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BACKGROUND: Epidemiological evidence suggests that there is an association between rheumatoid arthritis (RA) and Alzheimer's disease (AD). However, the causal relationship between RA and AD remains unclear. Therefore, this study aimed to investigate the causal relationship between RA and AD. METHODS: Using publicly available genome-wide association study datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using the inverse-variance weighted (IVW), weighted median, MRâEgger regression, simple mode, and weighted mode methods. RESULTS: The results of MR for the causal effect of RA on AD (IVW, odds ratio [OR] = 0.959, 95% confidence interval [CI]: 0.941-0.978, P = 2.752E-05; weighted median, OR = 0.960, 95% CI: 0.937-0.984, P = 0.001) revealed a causal association between genetic susceptibility to RA and an increased risk of AD. The results of MR for the causal effect of AD on RA (IVW, OR = 0.978, 95% CI: 0.906-1.056, P = 0.576; weighted median, OR = 0.966, 95% CI: 0.894-1.043, P = 0.382) indicated that there was no causal association between genetic susceptibility to AD and an increased risk of RA. CONCLUSIONS: The results of this two-way two-sample Mendelian randomization analysis revealed a causal association between genetic susceptibility to RA and a reduced risk of AD but did not reveal a causal association between genetic susceptibility to AD and an increased or reduced risk of RA.
Assuntos
Doença de Alzheimer , Artrite Reumatoide , Humanos , Fatores de Proteção , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Artrite Reumatoide/genética , Predisposição Genética para Doença/genéticaRESUMO
Quasi-one-dimensional (Q1D) semiconductor antimony selenide (Sb2Se3) shows great potential in the photovoltaic field, but the photoelectric conversion efficiency (PCE) of Sb2Se3-based solar cells has shown no obvious breakthrough during the past several years, of which the intrinsic reasons are pending experimentally. Here, we prepare high-quality Q1D Sb2Se3 thin films via the vapor transport deposition technique. By investigating the bandedge electronic level structure and carrier relaxation/recombination dynamics, we find that (i) the optimized Se-rich growth conditions can highly improve the crystal quality of the Q1D Sb2Se3 thin films, the carrier lifetime of which is substantially increased up to â¼8.3 µs; (ii) the Se-rich growth conditions have advantages to annihilate the deep selenium vacancies VSei (i = 1 and 3 for non-equivalent Se atomic sites) but is not effective for the deep donor VSe2, which locates at â¼0.3 eV (300 K) below the conduction band and intrinsically limits the PCE value of devices below â¼7.63%. This work suggests that further optimizing the Se-rich conditions to technically eliminate this kind of deep defect is still essential for preparing high-performance Sb2Se3 film solar cells.
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A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Naftalimidas/química , Compostos Organoplatínicos/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , DNA/efeitos dos fármacos , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Transdução de SinaisRESUMO
A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.
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Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Platina/química , Umbeliferonas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dano ao DNA/efeitos dos fármacos , Humanos , Ligação Proteica , Albumina Sérica/química , Albumina Sérica/metabolismoRESUMO
The study aims to qualitatively analyze the chemical composition of compound Nanxing acesodyne plaster by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry( UPLC-Q-TOF-MS/MS). The analysis was performed on Agilent Zorbax SB-C_(18)( 4. 6 mm×250 mm,5 µm) column. The mobile phase consisted of methanol and 0. 2% formic acid-water was used as gradient elution. The flow rate was 1 mL·min~(-1) and column temperature was 30 â. The Mass spectrometry was acquired in both positive and negative ion modes using ESI. The components were identified by the precise mass-to-charge ratio,secondary fragmentation and other information combined with reference substance and literature data. As a result,58 compounds were identified and predicted,including alkaloids,flavonoids,coumarins,organic acids and lactone compounds,of which 12 compounds were verified by the reference substances. The results provide reference for the quality control of compound Nanxing acesodyne plaster,and lay the foundation for elucidating the active components mechanism.
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Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Compostos Fitoquímicos/análise , Espectrometria de Massas em TandemRESUMO
Benzylamines belong to an important class of building blocks in the synthesis of biologically active natural products and drugs. Encumbered by amide-directed ortho-C-H activation, remote para-selective C-H functionalization of benzylamines has hitherto not been realized to date. Here, we report a palladium-catalyzed para-selective C-H olefination and acetoxylation of benzylamines using a functionalized benzoyl template. Enhancing the coordination strength of the directing group in the template significantly improved the site selectivity of C-H functionalization.
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For transition-metal-catalyzed C-H functionalization, precise differentiation between remote adjacent C(sp2)-H bonds remains a long-standing challenge. Here, the template structure-directivity relationship on remote C-H functionalization of arenes was experimentally and computationally studied. By using geometry-tunable templates, Pd-catalyzed remote meta- and para-C-H activation of benzoic acids was achieved with high site selectivity.
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The synthesis of macrocyclic compounds with different sizes and linkages remains a great challenge via transition metal-catalysed intramolecular C-H activation. Herein, we disclose an efficient macrocyclization strategy via Pd-catalysed remote meta-C-H olefination using a practical indolyl template. This approach was successfully employed to access macrolides and coumarins. In addition, the intermolecular meta-C-H olefination also worked well and was exemplified by the synthesis of antitumor drug belinostat from inexpensive and readily available benzenesulfonyl chloride. Notably, catalytic copper acetate and molecular oxygen were used in place of silver salts as oxidants. Furthermore, for the first time, the formation of a macrocyclophane cyclopalladated intermediate was detected through in situ Fourier-transform infrared monitoring experiments and ESI-MS.
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The global surface temperature has witnessed a warming hiatus in the first decade of this century, but how this slowing down of warming will impact spring phenology over Pan-Third Pole remains unclear. Here, we combined multiple satellite-derived vegetation indices with eddy covariance datasets to evaluate the spatiotemporal changes in spring phenological changes over the Pan-Third Pole. We found that the spring phenology over Pan-Third Pole continues to advance at the rate of 4.8 days decade-1 during the warming hiatus period, which is contrasted to a non-significant change over the northern hemisphere. Such a significant and continued advance in spring phenology was mainly attributed to an increase in preseason minimum temperature and water availability. Moreover, there is an overall increasing importance of precipitation on changes in spring phenology during the last four decades. We further demonstrated that this increasingly negative correlation was also found across more than two-thirds of the dryland region, tentatively suggesting that spring phenological changes might shift from temperature to precipitation-controlled over the Pan-Third Pole in a warmer world.
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In order to assess the rationality of the rated shield support capacity (RSSC) experienced selection and guide the reasonable RSSC selection for the subsequent working faces of each coal seam, the coupling relationship between shield and roof strata was revealed during each coal seams mining. According to whether the fractured rock blocks generated by the main roof are articulated and whether the upper coal seam has been mined and influenced on the lower coal seam, two roof structure mechanical models of the rock blocks generated by the thick main roof and two calculation methods of a given load on the rock blocks are proposed. In addition, a selection method of roof structure model for maximum shield support capacity (MSSC) of close-multiple coal seams with the coordinated mining is put forward. Three roof structures to calculate the MSSC are established. Based on a case study of close-multiple coal seams with the coordinated mining in the Qianjiaying coal mine, the MSSC is calculated and analyzed in each coal seam combined with roof structure characteristics description, theoretical analysis, and field measurement. No.7, No.12-1, and No.5 coal seams mining are applicable to a voussoir beam balanced structure. No.8 coal seam mining is applicable to a balanced structure with a given load of loose body. No.9 coal seam mining is applicable to a voussoir beam balanced structure with a given load of loose body. Through the calculation, the MSSC of No.7, No.8, No.12-1, No.9, and No.5 coal seam is 3948.55kN, 4018.32kN, 4101.63kN, 3560.03kN, and 4015.30kN, respectively. And the RSSC suggested selection of each coal seam is 4500kN, 4300kN, 4300kN, 4000kN, and 4300kN, respectively. By field measurement, the RSSC experienced selection of each coal seam in the Qianjiaying coal mine is unreasonable with low support load utilization. However, after adopting the RSSC suggested selection in each coal seam, the support load utilization increased by 29.07%, 9.6%, 8.57%, 15.33%, and 11.39%.
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Minas de Carvão , Carvão Mineral , Minas de Carvão/métodos , Equipamentos de ProteçãoRESUMO
The design of novel platinum(iv) complexes with mitochondria injury competence, besides the DNA damage mechanism, is a promising way to develop new platinum drugs. Herein, dihydro-2-quinolone (DHQLO) as a mitocan was incorporated into the platinum(iv) system for the first time to prepare a new series of DHQLO platinum(iv) compounds. Complex 1b could effectively inhibit the proliferation of tumor cells in vitro and in vivo. It accumulated at higher levels in both whole cells and DNA, and easily underwent intercellular reduction to release platinum(ii) and DHQLO moieties. The released platinum(ii) complex caused serious DNA damage by covalent conjunction with the DNA duplex, and remarkably increased the expression of the γ-H2AX protein. Moreover, 1b also caused serious mitochondria injury to induce mitochondrial membrane depolarization and increase ROS generation. Such actions upon DNA and mitochondria activate the p53 apoptotic pathway synergetically in tumor cells by upregulating the protein p53 and apoptotic proteins caspase9 and caspase3, which efficiently promoted the apoptotic death of tumor cells. Compound 1b with such synergic mechanism exhibited great potential in reversing cisplatin resistance and improving antitumor efficacies.
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Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Quinolonas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , DNA/metabolismo , Dano ao DNA , Histonas/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Neoplasias/metabolismo , Compostos Organoplatínicos/química , Quinolonas/química , Espécies Reativas de Oxigênio/metabolismo , Albumina Sérica/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
A series of new 4-hydroxycoumarin platinum(IV) complexes were designed, synthesized and evaluated as antitumor agents. All the title compounds display moderate to effective antitumor activities toward the tested cell lines and two prominent compounds were screened out with activities comparable to cisplatin and oxaliplatin. The mechanism investigation demonstrates that the platinum(IV) compounds could be reduced to bivalence and exert significant genotoxicity to tumor cells. Meanwhile the coumarin moiety endows the title compounds with cyclooxygenase inhibitory competence which might favour the reduction of tumor-related inflammation and further influence tumor proliferation. The coumarin platinum(IV) complex could effectively induce apoptosis of SKOV-3 cells through up-regulating the expression of caspase3 and caspase9. Furthermore, the conversion of platinum(II) drugs to platinum(IV) form via the conjunction with 4-hydroxycoumarin enhances the drug uptake in whole cells and DNA simultaneously. Moreover, the 4-hydroxycoumarin platinum(IV) complex could combine with human serum albumin via van der Waals force and hydrogen bond, which would influence their transport and bioactivities in vivo.
Assuntos
4-Hidroxicumarinas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , 4-Hidroxicumarinas/síntese química , 4-Hidroxicumarinas/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Platina/química , Albumina Sérica Humana/metabolismoRESUMO
Coastal zones and many small islands are highly susceptible to sea-level rise (SLR). Coastal zones have a large exposed population and integrated high-value assets, and islands provide diverse ecosystem services to millions of people worldwide. The coastal zones and small islands affected by SLR are likely to suffer from submergence, flooding and erosion in the future. However, very few studies have addressed the heterogeneity in SLR changes and the potential risk to coastal zones and small islands. Here we used the mean sea level (MSL) derived from satellite altimetry data to analyse the trends and accelerations of SLRs along global coastal zones and small islands. We found that except for the Antarctic coastal zone, the annual MSL within 50â¯km of the coasts presented an increasing trend of 3.09⯱â¯0.13â¯mm a-1 but a decreasing acceleration of -0.02⯱â¯0.02â¯mm a-2 from 1993 to 2017. The highest coastal MSL trend of 3.85⯱â¯0.60â¯mm a-1 appeared in Oceania, and the lowest trend of 2.32⯱â¯0.37â¯mm a-1 occured in North America. Africa, North America and South America showed acceleration trends, and Eurasia, Australia and Oceania had deceleration trends. Further, MSLs around global small islands reflected an increasing trend with a rate of 3.01⯱â¯0.16â¯mm a-1 but a negative acceleration of -0.02⯱â¯0.02â¯mm a-2. Regional heterogeneity in the trends and accelerations of MSLs along the coasts and small islands suggests that stakeholders should take discriminating precautions to cope with future disadvantageous impacts of the SLR.
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Naphthalimide platinum(IV) antitumor complexes with potential dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The incorporation of DNA targeted naphthalimide group to the platinum(IV) system exerts much positive impacts on their antitumor efficacy. The mechanism research reveals that the title compounds could interact with dsDNA in platinum(IV) form via the naphthalimide group and cause DNA lesion. The further reduction would release platinum(II) complexes and naphthalimide acids which would induce remarkable secondary damage to DNA. Furthermore, the naphthalimide platinum(IV) compounds could combine with human serum albumin via electrostatic force, which are favourable for their storage and transport in blood. Moreover, the title compounds exhibit higher accumulation in tumor cells, and exert lower toxic and higher safe properties than oxaliplatin in vivo.