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1.
Nat Commun ; 15(1): 3706, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698026

RESUMO

Electrochemical-mechanical coupling poses enormous challenges to the interfacial and structural stability but create new opportunities to design innovative all-solid-state batteries from scratch. Relying on the solid-solid constraint in the space-limited domain structure, we propose to exploit the lithiation-induced stress to drive the active materials creep, thereby improving the structural integrity. For demonstration, we fabricate the creep-type all-solid-state cathode using creepable Se material and an all-in-one rigid ionic/electronic conducting Mo6Se8 framework. As indicated by the in-situ experiment and numerical simulation, this cathode presents unique capabilities in improving interparticle contact and avoiding particle fracture, leading to its superior electrochemical performance, including a superior long-cycle life of more than 3000 cycles at 0.5 C and a high volumetric energy density of 2460 Wh/L at the cathode level. We believe this innovative strategy to utilize mechanics to boost the electrochemical performance could shed light on the future design of all-solid-state batteries for practical applications.

2.
Sci Rep ; 14(1): 5802, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461155

RESUMO

Beyond its economic value, copper (Cu) serves as a valuable tracer of deep magmatic processes due to its close relationship with magmatic sulfide evolution and sensitivity to oxygen fugacity (fO2). However, determining Cu's oxidation state (+ 1 or + 2) in silicate melts, crucial for interpreting its behavior and reconstructing fO2 in the Earth's interior, has long been a challenge. This study utilizes X-ray Absorption Near Edge Structure spectroscopy to investigate the Cu oxidation state in hydrous mafic silicate melts equilibrated under diverse fO2 (- 1.8 to 3.1 log units relative to the Fayalite-Magnetite-Quartz buffer), temperature (1150-1300 °C), and pressure (1.0-2.5 GPa) conditions. Our results reveal that Cu predominantly exists as Cu+ across all fO2 conditions, with a minor Cu2+ component. This dominance of Cu+ persists even in relatively oxidized melts, highlighting its limited sensitivity to fO2 under upper mantle conditions. This significantly constrains the utility of Cu as an oxybarometer in hydrous silicate melts in the deep Earth. However, our findings suggest that Cu isotopes primarily reflect the interplay of sulfide segregation/accumulation during magmatic differentiation, shedding light on these fundamental processes in Earth's interior.

3.
J Am Chem Soc ; 146(12): 8547-8556, 2024 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-38498689

RESUMO

Photocatalysis has found increasing applications in biological systems, for example, in localized prodrug activation; however, high-energy light is usually required without giving sufficient efficiency and target selectivity. In this work, we report that ion pairing between photocatalysts and prodrugs can significantly improve the photoactivation efficiency and enable tumor-targeted activation by red light. This is exemplified by a gold-based prodrug (1d) functionalized with a morpholine moiety. Such a modification causes 1d to hydrolyze in aqueous solution, forming a cationic species that tightly interacts with anionic photosensitizers including Eosin Y (EY) and Rose Bengal (RB), along with a significant bathochromic shift of absorption tailing to the far-red region. As a result, a high photoactivation efficiency of 1d by EY or RB under low-energy light was found, leading to an effective release of active gold species in living cells, as monitored by a gold-specific biosensor (GolS-mCherry). Importantly, the morpholine moiety, with pKa ∼6.9, in 1d brings in a highly pH-sensitive and preferential ionic interaction under a slightly acidic condition over the normal physiological pH, enabling tumor-targeted prodrug activation by red light irradiation in vitro and in vivo. Since a similar absorption change was found in other morpholine/amine-containing clinic drugs, photocages, and precursors of reactive labeling intermediates, it is believed that the ion-pairing strategy could be extended for targeted activation of different prodrugs and for mapping of an acidic microenvironment by low-energy light.


Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/química , Luz Vermelha , Morfolinas , Microambiente Tumoral
4.
mBio ; 14(4): e0093323, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37260233

RESUMO

DndABCDE-catalyzed DNA phosphorothioation (PT), in which the nonbridging oxygen is swapped with a sulfur atom, was first identified in the bacterial genome. Usually, this modification gene cluster is paired with a restriction module consisting of DndF, DndG, and DndH. Although the mechanisms for the antiphage activity conferred by this Dnd-related restriction and modification (R-M) system have been well characterized, several features remain unclear, including the antiphage spectrum and potential interference with DNA methylation. Recently, a novel PT-related R-M system, composed of the modification module SspABCD paired with a single restriction enzyme, SspE, was revealed to be widespread in the bacterial kingdom, which aroused our interest in the interaction between Dnd- and Ssp-based R-M systems. In this study, we discussed the action of Dnd-related R-M systems against phages and demonstrated that the host could benefit from the protection provided by Dnd-related R-M systems against infection by various lytic phages as well as temperate phages. However, this defense barrier would fail against lysogenic phages. Interestingly, DNA methylation, even in the consensus sequence recognized by the Dnd system, could not weaken the restriction efficiency. Finally, we explored the interaction between Dnd- and Ssp-based R-M systems and found that these two systems were compatible. This study not only expands our knowledge of Dnd-associated R-M systems but also reveals a complex interaction between different defense barriers that coexist in the cell. IMPORTANCE Recently, we decoded the mechanism of Dnd-related R-M systems against genetic parasites. In the presence of exogenous DNA that lacks PT, the macromolecular machine consisting of DndF, DndG, and DndH undergoes conformational changes to perform DNA binding, translocation, and DNA nicking activities and scavenge the foreign DNA. However, several questions remain unanswered, including questions regarding the antiphage spectrum, potential interference by DNA methylation, and interplay with other PT-dependent R-M systems. Here, we revealed that the host could benefit from Dnd-related R-M systems for a broad range of antiphage activities, regardless of the presence of DNA methylation. Furthermore, we demonstrated that the convergence of Dnd- and Ssp-related R-M systems could confer to the host a stronger antiphage ability through the additive suppression of phage replication. This study not only deepens our understanding of PT-related defense barriers but also expands our knowledge of the arms race between bacteria and their predators.


Assuntos
Bacteriófagos , Bacteriófagos/genética , Genoma Bacteriano , Bactérias/genética , DNA , Metilação de DNA
5.
J Am Chem Soc ; 145(18): 10082-10091, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-37098902

RESUMO

Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH2 even in limited O2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.


Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Humanos , Animais , Camundongos , Pró-Fármacos/uso terapêutico , Irídio , Espécies Reativas de Oxigênio , Neoplasias/tratamento farmacológico , Ácidos Borônicos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Microambiente Tumoral
6.
Acc Chem Res ; 56(9): 1043-1056, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37079555

RESUMO

Over the past few decades, research on the chemistry of gold has progressed rapidly, encompassing topics like catalysis, supramolecular chemistry, molecular recognition, etc. These chemical properties are of great value in developing therapeutics or orthogonal catalysts in biology. However, the presence of concentrated nucleophiles and reductants, particularly thiol-containing serum albumin in blood and glutathione (GSH) inside cells that can strongly bind and quench the active gold species, makes it difficult to translate the chemistry of gold from test tubes into living systems. In this regard, modulating the chemical reactivity of gold complexes to conquer nonspecific interactions with thiols and meanwhile to controllably activate their reactivity in a spatiotemporal manner is of pivotal importance to develop gold complexes for biomedical applications. In this account, we aim to highlight the concept of developing stimuli-activatable gold complexes with masked chemical properties, the bioactivity of which can be spatiotemporally activated at the target site by leveraging approaches from classic structure design to recently emerged photo- and bioorthogonal-activation.A straightforward approach to tuning the reactivity of gold complexes is based on structure modification. This is achieved by introducing strong carbon donor ligands, such as N-heterocyclic carbene, alkynyl, and diphosphine, to improve the stability of gold(I) complexes against off-target thiols. Likewise, GSH-responsive gold(III) prodrug and supramolecular Au(I)-Au(I) interaction have been harnessed to keep a reasonable stability against serum albumin and confer tumor-targeted cytotoxicity by inhibiting thiol- and selenol-containing thioredoxin reductase (TrxR) for potent cancer treatment in vivo. To achieve better spatiotemporal controllability, photoactivatable prodrugs are developed. These complexes are equipped with cyclometalated pincer-type ligands and carbanion or hydride as ancillary ligands, rendering high thiol-stability in the dark, but upon photoirradiation, the complexes can undergo unprecedented photoinduced ligand substitution, ß-hydride elimination, and/or reduction to release active gold species for TrxR inhibition at the diseased tissue. To further improve the therapeutic activity, an oxygen-dependent conditional photoreactivity of gold(III) complexes by evolving from photodynamic into photoactivated chemotherapy has been achieved, resulting in highly potent antitumor efficacy in tumor-bearing mice. Of equal importance is harnessing the bioorthogonal activation approach by chemical inducers, as exemplified by a palladium-triggered transmetalation reaction to selectively activate the chemical reactivities of gold including its TrxR inhibition and catalytic activity in living cells and zebrafish. Collectively, strategies to modulate gold chemistry in vitro and in vivo are emerging, and it is hoped that this Account will spur the creation of better approaches to advance gold complexes closer to clinical application.


Assuntos
Antineoplásicos , Complexos de Coordenação , Camundongos , Animais , Ouro/química , Linhagem Celular Tumoral , Antineoplásicos/química , Ligantes , Peixe-Zebra/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Compostos de Sulfidrila , Complexos de Coordenação/química
7.
Chembiochem ; 24(6): e202200621, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36445798

RESUMO

The discovery of immunogenic cell death (ICD) by small molecules (e. g., chemotherapeutic drugs) intrigued medicinal chemists and led them to exploit anticancer agents with such a trait because ICD agents provoke anticancer immune responses in addition to their cytotoxicity. However, the unclear molecular mechanism of ICD hampers further achievements in drug development. Fortunately, increasing efforts have been made in this area in recent years by using either chemical or biological approaches. Here, we review the current achievements towards understanding the mechanisms of small molecule-induced ICD effects. Based on the established role of the unfolded protein response (UPR) in ICD, we classify the mechanisms of different inducers by their dependency on UPR. Key proteins and pathways with important implications are discussed in depth. We also give our perspectives on the research strategies for future investigation in this field.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/metabolismo , Morte Celular , Morte Celular Imunogênica , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fenótipo
8.
J Agric Food Chem ; 70(50): 15818-15829, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36479857

RESUMO

The aim of this experiment was to assess the effect of different storage temperatures on the texture quality, phenolic profile, and antioxidant capacity of a grape. Fresh grapes were stored at 4 and 25 °C for nine days and sampled on alternate days. The hardness, total phenolics, total flavanones, total flavanols, total anthocyanin content, antioxidant activity, differential metabolite screening, and key gene expression were evaluated. In addition, four phenolic compounds were screened out as differential metabolites in response to storage temperature by OPLS-DA analysis. The results showed that the fruit firmness was better maintained in low-temperature storage and the storage life was longer than that at 25 °C. During the whole storage process, the contents of phenolics, flavanones, flavanols, and anthocyanins all showed an increasing trend first and then decreased regardless of what temperature. Since the antioxidant capacity of a grape was positively correlated with the contents of total phenols and total flavonoids, the same trend was also shown. However, the grape's phenolic compound content and antioxidant activity were higher at 25 °C than at 4 °C. Furthermore, through qualitative and quantitative analysis of 16 monomeric phenols, this study selected catechin, 1-O-vanilloyl-ß-d-glucose, p-coumaric acid 4-glucoside, and resveratrol-3-O-glucoside as the main differentially expressed metabolites at the two temperatures. In conclusion, for a short shelf life or immediate consumption, keeping grapes at room temperature is more beneficial to obtain high antioxidants. However, if the goal is to prolong the storage period of the fruit, keeping the fruit at 4 °C is recommended.


Assuntos
Flavanonas , Vitis , Antioxidantes , Antocianinas , Temperatura , Polifenóis/análise , Fenóis/análise , Frutas/química
9.
Front Cardiovasc Med ; 9: 1046273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465436

RESUMO

Introduction: Despite multiple studies in the past, the role of peptidylarginine deiminase 4 (PAD4) in atherosclerosis is currently insufficiently understood. In this regard, PAD4 deletion or inhibition of enzymatic activity was previously reported to ameliorate disease progression and inflammation. Besides, strong influence of neutrophil extracellular traps (NETs) on atherosclerosis burden has been proposed. Here, we studied the role of PAD4 for atherogenesis and plaque progression in a mouse model of atherosclerosis. Methods and results: Lethally irradiated ApoE -/- mice were reconstituted with ApoE -/-/Pad4 -/- bone marrow cells and fed a high-fat diet (HFD) for 4 and 10 weeks, respectively. PAD4 deficiency did not prevent the development of atherosclerotic lesions after 4 weeks of HFD. However, after 10 weeks of HFD, mice with bone marrow cells-restricted PAD4 deficiency displayed significantly reduced lesion size, impaired lipid incorporation, decreased necrotic core area and less collagen when compared to ApoE -/- bone marrow-transplanted mice as demonstrated by histological staining. Moreover, flow cytometric analysis and quantitative real-time PCR revealed different macrophage subsets in atherosclerotic lesions and higher inflammatory response in these mice, as reflected by increased content of M1-like macrophages and upregulated aortic expression of the pro-inflammatory genes CCL2 and iNOS. Notably, diminished oxLDL uptake by in vitro-polarized M1-like macrophages was evidenced when compared to M2-like cells. Conclusion: These results suggest that pharmacological inhibition of PAD4 may impede lipid accumulation and lesion progression despite no beneficial effects on vascular inflammation.

10.
Angew Chem Int Ed Engl ; 61(45): e202212689, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36109339

RESUMO

Photodynamic therapy (PDT) is a spatiotemporally controllable, powerful approach in combating cancers but suffers from low activity under hypoxia, whereas photoactivated chemotherapy (PACT) operates in an O2 -independent manner but compromises the ability to harness O2 for potent photosensitization. Herein we report that cyclometalated gold(III)-alkyne complexes display a PDT-to-PACT evolving photoactivity for efficient cancer treatment. On the one hand, the gold(III) complexes can act as dual photosensitizers and substrates, leading to conditional PDT activity in oxygenated condition that progresses to highly efficient PACT (ϕ up to 0.63) when O2 is depleted in solution and under cellular environment. On the other hand, the conditional PDT-to-PACT reactivity can be triggered by external photosensitizers in a similar manner in vitro and in vivo, giving additional tumor-selectivity and/or deep tissue penetration by red-light irradiation that leads to robust anticancer efficacy.


Assuntos
Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Luz , Ouro , Neoplasias/tratamento farmacológico
11.
J Am Chem Soc ; 144(23): 10407-10416, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35658433

RESUMO

Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.


Assuntos
Antineoplásicos , Morte Celular Imunogênica , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Irídio/farmacologia , Resposta a Proteínas não Dobradas
12.
Angew Chem Int Ed Engl ; 61(16): e202201103, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35165986

RESUMO

Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo-induced ß-hydride elimination, releasing alkyl ligands and forming gold(III)-hydride intermediates that could be quickly converted into bioactive [AuIII -S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo-catalytically reduce [AuIII -S] into more bioactive AuI species. Such photo-reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal-biomacromolecule interactions. As a result, the gold(III) complexes containing glucose-functionalized alkyl ligands displayed efficient and tumor-selective uptake; notably, after one- or two-photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ouro , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tiorredoxina Dissulfeto Redutase
13.
Expert Rev Med Devices ; 18(12): 1209-1217, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34886730

RESUMO

OBJECTIVES: To investigate safety and effectiveness of left atrial appendage closure (LAAC) in atrial fibrillation patients with prior major bleeding. METHODS: A total of 377 consecutive patients scheduled for LAAC with Watchman device were divided into bleeding group (n = 137) and non-bleeding group (n = 240). Data were compared between groups. RESULTS: The bleeding group had more patients ≥75 years old (P = 0.044), higher CHA2DS2-VASc (P = 0.029) and HAS-BLED scores (P = 0.001) than the non-bleeding group. During the long-term follow-up, except for thromboembolism event (P = 0.031), the incidences of major bleeding  , all-cause death  , co-primary efficacy events  , and the cumulative survival ratio after adjustment of confounding factors    were comparable. The observed thromboembolism rate was reduced by 86.3% (P = 0.0002) and 55.1% (P = 0.0293) and the observed major bleeding rate was decreased by 61.9% (P = 0.0393) and 35.7% (P = 0.2426) compared with expected risks in bleeding and non-bleeding groups, respectively. The risk reduction in thromboembolism and major bleeding were significantly greater in bleeding group versus non-bleeding group (all P < 0.0001). CONCLUSIONS: Among patients with prior bleeding, LAAC is a safe and effective alternative to anticoagulation therapy and seems to emerge as a higher efficacy in risk reduction of thromboembolism and major bleeding compared to those without prior bleeding.


Assuntos
Apêndice Atrial , Fibrilação Atrial , Acidente Vascular Cerebral , Idoso , Apêndice Atrial/cirurgia , Fibrilação Atrial/complicações , Hemorragia/etiologia , Humanos , Resultado do Tratamento
14.
Can J Microbiol ; 67(10): 724-736, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34153193

RESUMO

Lavender essential oil (LEO), a natural antimicrobial agent, is generally recognized as safe and effective in the inhibition of phytopathogenic fungi. Direct contact and fumigation (in vivo and in vitro) were used to study the fungistatic effect of LEO on Monilinia fructicola. Additionally, the effect on the ultrastructure of cells and the degree of destruction of the cell membrane of M. fructicola were revealed. In addition, the effects of LEO on the expression levels of apoptosis-related genes in M. fructicola cells were detected, and GC-MS was used to analyze the main components of LEO. LEO had a good inhibitory efficacy against M. fructicola in flat peaches, with almost complete growth inhibition at 800 µL/L. These effects were associated with the leakage of cytoplasmic contents, hyphal distortion, and spore disruption. Moreover, the expression of apoptosis RTG1 and RLM1 genes increased with LEO treatment. These results demonstrate that LEO can inhibit M. fructicola by inducing cytoplasmic membrane damage and cell apoptosis in fungi, and that the major ingredients of LEO are monoterpenes and sesquiterpenes, which are presumed to contribute to the inhibitory effects.


Assuntos
Ascomicetos , Lavandula , Óleos Voláteis , Prunus persica , Antifúngicos/farmacologia , Ascomicetos/genética , Frutas , Óleos Voláteis/farmacologia
15.
Biochem Pharmacol ; 190: 114620, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34043966

RESUMO

MET, the receptor of hepatocyte growth factor (HGF), is a driving factor in renal cell carcinoma (RCC) and also a proven drug target for cancer treatment. To improve the activity and to investigate the mechanisms of action of Apigenin (APG), novel derivatives of APG with improved properties were synthesized and their activities against Caki-1 human renal cancer cell line were evaluated. It was found that compound 15e exhibited excellent potency against the growth of multiple RCC cell lines including Caki-1, Caki-2 and ACHN and is superior to APG and Crizotinib. Subsequent investigations demonstrated that compound 15e can inhibit Caki-1 cell proliferation, migration and invasion. Mechanistically, 15e directly targeted the MET kinase domain, decreased its auto-phosphorylation at Y1234/Y1235 and inhibited its kinase activity and downstream signaling. Importantly, 15e had inhibitory activity against mutant MET V1238I and Y1248H which were resistant to approved MET inhibitors Cabozantinib, Crizotinib or Capmatinib. In vivo tumor graft study confirmed that 15e repressed RCC growth through inhibition of MET activation. These results indicate that compound 15e has the potential to be developed as a treatment for RCC, and especially against drug-resistant MET mutations.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apigenina/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Apigenina/química , Domínio Catalítico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Neoplasias Experimentais/tratamento farmacológico , Fitoterapia , Conformação Proteica , Proteínas Proto-Oncogênicas c-met/genética
16.
Angew Chem Int Ed Engl ; 60(8): 4133-4141, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33151608

RESUMO

Controllably activating the bio-reactivity of metal complexes in living systems is challenging but highly desirable because it can minimize off-target bindings and improve spatiotemporal specificity. Herein, we report a new bioorthogonal activation approach by employing Pd(II)-triggered transmetallation reactions to conditionally activate the bio-reactivity of NHC-Au(I)-phenylacetylide complexes (1 a) in vitro and in vivo. A combination of 1 H NMR, LC-MS, DFT calculation and fluorescence screening assays reveals that 1 a displays a reasonable stability against biological thiols, but its phenylacetylide ligand can be efficiently transferred to Pd(II), leading to in situ formation of labile NHC-Au(I) species that is catalytically active inside living cells and zebrafish, and can meanwhile effectively suppress the activity of thioredoxin reductase, potently inhibit the proliferation of cancer cells and efficiently suppress angiogenesis in zebrafish models.


Assuntos
Complexos de Coordenação/química , Ouro/química , Alcinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Teoria da Densidade Funcional , Embrião não Mamífero/química , Embrião não Mamífero/metabolismo , Humanos , Metano/análogos & derivados , Metano/química , Imagem Óptica , Paládio/química , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
17.
Nat Microbiol ; 5(7): 917-928, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251370

RESUMO

Bacteria have evolved diverse mechanisms to fend off predation by bacteriophages. We previously identified the Dnd system, which uses DndABCDE to insert sulfur into the DNA backbone as a double-stranded phosphorothioate (PT) modification, and DndFGH, a restriction component. Here, we describe an unusual SspABCD-SspE PT system in Vibrio cyclitrophicus, Escherichia coli and Streptomyces yokosukanensis, which has distinct genetic organization, biochemical functions and phenotypic behaviour. SspABCD confers single-stranded and high-frequency PTs with SspB acting as a nickase and possibly introducing nicks to facilitate sulfur incorporation. Strikingly, SspABCD coupled with SspE provides protection against phages in unusual ways: (1) SspE senses sequence-specific PTs by virtue of its PT-stimulated NTPase activity to exert its anti-phage activity, and (2) SspE inhibits phage propagation by introducing nicking damage to impair phage DNA replication. These results not only expand our knowledge about the diversity and functions of DNA PT modification but also enhance our understanding of the known arsenal of defence systems.


Assuntos
Bacteriófagos/fisiologia , Interações Hospedeiro-Patógeno , Fosfatos/metabolismo , Streptomyces/fisiologia , Streptomyces/virologia , Adesinas Bacterianas/química , Adesinas Bacterianas/genética , Adesinas Bacterianas/metabolismo , Sítios de Ligação , Ativação Enzimática , Genoma Bacteriano , Interações Hospedeiro-Patógeno/genética , Modelos Moleculares , Fases de Leitura Aberta , Fosfatos/química , Ligação Proteica , Conformação Proteica , Multimerização Proteica
18.
Nat Immunol ; 19(9): 1036, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29449628

RESUMO

In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.

19.
RNA Biol ; 15(4-5): 649-658, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28910573

RESUMO

Tryptophanyl-tRNA synthetase (TrpRS) in vertebrates contains a N-terminal extension in front of the catalytic core. Proteolytic removal of the N-terminal 93 amino acids gives rise to T2-TrpRS, which has potent anti-angiogenic activity mediated through its extracellular interaction with VE-cadherin. Zinc has been shown to have anti-angiogenic effects and can bind to human TrpRS. However, the connection between zinc and the anti-angiogenic function of TrpRS has not been explored. Here we report that zinc binding can induce structural relaxation in human TrpRS to facilitate the proteolytic generation of a T2-TrpRS-like fragment. The zinc-binding site is likely to be contained within T2-TrpRS, and the zinc-bound conformation of T2-TrpRS is mimicked by mutation H130R. We determined the crystal structure of H130R T2-TrpRS at 2.8 Å resolution, which reveals drastically different conformation from that of wild-type (WT) T2-TrpRS. The conformational change creates larger binding surfaces for VE-cadherin as suggested by molecular dynamic simulations. Surface plasmon resonance analysis indicates more than 50-fold increase in binding affinity of H130R T2-TrpRS for VE-cadherin, compared to WT T2-TrpRS. The enhanced interaction is also confirmed by a cell-based binding analysis. These results suggest that zinc plays an important role in activating TrpRS for angiogenesis regulation.


Assuntos
Inibidores da Angiogênese/química , Antígenos CD/química , Caderinas/química , Triptofano-tRNA Ligase/química , Zinco/química , Inibidores da Angiogênese/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Sítios de Ligação , Caderinas/genética , Caderinas/metabolismo , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Termodinâmica , Triptofano-tRNA Ligase/genética , Triptofano-tRNA Ligase/metabolismo , Zinco/metabolismo
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