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Determining the differences in flower hydraulic traits and structural resource allocation among closely related species adapted to low mean annual precipitation (MAP) can provide insight into plant adaptation to arid environments. Here, we measured the maximum flower hydraulic conductance (Kmax-flower), water potential at induction 50% loss of Kmax-flower (P50-flower), flower pressure-volume parameters, dry mass of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) of six Caragana species growing in regions ranging from 110 to 1400 mm MAP. Compared with species from high-MAP environments, those from low-MAP environments presented lower Kmax-flower, more negative P50-flower, osmotic potential at full turgor (πo) and turgor loss points (πtlp), and a greater bulk modulus of elasticity (ε). Consequently, a negative correlation between Kmax-flower (hydraulic efficiency) and P50-flower (hydraulic safety) was observed across Caragana species. Furthermore, the dry masses of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) were greater in the species from the low-MAP environment than in those from the high-MAP environment. These findings suggest that greater flower hydraulic safety and drought tolerance combined with greater structural resource allocation promote drought adaptation in Caragana species to low-MAP environments.
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The treatment of ovarian cancer remains a medical challenge and its malignant progression is connected with obvious changes in both tissue and cell stiffness. However, the accurate mechanical-responsive molecules and mechanism remains unclear in ovarian cancer. Based on our previous results combined with the crucial regulatory role of STAT3 in the malignant progression of various cancer types, we want to investigate the relationship between STAT3 and matrix stiffness in ovarian cancer and further explore the potential mechanisms. Collagen-coated polyacrylamide gels (1, 6, and 60 kPa) were prepared to mimic soft or hard matrix stiffness. Western blotting, qRT-PCR, flow cytometry, IHC, EdU assays, and TEM were used to evaluate the effect of STAT3 in vitro under different matrix stiffnesses. Furthermore, a BALB/c nude mouse model was established to assess the relationship in vivo. Our results confirmed the differential expression of STAT3/p-STAT3 not only in normal and malignant ovarian tissues but also under different matrix stiffnesses. Furthermore, we verified that STAT3 was a mechanically responsive gene both in vitro and in vivo, and the mechanical response was carried out by altering the migration-related molecules (TNFAIP1) and adhesion-related molecules (LPXN, CNN3). The novel findings suggest that STAT3, a potential therapeutic target for clinical diagnosis and treatment, is a mechanically responsive gene that responds to matrix stiffness, particularly regulation in migration and adhesion in the progression of ovarian cancer.
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Excellent electrocatalytic CO2 reduction reaction activity has been demonstrated by transition metals and nitrogen-codoped carbon (M-N-C) catalysts, especially for transition-metal porphyrin (MTPP)-based catalysts. In this work, we propose to use one-step low-temperature pyrolysis of the isostructural MTPP-based metal-organic frameworks (MOFs) and electrochemical in situ reduction strategies to obtain a series of hybrid catalysts of Co nanoparticles (Co NPs) and MTPP, named Co NPs/MTPP (M = Fe, Co, and Ni). The in situ introduction of Co NPs can efficiently enhance the electrocatalytic ability of MTPP (M = Fe, Co, and Ni) to convert CO2 to CO, particularly for FeTPP. Co NPs/FeTPP endowed a high CO faradaic efficiency (FECOmax = 95.5%) in the H cell, and the FECO > 90.0% is in the broad potential range of -0.72 to -1.22 VRHE. In addition, the Co NPs/FeTPP achieved 145.4 mA cm-2 at a lower potential of -0.70 VRHE with an FECO of 94.7%, and the CO partial currents increased quickly to reach 202.2 mA cm-2 at -0.80 VRHE with an FECO of 91.6% in the flow cell. It is confirmed that Co NPs are necessary for hybrid catalysts to get superior electrocatalytic activity; Co NPs also can accelerate H2O dissociation and boost the proton supply capacity to hasten the proton-coupled electron-transfer process, effectively adjusting the adsorption strength of the reaction intermediates.
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Designing highly active and cost-effective electrocatalysts for the alkaline hydrogen oxidation reaction (HOR) is critical for advancing anion-exchange membrane fuel cells (AEMFCs). While dilute metal alloys have demonstrated substantial potential in enhancing alkaline HOR performance, there has been limited exploration in terms of rational design, controllable synthesis, and mechanism study. Herein, we developed a series of dilute Pd-Ni alloys, denoted as x% Pd-Ni, based on a trace-Pd decorated Ni-based coordination polymer through a facile low-temperature pyrolysis approach. The x% Pd-Ni alloys exhibit efficient electrocatalytic activity for HOR in alkaline media. Notably, the optimal 0.5 % Pd-Ni catalyst demonstrates high intrinsic activity with an exchange current density of 0.055â mA cm-2, surpassing that of many other alkaline HOR catalysts. The mechanism study reveals that the strong synergy between Pd single atoms (SAs)/Pd dimer and Ni substrate can modulate the binding strength of proton (H)/hydroxyl (OH), thereby significantly reducing the activation energy barrier of a decisive reaction step. This work offers new insights into designing advanced dilute metal or single-atom-alloys (SAAs) for alkaline HOR and potentially other energy conversion processes.
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In principle, porous physisorbents are attractive candidates for the removal of volatile organic compounds such as benzene by virtue of their low energy for the capture and release of this pollutant. Unfortunately, many physisorbents exhibit weak sorbate-sorbent interactions, resulting in poor selectivity and low uptake when volatile organic compounds are present at trace concentrations. Herein, we report that a family of double-walled metal-dipyrazolate frameworks, BUT-53 to BUT-58, exhibit benzene uptakes at 298 K of 2.47-3.28 mmol g-1 at <10 Pa. Breakthrough experiments revealed that BUT-55, a supramolecular isomer of the metal-organic framework Co(BDP) (H2BDP = 1,4-di(1H-pyrazol-4-yl)benzene), captures trace levels of benzene, producing an air stream with benzene content below acceptable limits. Furthermore, BUT-55 can be regenerated with mild heating. Insight into the performance of BUT-55 comes from the crystal structure of the benzene-loaded phase (C6H6@BUT-55) and density functional theory calculations, which reveal that C-H···X interactions drive the tight binding of benzene. Our results demonstrate that BUT-55 is a recyclable physisorbent that exhibits high affinity and adsorption capacity towards benzene, making it a candidate for environmental remediation of benzene-contaminated gas mixtures.
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Estruturas Metalorgânicas , Compostos Orgânicos Voláteis , Adsorção , Benzeno/química , GasesRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica , Humanos , Prognóstico , Transplante Homólogo/efeitos adversos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologiaRESUMO
Stomatal closure is regulated by plant hormones and some small molecules to reduce water loss under stress conditions. Both abscisic acid (ABA) and polyamines alone induce stomatal closure; however, whether the physiological functions of ABA and polyamines are synergistic or antagonistic with respect to inducing stomatal closure is still unknown. Here, stomatal movement in response to ABA and/or polyamines was tested in Vicia faba and Arabidopsis thaliana, and the change in the signaling components under stomatal closure was analyzed. We found that both polyamines and ABA could induce stomatal closure through similar signaling components, including the synthesis of hydrogen peroxide (H2 O2 ) and nitric oxide (NO) and the accumulation of Ca2+ . However, polyamines partially inhibited ABA-induced stomatal closure both in epidermal peels and in planta by activating antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), to eliminate the ABA-induced increase in H2 O2 . These results strongly indicate that polyamines inhibit abscisic acid-induced stomatal closure, suggesting that polyamines could be used as potential plant growth regulators to increase photosynthesis under mild drought stress.
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Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/farmacologia , Peróxido de Hidrogênio , Poliaminas , Estômatos de Plantas/fisiologia , Reguladores de Crescimento de Plantas , Arabidopsis/fisiologiaRESUMO
Metal-organic frameworks (MOFs) are emerging as promising candidates for electrochemical glucose sensing owing to their ordered channels, tunable chemistry, and atom-precision metal sites. Herein, the efficient nonenzymatic electrochemical glucose sensing is achieved by taking advantage of Ni(II)-based metal-organic frameworks (Ni(II)-MOFs) and acquiring the ever-reported fastest response time. Three Ni(II)-MOFs ({[Ni6L2(H2O)26]4H2O}n (CTGU-33), {Ni(bib)1/2(H2L)1/2(H2O)3}n (CTGU-34), {Ni(phen)(H2L)1/2(H2O)2}n (CTGU-35)) have been synthesized for the first time, which use benzene-1,2,3,4,5,6-hexacarboxylic acid (H6L) as an organic ligand and introduce 1,4-bis(1-imidazoly)benzene (bib) or 1,10-phenanthroline (phen) as spatially auxiliary ligands. Bib and phen convert the coordination mode of CTGU-33, affording structural dimensions from 2D of CTGU-33 to 3D of CTGU-34 or 1D of CTGU-35. By tuning the dimension of the skeleton, CTGU-34 with 3D interconnected channels exhibits an ultrafast response of less than 0.4 s, which is superior to the existing nonenzymatic electrochemical sensors. Additionally, a low detection limit of 0.12 µM (S/N = 3) and a high sensitivity of 1705 µA mM-1 cm-2 are simultaneously achieved. CTGU-34 further showcases desirable anti-interference and cycling stability, which demonstrates a promising application prospect in the real-time detection of glucose.
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Two-dimensional metal-organic framework (MOF) crystalline materials possess promising potential in the electrochemical sensing process owing to their tunable structures, high specific surface area, and abundant metal active sites; however, developing MOF-based nonenzymatic glucose (Glu) sensors which combine electrochemical activity and environmental stability remains a challenge. Herein, utilizing the tripodic nitrogen-bridged 1,3,5-tris(1-imidazolyl) benzene (TIB) linker, Co2+ and Ni2+, two 2D isomorphic crystalline materials, including Co/Ni-MOF {[Co (TIB)]·2BF4} (CTGU-31) and {[Ni(TIB)]·2NO3} (CTGU-32), with a binodal (3, 6)-connected kgd topological net were firstly synthesized and fabricated with conducting acetylene black (AB). When modified on a glassy carbon electrode, the optimized AB/CTGU-32 (1:1) electrocatalyst demonstrated a higher sensitivity of 2.198 µA µM-1 cm-2, a wider linear range from 10 to 4000 µM, and a lower detection limit (LOD) value (0.09 µM, S/N = 3) compared to previously MOF-based Glu sensors. Moreover, AB/CTGU-32 (1:1) exhibited desirable stability for at least 2000 s during the electrochemical process. The work indicates that MOF-based electrocatalysts are a promising candidate for monitoring Glu and demonstrate their potential for preliminary screening for diabetes.
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Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Carbono/química , Níquel/química , Eletrodos , Acetileno , Glucose/químicaRESUMO
Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.
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Alcaloides de Berberina , Telomerase , Animais , Telomerase/metabolismo , RNA/químicaRESUMO
Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds inâ vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31â µM and 0.41â µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.
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Alcaloides , Antineoplásicos , Neoplasias Colorretais , Humanos , Alcaloides/farmacologia , Alcaloides/química , Linhagem Celular , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Estrutura MolecularRESUMO
Wernekink commissure syndrome is a rare midbrain syndrome with bilateral cerebellar dysfunction,eye movement disorder,and palatal myoclonus.Few cases of this syndrome have been reported in China,let alone those combined with hallucinations and involuntary groping.This paper reports the diagnosis and treatment of a case of Wernekink commissure syndrome with hallucinations and involuntary groping,aiming to enrich the knowledge about this disease for clinicians.
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Mesencéfalo , Transtornos da Motilidade Ocular , Humanos , Transtornos da Motilidade Ocular/diagnóstico , Medula Espinal , Síndrome , AlucinaçõesRESUMO
Abscisic acid (ABA) can induce rapid stomatal closure in seed plants, but the action of this hormone on the stomata of fern and lycophyte species remains equivocal. Here, ABA-induced stomatal closure, signaling components, guard cell K+ and Ca2+ fluxes, vacuolar and actin cytoskeleton dynamics, and the permeability coefficient of guard cell protoplasts (Pf) were analyzed in species spanning the diversity of vascular land plants including 11 seed plants, 6 ferns, and 1 lycophyte. We found that all 11 seed plants exhibited ABA-induced stomatal closure, but the fern and lycophyte species did not. ABA-induced hydrogen peroxide elevation was observed in all species, but the signaling pathway downstream of nitric oxide production, including ion channel activation, was only observed in seed plants. In the angiosperm faba bean (Vicia faba), ABA application caused large vacuolar compartments to disaggregate, actin filaments to disintegrate into short fragments and Pf to increase. None of these changes was observed in the guard cells of the fern Matteuccia struthiopteris and lycophyte Selaginella moellendorffii treated with ABA, but a hypertonic osmotic solution did induce stomatal closure in fern and the lycophyte. Our results suggest that there is a major difference in the regulation of stomata between the fern and lycophyte plants and the seed plants. Importantly, these findings have uncovered the physiological and biophysical mechanisms that may have been responsible for the evolution of a stomatal response to ABA in the earliest seed plants.
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Ácido Abscísico/metabolismo , Estômatos de Plantas/anatomia & histologia , Estômatos de Plantas/fisiologia , Transdução de Sinais , Gleiquênias/anatomia & histologia , Gleiquênias/fisiologia , Selaginellaceae/anatomia & histologia , Selaginellaceae/fisiologia , Vicia faba/anatomia & histologia , Vicia faba/fisiologiaRESUMO
Activation of N2 on anionic trimetallic V3-x Tax C4- (x=0-3) clusters was theoretically studied employing density functional theory. For all studied clusters, initial adsorption of N2 (end-on) on one of the metal atoms (denoted as Siteâ 1) is transferred to an of end-on: side-on: side-on coordination on three metal atoms, prior to N2 dissociation. The whole reaction is exothermic and has no global energy barriers, indicating that the dissociation of N2 is facile under mild conditions. The reaction process can be divided into two processes: N2 transfer (TRF) and N-N dissociation (DIS). For V-series clusters, which has a V atom on Siteâ 1, the rate-determining step is DIS, while for Ta-series clusters with a Ta on Siteâ 1, TRF may be the rate-determining step or has energy barriers similar to those of DIS. The overall energy barriers for heteronuclear V2 TaC4- and VTa2 C4- clusters are lower than those for homonuclear V3 C4- and Ta3 C4- , showing that the doping effect is beneficial for the activation and dissociation of N2 . In particular, V-Ta2 C4- has low energy barriers in both TRF and DIS, and it has the highest N2 adsorption energy and a high reaction heat release. Therefore, a trimetallic heteronuclear V-series cluster, V-Ta2 C4- , is suggested to have high reactivity to N2 activation, and may serve as a prototype for designing related catalysts at a molecular level.
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Metais , Ânions , Catálise , Metais/químicaRESUMO
Metal-organic frameworks (MOFs) provide an ideal platform for ion exchange due to their high porosity and structural designability; however, developing MOFs that have the essential characteristics for ion exchange remains a challenge. These crucial features include fast kinetics, selectivity, and stability. We present two anionic isomers, DGIST-2 (2D) and DGIST-3 (3D), comprising distinctly arranged 5-(1,8-naphthalimido)isophthalate ligands and In3+ cations. Interestingly, in protic solvents, DGIST-2 transforms into a hydrolytically stable crystalline phase, DGIST-2'. DGIST-2' and DGIST-3 exhibit rapid Cs+ adsorption kinetics, as well as high Cs+ affinity in the presence of competing cations. The mechanism for rapid and selective sorption is explored based on the results of single-crystal X-ray diffraction analysis of Cs+-incorporated DGIST-3. In Cs+-containing solutions, the loosely incorporated dimethylammonium countercation of the anionic framework is replaced by Cs+, which is held in the hydrophobic cavity by supramolecular ion-ion and cation-π interactions.
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A series of dihydrotriazine derivatives bearing 5-aryloxypyrazole moieties were designed, and their anticancer activities against three human cancer cell lines (SGC-7901, HepG-2 and MCF-7) and one non-cancer cell line (LO2) were explored using the MTT assay in vitro. Most of the compounds exhibited potent antiproliferative activities against the three cancer cell lines, with compound 10e (IC50 = 2.12 µM) exhibiting the most potent antiproliferative activity against HepG-2 cells. Interestingly, autophagy was observed in the 10e-treated HepG-2 cells. Compound 10e also increased reactive oxygen species (ROS) levels and resulted in marked HepG-2 cells apoptosis. Further studies revealed that compound 10e could enhance the expression of Cl-PARP, Cl-caspase-3, and Cl-caspase-9. In addition, 10e triggered the formation of autophagosomes by promoting LC3-II and Beclin-1 expression. These results might be useful for exploring and developing dihydrotriazine derivatives as novel anticancer agents.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is closely related to gut barrier dysfunction. Emerging evidence shows that interleukin-22 (IL-22) derived from group 3 innate lymphoid cells (ILC3s) confers benefits on intestinal barrier, and IL-22 expression is controlled by aryl hydrocarbon receptor (AhR). Previous studies show that baicalein protects the colon from inflammatory damage. In this study we elucidated the molecular mechanisms underlying the protective effect of baicalein on intestinal barrier function in colitis mice. Mice were administered baicalein (10, 20, 40 mg·kg-1·d-1, i.g.) for 10 days; the mice freely drank 3% dextran sulfate sodium (DSS) on D1-D7 to induce colitis. We showed that baicalein administration simultaneously ameliorated gut inflammation, decreased intestinal permeability, restored tight junctions of colons possibly via promoting AhR/IL-22 pathway. Co-administration of AhR antagonist CH223191 (10 mg/kg, i.p.) partially blocked the therapeutic effects of baicalein in colitis mice, whereas AhR agonist FICZ (1 µg, i.p.) ameliorated symptoms and gut barrier function in colitis mice. In a murine lymphocyte line MNK-3, baicalein (5-20 µM) dose-dependently increased the expression of AhR downstream target protein CYP1A1, and enhanced IL-22 production through facilitating AhR nuclear translocation, these effects were greatly diminished in shAhR-MNK3 cells, suggesting that baicalein induced IL-22 production in AhR-dependent manner. To further clarify that, we constructed an in vitro system consisting of MNK-3 and Caco-2 cells, in which MNK-3 cell supernatant treated with baicalein could decrease FITC-dextran permeability and promoted the expression of tight junction proteins ZO-1 and occluding in Caco-2 cells. In conclusion, this study demonstrates that baicalein ameliorates colitis by improving intestinal epithelial barrier via AhR/IL-22 pathway in ILC3s, thus providing a potential therapy for UC.
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Colite Ulcerativa , Colite , Animais , Células CACO-2 , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Flavanonas , Humanos , Imunidade Inata , Interleucinas , Mucosa Intestinal/metabolismo , Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/uso terapêutico , Interleucina 22RESUMO
In order to discover novel anti-inflammatory agents, three series of compounds obtained by appending 1,2,3-triazole moieties on ursolic acid were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by using an ear edema model. The potent anti-inflammatory compound was subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. In general, the derivatives were found to be potent anti-inflammatory activity. Especially, the compound 11b exhibited the strongest activity of all of the compounds prepared, with 82.81% inhibition after intraperitoneal administration, which was better than celecoxib as a positive control. Molecular docking results unclose the rationale for the interaction of the compound 11b with COX-2 enzyme. Further studies revealed that compound 11b exhibited effective COX-2 inhibitory activity, with half-maximal inhibitor concentration (IC50) value of 1.16 µM and selectivity index (SI = 64.66) value close to that of celecoxib (IC50 = 0.93 µM, SI = 65.47). Taken together, these results could suggest a promising chemotype for development of new COX-2-targeting anti-inflammatory agent.
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Inibidores de Ciclo-Oxigenase 2 , Triazóis , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacologia , Triterpenos , Ácido UrsólicoRESUMO
Here, two series of novel ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives were synthesized and screened for their anti-inflammatory activity by evaluating their inhibition effect of using LPS-induced inflammatory response in RAW 264.7 macrophages in vitro; the effects of different concentrations of the compounds on the secretion of nitric oxide (NO) and inflammatory cytokines including TNF-α and IL-6 were evaluated. Their toxicity was also assessed in vitro. Results showed that the most prominent compound 3 could significantly decrease production of the above inflammatory factors. Docking study was performed for the representative compounds 3, UA, and Celecoxib to explain their interaction with cyclooxygenase-2 (COX-2) receptor active site. In vitro enzyme study implied that compound 3 exerted its anti-inflammatory activity through COX-2 inhibition.
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Anti-Inflamatórios , Pirimidinas , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos/toxicidade , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triterpenos , Ácido UrsólicoRESUMO
Lupus nephritis (LN) occurs with inflammatory lesion in patients suffering from systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is an important mediator in inflammation. To explore the roles of TRAF3 in LN, the LN mouse model was firstly established with intraperitoneal (i.p.) injection of pristine. Our results found that the amount of urinary protein was increased evidently at day 28, and renal damage occurred in the LN mouse model, but the TRAF3 knockdown reduced the urinary protein and alleviated the inflammatory lesion. The proinflammatory cytokines TNF-α, IL-1ß, IL-17a, IFN-γ and IgM, IgG antibody were enriched, but there was little amount of IL-10 in the LN mouse model. Moreover, the amount of CD40+ B cells, CD4+ T cells sub-type, Th17 cells were abundant, and the proteins TRAF3, TRAF2, NF-κBp52, IKKα, ICAM1 in the kidney were highly expressed in the LN mouse model. However, TRAF3 knockdown enhanced the production of IL-10 and reduced the amount of pro-inflammatory cytokines, immunoglobulin, and the protein expressions of TRAF3, TRAF2, NF-κBp52, IKKα, ICAM1. In conclusion, TRAF3 plays a role in LN by regulating Th17 cell and Treg cell balance as well as NF-κB signaling pathway in mice.