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Nitrosobenzene (PhNO) and phenylhydroxylamine (PhNHOH) are of paramount importance because of their involvement as crucial intermediates in the biological metabolism and catalytic transformation of nitrobenzene (PhNO2) to aniline (PhNH2). However, a complete reductive transformation cycle of PhNO to PhNH2 via the PhNHOH intermediate has not been reported yet. In this context, we design and construct a new thiolate-bridged dicobalt scaffold that can accomplish coordination activation and reductive transformation of PhNO. Notably, an unprecedented reversible ligand-based redox sequence PhNO0 â PhNOâ¢- â PhNO2- can be achieved on this well-defined {CoIII(µ-SPh)2CoIII} functional platform. Further detailed reactivity investigations demonstrate that the PhNO0 and PhNOâ¢- complexes cannot react with the usual hydrogen and hydride donors to afford the corresponding phenylhydroxylamino (PhNHO-) species. However, the double reduced PhNO2- complex can readily undergo N-protonation with an uncommon weak proton donor PhSH to selectively yield a stable dicobalt PhNHO- bridged complex with a high pKa value of 13-16. Cyclic voltammetry shows that there are two successive reduction events at E1/2 = -0.075 V and Ep = -1.08 V for the PhNO0 complex, which allows us to determine both bond dissociation energy (BDEN-H) of 59-63 kcal·mol-1 and thermodynamic hydricity (ΔGH-) of 71-75 kcal·mol-1 of the PhNHO- complex. Both values indicate that the PhNOâ¢- complex is not a potent hydrogen abstractor and the PhNO0 complex is not an efficient hydride acceptor. In the presence of BH3 as a combination of protons and electrons, facile N-O bond cleavage of the coordinated PhNHO- group can be realized to generate PhNH2 and a dicobalt hydroxide-bridged complex. Overall, we present the first stepwise reductive sequence, PhNO0 â PhNOâ¢- â PhNO2- â PhNHO- â PhNH2.
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A general and efficient method has been developed to access axially chiral 2-arylpyrroles using catalytic asymmetric Suzuki-Miyaura cross-coupling. A wide range of axially chiral arylpyrroles were obtained in high yields with good to excellent enantioselectivities. The key to success is the use of a combined catalytic system involving a palladium catalyst and chiral ferrocene diphosphine ligand for achieving effective enantiocontrol. More importantly, this axially chiral CF3-substituted 2-arylpyrrole serves as a key intermediate in the preparation of the anti-hypertensive and diabetic nephropathy drug esaxerenone. It was directly asymmetrically synthesized with high enantioselectivity (92% ee). Thus, a new strategy is provided for the catalytic asymmetric synthesis of esaxerenone.
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Residential solid fuel combustion significantly impacts air quality and human health. Pelletized biomass fuels are promoted as a cleaner alternative, particularly for those who cannot afford the high costs of gas/electricity, but their emission characteristics and potential effects remain poorly understood. The present laboratory-based study evaluated pollution emissions from pelletized biomass burning, including CH4 (methane), NMHC (nonmethane hydrocarbon compounds), CO, SO2, NOx, PM2.5 (particulate matter with an aerodynamic diameter ≤2.5 µm), OC (organic carbon), EC (element carbon), PAHs (polycyclic aromatic hydrocarbons), EPFRs (environmentally persistent free radicals), and OP (oxidative potential) of PM2.5, and compared with those from raw biomass burning. For most targets, except for SO2 and NOx, the mass-based emission factors for pelletized biomass were 62-96% lower than those for raw biomass. SO2 and NOx levels were negatively correlated with other air pollutants (p < 0.05). Based on real-world daily consumption data, this study estimated that households using pelletized biomass could achieve significant reductions (51-95%) in emissions of CH4, NMHC, CO, PM2.5, OC, EC, PAHs, and EPFRs compared to those using raw biomass, while the differences in emissions of NOx and SO2 were statistically insignificant. The reduction rate of benzo(a)pyrene-equivalent emissions was only 16%, much lower than the reduction in the total PAH mass (78%). This is primarily attributed to the more PAHs with high toxic potentials, such as dibenz(a,h)anthracene, in the pelletized biomass emissions. Consequently, impacts on human health associated with PAHs might be overestimated if only the mass of total PAHs was counted. The OP of particles from the pellet burning was also significantly lower than that from raw biomass by 96%. The results suggested that pelletized biomass could be a transitional substitution option that can significantly improve air quality and mitigate human exposure.
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Inspired by the brilliant photochemical and photophysical properties of organic molecules containing chalcogenide substitutions that could be potentially applied across various disciplines, in this work, the effects of the atomic electronegativity of chalcogens (O, S, and Se) on hydrogen bond interactions and excited state proton transfer (ESPT) are mainly focused. We present characteristic oxygen-hydroxybenzazole-substituted 2,5-bis(4,5-diphenyl-1H-imidazol-2-yl)benzene-1,4-diol (BDIBD) derivatives that contain intramolecular double hydrogen bonds. The main objective of this study was to explore in detail the influence of the change of chalcogen atomic electronegativity on dual hydrogen bond interaction and ESPT behavior. By comparing the structural changes and infrared (IR) vibrational spectra of BDIBD derivative (BDIBD-O, BDIBD-S and BDIBD-Se) fluorophores in S0 and S1 states, combined with the preliminary detection of hydrogen bond interaction via the core-valence bifurcation (CVB) index and predicted hydrogen bonding energy (EHB), we conclude that dual hydrogen bonds should be strengthened in the S1 state, which is favorable for the occurrence of ESPT reactions. The charge recombination behavior of hydrogen bonds, induced by photoexcitation, further illustrates this point. By constructing potential energy surfaces (PESs) based on restrictive optimization and by searching the transition state (TS) structure, we finally elucidate stepwise excited-state double proton transfer (ESDPT). Specifically, we confirm that a change in atomic electronegativity has a regulatory effect on the ESDPT behavior in BDIBD derivatives, that is, lower atomic electronegativity is more conducive to stepwise ESDPT.
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Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)-N'-((6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-ylidene)acetohydrazide (F26, IC50 = 4.55 ± 0.92 µM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX-2 and cPLA2 was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-κB p65, as well as the protein expression of IκB, cPLA2, COX-2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-κB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-κB pathways by binding to COX-2 and cPLA2. In the adjuvant-induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA2/COX-2/PGE2 and NF-κB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA2 and COX-2 are implicated in the pathophysiology.
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Artritis Reumatoide , Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Animales , Ratones , Ciclooxigenasa 2/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Células RAW 264.7 , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Ratas , Relación Estructura-Actividad , Estructura Molecular , Inflamación/tratamiento farmacológico , Masculino , Relación Dosis-Respuesta a Droga , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis química , Fosfolipasas A2/metabolismo , Administración Oral , Ratas Sprague-DawleyRESUMEN
The pachysandra alkaloids found in Sarcococca ruscifolia demonstrate notable anti-hepatocellular carcinoma activity. Despite their efficacy, the structural diversity of these compounds remains limited, and their precise antitumor mechanism is still unclear. In pursuit of identifying novel lead compounds with high efficacy and low toxicity for combating hepatocellular carcinoma, twenty-three compounds of C20-ketone pachysandra alkaloid derivatives were designed and synthesized by using 3-dimethylamine pachysandra alkaloids as scaffolds. Subsequent in vitro anticancer activity experiments showed that synthetic pachysandra alkaloids had a stronger effect on HepG2 cells than did their natural counterparts, with low toxicity and high selectivity. The most potent derivative, 6k, had an IC50 value of 0.75 µM, demonstrating 25.7-fold greater anticancer activity than sarcovagine D against HepG2 cells. Through network pharmacology and molecular docking analysis, it was revealed that synthetic pachysandra alkaloids may exert their effects by inhibiting the JAK2/STAT3 pathway, thereby preventing the proliferation of liver cancer cells. Further research through scratch tests, immunofluorescence experiments, and Western blot analysis revealed that compound 6k effectively inhibited the migration of HepG2 cells and induced mitochondria-mediated intrinsic apoptosis of HepG2 cells by regulating the JAK2/STAT3 signaling pathway. The aforementioned results indicate that compound 6k could be developed as a potential candidate for the treatment of hepatocellular carcinoma.
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The impact of the chalcogen atomic electronegativity (O, S, and Se atoms) of new organic molecules on excited-state dynamical reactions is self-evident. Inspired by this kind of distinguished photochemical characteristic, in this work, we performed a computational investigation of chalcogen-substituted 3,6-bis(4,5-dihydroxyoxazo-2-yl)benzene-1,2-diol (BDYBD) derivatives (i.e., BDYBD-O, BDYBD-S, and BDYBD-Se). In this paper, we pay close attention to characteristic BDYBD derivatives that contain intramolecular double hydrogen bonds (O1-H2···N3 and O4-H5···N6). The main goal of this study was to explore how changes in atomic electronegativity affect the way hydrogen bonds interact and how excited molecules affect transfer protons. We go into further detail in the main text of the paper. By fixing our attention to geometrical variations and infrared (IR) vibrational spectra between the S0 and S1 states, exploring hydrogen bonding behaviors using the core-valence bifurcation (CVB) index, and simulating hydrogen bonding energy (EHB) via the atom in molecule (AIM) method, we clarified the photo-induced strengthened dual hydrogen bonding interactions that facilitate the excited-state dual-proton transfer (ESDPT) behavior of BDYBD derivatives. The reorganization of charge stemming from photoexcitation further verifies the tendencies of ESDPT reactions. We relied on constructing potential energy surfaces (PESs) by adopting a restrictive optimization approach, and herein, we finally clarify the gradual ESDPT mechanism of BDYBD derivatives. Particularly, we confirm that the variation in chalcogen atomic electronegativity has a regulatory effect on the ESDPT behavior of BDYBD derivatives; that is, the lower the atomic electronegativity, the more favorable it is for the gradual ESDPT reaction.
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Inspired by the captivating allure of exquisitely regulated characteristics exhibited by 2-(2-hydroxyphenyl)-benzoxazole and its derivatives in the realms of photochemistry and photophysics, our current endeavor primarily revolves around delving into the intricacies of photo-induced excited state reactions for derivatives of 2,5-bis(2-benzoxazolyl)-hydroquinone (BBHQ). Given the significant impact of chalcogen element doping, herein we predominantly focus on exploring the excited state behaviors of BBHQ-OO, BBHQ-SS, and BBHQ-SeSe fluorophores. Our simulations, resulting from variations in geometry and vertical excitation charge reorganization, reveal atomic-electronegativity-dependent hydrogen bonding interactions and charge recombination induced by photoexcitation that can significantly enhance the excited state intramolecular double proton transfer (ESDPT) reaction for BBHQ-OO, BBHQ-SS, and BBHQ-SeSe fluorophores. By constructing potential energy surfaces (PESs) and identifying transition states (TS), we unveil the ultrafast stepwise ESDPT mechanism due to the low potential barriers. Additionally, by employing heterosubstituted BBHQ-OS and BBHQ-OSe compounds, we rigorously validate the stepwise ESDPT mechanism regulated by chalcogen atomic electronegativity. We sincerely anticipate that the modulation of solvent polarity on excited state behaviors will pave the way for groundbreaking advancements in luminescent materials.
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CONTEXT: Inspired by the excellent potential application prospects from the precisely controlled attributes displayed by fluorine-substituted-bis(salicylidene)-1,5-diaminonaphthalene (F-BSD) and its derivatives in the domains of photochemistry and photophysics, our present undertaking predominantly focuses on exploring the complexities of photo-induced excited state reactions for F-BSD fluorophores dissolved in solvents with diverse levels of polarity. Our simulations reveal that the excited state intramolecular double proton transfer (ESIDPT) reaction for F-BSD chemosensor can be significantly regulated by solvent polarity-dependent hydrogen bonding interactions and charge recombination induced by photoexcitation, which result from variations in geometries and vertical excitation charge reorganizations. By constructing potential energy surfaces (PESs), we also demonstrate that the stepwise ESIDPT reaction of F-BSD occurs with alternative dual intramolecular hydrogen bonds (O1-H2···N3 or O4-H5···N6). Interestingly, we affirm polar solvents should be conducive to the first-step of ESIDPT process, while nonpolar solvents are in favor of the second step. We sincerely hope solvent polarity-dependent ESIDPT behavior will pave the way for future design of novel luminescent materials. METHODS: The molecular geometries were optimized by DFT//TDDFT D3-B3LYP/TZVP theoretical level with IEFPCM solvent model in S0 and S1 states, respectively. This work also explores the energy level of target molecules with the computational vertical absorption spectra by TDDFT. All the simulations were carried out based on Gaussian 16 software. The core-valence bifurcation (CVB) indexes were obtained by using Multiwfn 3.8. Potential energy surfaces were constructed by the DFT//TDDFT D3-B3LYP/TZVP level based on restricted optimization, also the transition state (TS) forms were searched using the same level.
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This study aimed to assess the impact of microbial agent and different compost material, on physicochemical parameters dynamic change, nitrogen-transfer gene/bacterial community interaction network during the pig manure composting. Incorporating a microbial agent into rice straw-mushroom compost reduced the NH3 and total ammonia emissions by 25.52 % and 14.41 %, respectively. Notably, rice straw-mushroom with a microbial agent reduced the total ammonia emissions by 37.67 %. NH4+-N and pH emerged as primary factors of phylum-level and genus-level microorganisms. Microbial agent increased the expression of narG, nirK, and nosZ genes. Rice straw-mushroom elevated the content of amoA, nirK, nirS, and nosZ genes. Alcanivorax, Luteimonas, Pusillimonas, Lactobacillus, Aequorivita, Clostridium, Moheibacter and Truepera were identified as eight core microbial genera during the nitrogen conversion process. This study provides a strategy for reducing ammonia emissions and analyzes the potential mechanisms underlying compost processes.
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Agaricales , Compostaje , Microbiota , Oryza , Porcinos , Animales , Nitrógeno/análisis , Amoníaco/análisis , Estiércol/análisis , Suelo/química , Bacterias/genética , Microbiota/genéticaRESUMEN
Background: Excessive inflammation poses significant risks to human physical and mental health. Astilbe grandis, a traditional Miao medicine, is renowned for its anti-inflammatory properties. However, the specific anti-inflammatory effects and mechanisms of many compounds within this plant remain unclear. This study aims to investigate the anti-inflammatory effects and mechanisms of two characteristic oleanane triterpenoids, 3α-acetoxyolean-12-en-27-oic acid (1) and 3ß-acetoxyolean-12-en-27-oic acid (2), isolated from Astilbe grandis, using lipopolysaccharide (LPS)-induced Macrophages. Methods: The anti-inflammatory effects and mechanisms of compounds 1 and 2 were investigated by establishing an LPS-induced inflammation model in RAW 264.7 cells and THP-1 cells. Nitric oxide (NO) levels were assessed using the Griess method. The concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß) were measured via enzyme-linked immunosorbent assay (ELISA). The expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was determined using western blotting and quantitative real-time PCR (qRT-PCR). Additionally, the phosphorylation level of p65 in nuclear factor-kappa B (NF-κB) was assessed through western blotting. The nuclear translocation of NF-κB p65 was assessed through immunofluorescence staining. Finally, the binding affinity of the compounds to NF-κB p65 target was validated through molecular docking. Results: Compounds 1 and 2 significantly inhibited the expression of NO, TNF-α, IL-6, IL-1ß, COX-2, and iNOS in LPS-induced Macrophages. Mechanistically, they attenuated the activation of the NF-κB signaling pathway by downregulating the phosphorylation level and nuclear translocation of p65. Conclusion: This study elucidates the anti-inflammatory activities and potential mechanism of the characteristic oleanane triterpenoids with C-14 carboxyl group, compounds 1 and 2, in LPS-induced Macrophages by inhibiting the NF-κB signaling pathway for the first time. These findings suggest that these two compounds hold promise as potential candidates for anti-inflammatory interventions in the future.
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This study explored the relationship between green space accessibility (GSA) in residential area and adolescents' mental well-being, and whether the relationship was moderated by sociodemographic factors (sex, ethnicity, neighbourhood deprivation), identities (gender and sexuality minority, disability) and perceived neighbourhood safety simultaneously. Data from 3813 adolescents who lived in Tamaki Makaurau Auckland, Aotearoa New Zealand were obtained from the Youth19 Rangatahi Smart Survey. A Gaussian-based two-step floating catchment area method was employed to measure the spatial accessibility to green space at the neighbourhood level. The World Health Organization-5 Well-being Index was used to assess emotional well-being (EW), and the Reynolds Adolescent Depression Scale-short form was employed to measure depressive symptoms (DS). Through moderation analyses, results showed that perceived neighbourhood safety plays a vital role in the GSA - mental well-being association, with a negative trend in adolescents who reported being less safe in neighbourhoods. Adverse associations of GSA were found in gender and sexuality minority, disabled, Asian and Pacific adolescents, under the condition of not feeling safe in neighbourhoods all the time. The results showed marginalised adolescents tended to feel less safe in neighbourhoods, have lower EW and a higher level of DS. Additionally, the results from bivariate correlations showed there were inequalities in GSA for adolescents who lived in most deprived neighbourhoods and adolescents of Maori ethnicity. This study provides novel evidence of the importance of safe and inclusive green space for effectively promoting mental health and mitigating health inequalities of adolescents in urban areas.
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Environmental DNA (eDNA) carrying antibiotic resistance gene (ARG) has attracted a great deal of attention because of its threat to the ecology and human health. Traditional porous adsorbents, such as microporous biochar and natural mineral, are low-effective in removing eDNA from sewage. This study used cuttlefish-bone (CB), a fishery waste, as an anticipated material to adsorb a model compound of eDNA from herring sperm (hsDNA). An interesting result was firstly observed that extremely high DNA adsorption on cuttlefish-bone pyrolysis derivative (CCB) was up to 88.7 mg/g, 3-10 folds higher than that of most other adsorbents in the existing literatures, which was attributed to the carbon film and large pores. To achieve an adsorption rate of 75 %, hsDNA adsorption took 96 h on CB but only 24 h on CCB, which was attributed to the fluent channel of CCB. The ligand exchange, Ca2+ bridge and π-π interaction were identified as dominated adsorption mechanisms, based on FTIR and phosphate competition experiments. This study exploited a high-efficient, environmentally friendly, and low-cost adsorbent for treating ARG-contaminated soil and water.
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ADN Ambiental , Contaminantes Químicos del Agua , Masculino , Humanos , Carbono/química , Adsorción , Pirólisis , Semen/química , Carbón Orgánico/química , Antibacterianos , Contaminantes Químicos del Agua/análisis , CinéticaRESUMEN
PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
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Maize moldy and spoilage due to microbial growth is a significant challenge in grain storage. This study aimed to evaluate the effectiveness of a zinc oxide nanocomposite, ZnO@mSiO2, prepared in our previous research, in inhibiting mold growth and preserving maize cell quality. The results demonstrated that ZnO@mSiO2 could effectively inhibit the growth of dominant microorganism, Aspergillus flavus, Talaromyces variabilis, Penicillium citrinum and Fusarium graminearum, in maize storage. Aspergillus flavus was selected as the model fungus, ZnO@mSiO2 effectively disrupted fungal hyphae structure, leading to reduced hyphal mass and inhibited spore germination. The inhibitory effect of ZnO@mSiO2 on mold growth was concentration-dependent. However, the ZnO@mSiO2 at an appropriate concentration (not exceeding 3.0 g/kg) preserved the integrity of maize cell membranes and enhancing the antioxidant activity within maize cells. The findings highlight the potential of ZnO@mSiO2 as an effective protectant to inhibit mold growth and preserve maize quality during storage.
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Óxido de Zinc , Óxido de Zinc/farmacología , Zea mays/microbiología , Aspergillus flavus , Hongos , Grano ComestibleRESUMEN
A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 µΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.
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Artritis Reumatoide , Cetoprofeno , Ratas , Animales , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2 , Lipopolisacáridos/farmacología , Artritis Reumatoide/tratamiento farmacológico , FN-kappa B/metabolismoRESUMEN
Topological phononic cavities, such as ring resonators with topological whispering gallery modes (TWGMs), offer a flexible platform for the realization of robust phononic circuits. However, the chiral mechanism governing TWGMs and their selective routing in integrated phononic circuits remain unclear. This work reveals, both experimentally and theoretically, that at a phononic topological interface, the elastic spin texture is intricately linked to, and can be explained through a knowledge of, the phonon eigenmodes inside each unit cell. Furthermore, for paired, counterpropagating TWGMs based on such interfaces in a waveguide resonator, this study demonstrates that the elastic spin exhibits locking at discrete frequencies. Backed up by theory, experiments on kHz TWGMs in thin honeycomb-lattice aluminum plates bored with clover-leaf shaped holes show that together with this spin-texture related angular-momentum locking mechanism at a single topological interface, there are triplicate parity-frequency-space selective wave routing mechanisms. In the future, these mechanisms can be harnessed for the versatile manipulation of elastic-spin based routing in phononic topological insulators.
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TGF-ß (transforming growth factor-ß) signaling is involved in a myriad of cellular processes and its dysregulation has been implicated in many human diseases, including fibrosis and cancer. TGF-ß transcriptional responses are controlled by tail phosphorylation of transcription factors SMAD2 and SMAD3 (mothers against decapentaplegic homolog 2/3). Therefore, targeted dephosphorylation of phospho-SMAD3 could provide an innovative mechanism to block some TGF-ß-induced transcriptional responses, such as the transcription of SERPINE-1, which encodes plasminogen activator inhibitor 1 (PAI-1). Here, by developing and employing a bifunctional molecule, BDPIC (bromoTAG-dTAG proximity-inducing chimera), we redirected multiple phosphatases, tagged with bromoTAG, to dephosphorylate phospho-SMAD3, tagged with dTAG. Using CRISPR-Cas9 technology, we generated homozygous double knock-in A549 bromoTAG/bromoTAG PPM1H/ dTAG/dTAG SMAD3 cells, in which the BDPIC-induced proximity between bromoTAG-PPM1H and dTAG-SMAD3 led to a robust dephosphorylation of dTAG-SMAD3 and a significant decrease in SERPINE-1 transcription. Our work demonstrates targeted dephosphorylation of phospho-proteins as an exciting modality for rewiring cell signaling.
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Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
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Accurate nucleocytoplasmic transport of signal molecules is essential for plant growth and development. Multiple studies have confirmed that nucleocytoplasmic transport and receptors are involved in regulating plant disease resistance responses, however, little is known about the regulatory mechanism in plants. In this study, we showed that the mutant of the importin beta-like protein SAD2 exhibited a more susceptible phenotype than wild-type Col-0 after treatment with Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) experiments demonstrated that SAD2 interacts with the hypersensitive response (HR)-positive transcriptional regulator MYB30. Subcellular localization showed that MYB30 was not fully localized in the nucleus in sad2-5 mutants, and western-blot experiments further indicated that SAD2 was required for MYB30 nuclear trafficking during the pathogen infection process. A phenotypic test of pathogen inoculation demonstrated that MYB30 partially rescued the disease symptoms of sad2-5 caused by Pst DC3000, and that MYB30 worked downstream of SAD2 in plant pathogen defense. These results suggested that SAD2 might be involved in plant pathogen defense by mediating MYB30 nuclear trafficking. Taken together, our results revealed the important function of SAD2 in plant pathogen defense and enriched understanding of the mechanism of nucleocytoplasmic transport-mediated plant pathogen defense.