high mortality. Thus far, no effective pharmacological treatment has been made for ALI in clinics. Inflammation is critical to the development of ALI. Curcumin analog C66, having reported as an inhibitor of c-Jun N-terminal kinase (JNK), exhibits anti-inflammatory property both in vitro and in vivo. However, whether C66 is capable of reducing lipopolysaccharide (LPS)-induced ALI through the inhibition of inflammation by targeting JNK remains unknown. Methods: Intratracheal injection of LPS was employed to build a mouse ALI model. H&E staining, wet/dry ratio, immunofluorescence staining, inflammatory cell detection, and inflammatory gene expression were used to evaluate lung injury and lung inflammation. In vitro, LPS was used to induce the expression of inflammatory cytokines both in protein and gene levels. Results: The results of our studies showed that the pretreatment with C66 and JNK inhibitor SP600125 was capable of attenuating the LPS-induced ALI by detecting pulmonary edema, pathological changes, total protein concentration, and inflammatory cell number in bronchoalveolar lavage fluid (BALF). Besides, C66 and SP600125 also suppressed LPS-induced inflammatory cytokine expression in BALF, serum, and lung tissue. In vitro, LPS-induced production of TNF-α and IL-6 and gene expression of TNF-α, IL-6, IL-1ß, and COX-2 could be inhibited by the pretreatment with C66 and SP600125. It was found that C66 and SP600125 could inhibit LPS-induced phosphorylation of JNK both in vitro and in vivo. Conclusion: In brief, our results suggested that C66 protects LPS-induced ALI through the inhibition of inflammation by targeting the JNK pathway. These findings further confirmed the pivotal role of JNK in ALI and implied that C66 is likely to serve as a potential therapeutic agent for ALI.

12.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861702

RESUMO

Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.

13.
Sci Rep ; 9(1): 17422, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758007

RESUMO

Hybrid two-dimensional (2D) halide perovskites has been widely studied due to its potential application for high performance perovskite solar cells. Understanding the relationship between microstructural and opto-electronic properties is very important for fabricating high-performance 2D perovskite solar cell. In this work, the effect of solvent annealing on grain growth was investigated to enhance the efficiency of photovoltaic devices with 2D perovskite films based on (BA)2(MA)3Pb4I13 prepared by single-source thermal evaporation. Results show that solvent annealing with the introduction of solvent vapor can effectively enhance the crystallization of the (BA)2(MA)3Pb4I13 thin films and produce denser, larger-crystal grains. The thin films also display a favorable band gap of 1.896 eV, which benefits for increasing the charge-diffusion lengths. The solvent-annealed (BA)2(MA)3Pb4I13 thin-film solar cell prepared by single-source thermal evaporation shows an efficiency range of 2.54-4.67%. Thus, the proposed method can be used to prepare efficient large-area 2D perovskite solar cells.

14.
Front Pharmacol ; 10: 1180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680962

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths globally. Despite advances in diagnosis and treatment, the incidence and mortality of HCC continue to rise. Piperlongumine (PL), an alkaloid isolated from the fruit of the long pepper, is known to selectively kill tumor tissues while sparing their normal counterparts. However, the killing effects of PL on HCC and the underlying mechanism of PL are not clear. We report that PL may interact with thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, and induce reactive oxygen species (ROS)-mediated apoptosis in HCC cells. Our results suggest that PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells by targeting TrxR1 and increasing intracellular ROS levels. Notably, PL treatment reduces TrxR1 activity and tumor cell burden in vivo. Additionally, TrxR1 is significantly upregulated in existing HCC databases and available HCC clinical specimens. Taken together, these results suggest PL as a novel anticancer candidate for the treatment of HCC. More importantly, this study reveals that TrxR1 might be an effective target in treating HCC.

15.
Cell Death Dis ; 10(11): 848, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699972

RESUMO

Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic nephropathy (DN). Here, we investigated the hypothesis that pharmacological blockade of STAT3 limits the progression of DN. Treatment with selective STAT3 inhibitor, S3I-201 for 16 weeks significantly attenuated kidney injuries in streptozotocin (STZ) induced diabetic mice, associated with downregulated expression of TGF-ß1, ACE/AT1, and VEGF in diabetic mouse kidneys. Similar results were confirmed using genetic knockdown of STAT3 in mouse kidneys by injections of AAV2 expressing STAT3 shRNA in diabetic mouse. Further, STAT3 localization in kidney tissue was evaluated using immunofluorescent double-staining analysis, which indicated that STAT3 expression was mainly in the tubular epithelial cells. As expected, in renal tubular epithelial NRK-52E cells, high glucose (HG)-induced overexpression of TGF-ß1, ACE/AT1, and VEGF were abrogated by S3I-201 pretreatment, as well as by genetic knockdown of STAT3 using specific siRNA sequence. This study found that renal tubular epithelial cells contributed to STAT3-mediated progression of DN and provided the first evidence that pharmacological inhibition of STAT3 attenuates DN.

16.
J Exp Clin Cancer Res ; 38(1): 460, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703744

RESUMO

BACKGROUND: Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear. METHODS: CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction. RESULTS: We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells. CONCLUSION: Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.

17.
Aging (Albany NY) ; 11(21): 9310-9327, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692453

RESUMO

Asthma is a type of chronic lung inflammation with restrictions in effective therapy. NF-κB pathway activation has been suggested to play an important role in the pathogenesis of asthma. Baicalein, one of the major active flavonoids found in Scutellaria baicalensis, exhibits potent anti-inflammatory properties by inhibiting NF-κB activity. Herein, we report that Baicalein significantly reduces OVA-induced airway hyperresponsiveness (AHR), airway inflammation, serum IgE levels, mucus production, and collagen deposition around the airway. Additionally, western blot analysis and immunofluorescence assay showed that Baicalein attenuates the activation of NF-κB, which was mainly reflected by IκBα phosphorylation and degradation, p65 nuclear translocation and downstream iNOS expression. Furthermore, in human epithelial cells, Baicalein blocked TNF-α-induced NF-κB activation. Our study provides evidence that Baicalein administration alleviates the pathological changes in asthma through inactivating the NF-κB/iNOS pathway. Baicalein might be a promising potential therapy agent for patients with allergic asthma in the future.

18.
Drug Des Devel Ther ; 13: 3539-3550, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631978

RESUMO

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. Methods: Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. Results: Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. Conclusion: Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway.

19.
Nanomaterials (Basel) ; 9(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546773

RESUMO

Photocatalysts are widely used for the elimination of organic contaminants from waste-water and H2 evaluation by water-splitting. Herein, the nanohybrids of lanthanum (La) and selenium (Se) co-doped bismuth ferrites with graphene oxide were synthesized. A structural analysis from X-ray diffraction confirmed the transition of phases from rhombohedral to the distorted orthorhombic. Scanning electron microscopy (SEM) revealed that the graphene nano-sheets homogenously covered La-Se co-doped bismuth ferrites nanoparticles, particularly the (Bi0.92La0.08Fe0.50Se0.50O3-graphene oxide) LBFSe50-G sample. Moreover, the band-gap nanohybrids of La-Se co-doped bismuth ferrites were estimated from diffuse reflectance spectra (DRS), which showed a variation from 1.84 to 2.09 eV, because the lowering of the band-gap can enhance photocatalytic degradation efficiency. Additionally, the photo-degradation efficiencies increased after the incorporation of graphene nano-sheets onto the La-Se co-doped bismuth ferrite. The maximum degradation efficiency of the LBFSe50-G sample was up to 80%, which may have been due to reduced band-gap and availability of enhanced surface area for incoming photons at the surface of the photocatalyst. Furthermore, photoluminescence spectra confirmed that the graphene oxide provided more electron-capturing sites, which decreased the recombination time of the photo-generated charge carriers. Thus, we can propose that the use of nanohybrids of La-Se co-doped bismuth ferrite with graphene oxide nano-sheets is a promising approach for both water-treatment and water-splitting, with better efficiencies of BiFeO3.

20.
Int J Mol Med ; 44(5): 1855-1865, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485644

RESUMO

Asthma is a common chronic airway inflammatory disease, characterized by airway inflammation and remodeling. Piperlongumine (PL) has a number of physiological and pharmacological properties. However, the anti­asthmatic effect of PL has not been reported to date. In the present study, ovalbumin (OVA) was used to sensitize and challenge mice to induce asthma. The results revealed that PL pretreatment reduced OVA­induced airway inflammatory cell infiltration, reduced Th2 cytokine expression, both in the bronchoalveolar lavage fluid and in lung tissues, reduced the serum IgE level, pro­inflammatory cytokine [tumor necrosis factor (TNF)­α and interleukin (IL)­6] and intercellular adhesion molecule expression, as well as nuclear factor (NF)­κB activation. In addition, PL also mitigated OVA­induced goblet cell metaplasia, inhibited mucus protein secretion, mitigated airway fibrosis and downregulated fibrosis marker expression. It was also demonstrated that PL inhibited TNF­α induced inflammatory cytokine expression and NF­κB activation in vitro. Taken together, the findings of the present study indicated that PL can reduce OVA­induced airway inflammation and remodeling in asthmatic mice, and that these effects may be mediated by inhibiting NF­κB signaling.

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