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1.
Adv Sci (Weinh) ; : e2103714, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791832

RESUMO

In flexible electronics, appropriate inlaid structures for stress dispersion to avoid excessive deformation that can break chemical bonds are lacking, which greatly hinders the fabrication of super-foldable composite materials capable of sustaining numerous times of true-folding. Here, mimicking the microstructures of both cuit cocoon possessing super-flexible property and Mimosa leaf featuring reversible scatheless folding, super-foldable C-web/FeOOH-nanocone (SFCFe) conductive nanocomposites are prepared, which display cone-arrays on fiber structures similar to Mimosa leaf, as well as non-crosslinked junctions, slidable nanofibers, separable layers, and compressible network like cuit cocoon. Remarkably, the SFCFe can undergo over 100 000 times of repeated true-folding without structural damage or electrical conductivity degradation. The mechanism underlying this super-foldable performance is further investigated by real-time scanning electron microscopy folding characterization and finite-element simulations. The results indicate its self-adaptive stress-dispersion mechanism originating from multilevel biomimetic structures. Notably, the SFCFe demonstrates its prospect as a super-foldable anode electrode for aqueous batteries, which shows not only high capacities and satisfactory cycling stability, but also completely coincident cyclic voltammetry and galvanostatic charge-discharge curves throughout the 100 000 times of true-folding. This work reports a mechanical design considering the self-adaptive stress dispersion mechanism, which can realize a scatheless super-foldable electrode for soft-matter electronics.

2.
Sensors (Basel) ; 21(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34770368

RESUMO

As a newly developed pile foundation, the snowflake shaped steel sheet pile is composed of three Y-shaped sections with an included angle of 120° and has a large specific surface area, which can give full play to the side friction of pile and improve the bearing capacity of single pile. At the same time, the snowflake shaped steel sheet pile has a high strength, relatively few materials, and it has good prospects with engineering applications. In order to accurately grasp the mechanical characteristics of the snowflake shaped steel sheet pile, this paper carried out the model test of snowflake shaped steel sheet pile based on OFDR (optical frequency domain reflector) distributed optical fiber sensor technology. The results show that: (1) OFDR distributed optical fiber sensing technology can effectively monitor the strain of snowflake steel sheet pile; (2) under the vertical load, the strain of snowflake steel sheet pile decreases along the length of the pile; (3) the strain of the same section of snowflake steel sheet pile is different at different positions, the strain at the junction between web and web is basically the same as the junction between web and flange, and the strain of the pile shaft on the flange edge is larger.

3.
J Med Chem ; 64(19): 14587-14602, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34609868

RESUMO

To overcome the resistance of cancer cells to platinum-based drugs and effectively suppress tumor growth, we developed a novel indium (In) agent based on liposomes (Lips). Thus, we not only obtained an In(III) thiosemicarbazone agent (5b) with remarkable cytotoxicity by optimizing a series of In(III) thiosemicarbazone agents (1b-5b) but also successfully constructed a novel 5b-loaded Lip (5b-Lip) delivery system. Importantly, in vitro and in vivo results revealed that 5b/5b-Lip overcame the tumor cell resistance and effectively inhibited MCF-7/DDP tumor growth. In addition, Lips improved the intracellular accumulation of 5b. We also confirmed the mechanism by which 5b/5b-Lip overcomes breast cancer cell resistance. 5b/5b-Lip cannot act against DNA in cancer cells but attacks the two cell components in the tumor microenvironment, namely, by inducing apoptosis and lethal autophagy of cancer cells and resetting tumor-promoting M2 macrophages to the tumor-killing M1 phenotype.

4.
Exp Mol Med ; 53(10): 1547-1558, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34611269

RESUMO

The abnormal expression of circular RNAs (circRNAs) is associated with numerous human diseases. This study investigated the mechanism by which circRNA acts as competitive endogenous RNA in the regulation of degenerative intervertebral disc disease (IVDD). Decreased expression of circSPG21 was detected in degenerated nucleus pulposus cells (NPCs), the function of circSPG21 in NPCs was explored and verified, and the downstream target of circSPG21 was investigated. The interaction between circSPG21 and miR-1197 and its target gene (ATP1B3) was studied by online database prediction and molecular biological verification. Finally, the circSPG21/miR-1197/ATP1B3 axis was verified in the mouse tail-looping model. The expression of circSPG21 in the nucleus pulposus in IVDD was directly related to an imbalance of anabolic and catabolic factors, which affected cell senescence. circSPG21 was found to play a role in human NPCs by acting as a sponge of miR-1197 and thereby affecting ATP1B3. The regulation of circSPG21 provides a potentially effective therapeutic strategy for IVDD.

5.
Oncogene ; 40(39): 5799-5813, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34345013

RESUMO

Emerging evidence suggests that the cancer stem cells (CSCs) are key culprits of cancer metastasis and drug resistance. Understanding mechanisms regulating the critical oncogenic pathways and CSCs function could reveal new diagnostic and therapeutic strategies. We now report that miR-22, a miRNA critical for hair follicle stem/progenitor cell differentiation, promotes tumor initiation, progression, and metastasis by maintaining Wnt/ß-catenin signaling and CSCs function. Mechanistically, we find that miR-22 facilitates ß-catenin stabilization through directly repressing citrullinase PAD2. Moreover, miR-22 also relieves DKK1-mediated repression of Wnt/ß-catenin signaling by targeting a FosB-DDK1 transcriptional axis. miR-22 knockout mice showed attenuated Wnt/ß-catenin activity and Lgr5+ CSCs penetrance, resulting in reduced occurrence, progression, and metastasis of chemically induced cutaneous squamous cell carcinoma (cSCC). Clinically, miR-22 is abundantly expressed in human cSCC. Its expression is even further elevated in the CSCs proportion, which negatively correlates with PAD2 and FosB expression. Inhibition of miR-22 markedly suppressed cSCC progression and increased chemotherapy sensitivity in vitro and in xenograft mice. Together, our results revealed a novel miR-22-WNT-CSCs regulatory mechanism in cSCC and highlight the important clinical application prospects of miR-22, a common target molecule for Wnt/ß-catenin signaling and CSCs, for patient stratification and therapeutic intervention.

6.
J Med Chem ; 64(10): 6777-6791, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34000198

RESUMO

To effectively treat gastric cancer, we innovatively attempted to develop a metal agent to integrate immunotherapy and chemotherapy by dual targeting the cellular components in the tumor microenvironment (TME) based on the specific residue of human serum albumin (HSA) nanoparticles (NPs). We synthesized a series of Au(III) α-N-heterocyclic thiosemicarbazone compounds and obtained a Au agent (5b) with remarkable cytotoxicity to gastric cancer cells; moreover, we successfully constructed a novel HSA-5b complex NP delivery system. Importantly, the in vivo results showed that 5b/HSA-5b NPs effectively inhibited gastric tumor growth and HSA-5b NPs enhanced the therapeutic efficiency, bioavailability, and targeting ability compared with those of 5b alone. Furthermore, the in vitro/in vivo results revealed that 5b/HSA-5b NPs could integrate chemotherapy and immunotherapy by synergistically attacking two different cellular components in TME at the same time, namely, polarizing the tumor-associated macrophages and inducing apoptosis of gastric cancer cells.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Ouro/química , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoterapia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Relação Estrutura-Atividade , Tiossemicarbazonas/química
7.
ACS Sustain Chem Eng ; 9(5): 2388-2399, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33585085

RESUMO

Acidolysis in conjunction with stabilization of reactive intermediates has emerged as one of the most powerful methods of lignin depolymerization that leads to high aromatic monomer yields. In particular, stabilization of reactive aldehydes using ethylene glycol results in the selective formation of the corresponding cyclic acetals (1,3-dioxolane derivatives) from model compounds, lignin, and even from softwood lignocellulose. Given the high practical utility of this method for future biorefineries, a deeper understanding of the method is desired. Here, we aim to elucidate key mechanistic questions utilizing a combination of experimental and multilevel computational approaches. The multiscale computational protocol used, based on ReaxFF molecular dynamics, represents a realistic scenario, where a typical experimental setup can be reproduced confidently given the explicit molecules of the solute, catalyst, and reagent. The nudged elastic band (NEB) approach allowed us to characterize the key intermolecular interactions involved in the reaction paths leading to crucial intermediates and products. The high level of detail obtained clearly revealed for the first time the unique role of sulfuric acid as a proton donor and acceptor in lignin ß-O-4 acidolysis as well as the reaction pathways for ethylene glycol stabilization, and the difference in reactivity between compounds with different methoxy substituents.

8.
J Med Chem ; 63(22): 13695-13708, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33185442

RESUMO

Effective delivery of anticancer agents across the blood-brain barrier (BBB) required innovative strategies to achieve glioma regression. To resolve this problem, we proposed to develop a metal agent that target and treat glioma based on the unique property of apoferritin (AFt) nanoparticles (NPs). Thus, we synthesized a series of Au(III) 3-(4-metyl piperidine)thiosemicarbazides compounds and analyzed their structure-activity relationships, obtaining a Au agent (C6) with remarkable cytotoxicity in glioma. Moreover, we confirmed that C6 kills glioma cells by inducing lethal autophagy and apoptosis. Importantly, our results revealed that the successfully constructed apoferritin-C6 NPs (AFt-C6 NPs) can effectively cross the BBB, inhibit glioma growth, and selectively accumulate in tumors.


Assuntos
Apoferritinas/química , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Ouro/química , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoferritinas/administração & dosagem , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Glioma/patologia , Ouro/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem
9.
Dalton Trans ; 49(47): 17207-17220, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33201167

RESUMO

The anticancer function and anticancer mechanism of indium (In) complexes still remain mysterious to date. Furthermore, it is greatly challenging to design a multi-functional metal agent that not only kills cancer cells but also inhibits their invasion and metastasis. Thus, to develop novel next-generation anticancer metal agents, we designed and synthesized a series of novel In(iii) 2,6-diacetylpyridine bis(thiosemicarbazide) complexes (C1-C4) for the first time and then investigated their structure-activity relationships with human urinary bladder cancer (T-24) cells. In particular, C4 not only showed higher cytotoxicity to cancer cells and less toxicity toward normal cells relative to cisplatin but also inhibited cell invasion and metastasis of T-24 cells. Interestingly, C4 acted against T-24 cells exhibiting multiple mechanisms: (1) arresting the S-phase of cell cycle via regulation of cytokine kinases, (2) activating the mitochondrial-mediated apoptosis, endoplasmic reticulum-stress-mediated cell death, PERK and c-Jun N-terminal kinase 1 (JNK) cell signaling pathways, and (3) inhibiting the expression of telomerase via the regulation of c-myc and h-TERT proteins. Our results suggested that C4 may be developed as a potential multi-functional and multi-targeting anticancer candidate.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Índio/farmacologia , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Índio/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química
10.
J Org Chem ; 85(20): 13029-13036, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-32954735

RESUMO

An intramolecular decarboxylative coupling reaction for the construction of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives was developed from readily available isatins and hydrazides by virtue of electrochemistry. In this reaction, isatins were employed as amino-attached C1 sources, providing a variety of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives with moderate to good yields.

11.
Mol Pharm ; 17(4): 1405-1414, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32096645

RESUMO

To cause tumor regression by acting against cancer cells and inhibiting neovascularization in the tumor microenvironment, we constructed human serum albumin (HSA)-based delivery systems of 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone-copper(II) [Cu(Ap44mT)]Cl and paclitaxel to improve both the therapeutic efficacy and the targeting ability in vivo. X-ray crystallography and matrix-assisted laser desorption/ionization time-of-flight mass spectra confirmed that [Cu(Ap44mT)]Cl complexed with HSA, whereas paclitaxel was tethered to the HSA complex by a linker sensitive to the active matrix metalloproteinase 2 (MMP2) protein. Up to 78% of paclitaxel was released from HSA within 2 h owing to MMP2 protein cleavage. In addition, a large amount of Cu(Ap44mT) was released from HSA in a pH 4.7 buffer. In vivo results revealed the following: (1) the tumor inhibitory rates of the HSA conjugate and the two-agent combination were 72.1 and 50.7%, respectively; (2) the inhibition rate of tumor angiogenesis of the HSA conjugate (73.3%) was higher than that of the two-agent combination (52.4%); (3) the increased amount of Cu in the tumor treated with the HSA conjugate was about 2-fold that in the tumor treated with the two-agent combination. Obviously, the HSA conjugate not only possessed a stronger capacity to inhibit neovascularization and the growth of liver tumors but also improved the targeting ability compared to the combination of the two agents alone.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Albumina Sérica Humana/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Cobre/química , Sistemas de Liberação de Medicamentos/métodos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Paclitaxel/química , Paclitaxel/farmacologia
12.
J Colloid Interface Sci ; 560: 795-801, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711662

RESUMO

Super-amphiphilic (highly oleophilic and hydrophilic) materials have attracted tremendous interest for fundamental research and potential applications, owing to their unique affinity for both oil and water. In this work, a novel super-amphiphilic porous polycaprolactone (PCL) was fabricated via an efficient and eco-friendly method, in which stearic acid (SA) was used as both a porogen and a dopant precursor. The porous PCL had an interconnected hierarchical pore structure and was capable of absorbing oil and water rapidly. The complementary cooperation of the oleophilic and hydrophilic domains on the pore surface induced the amphiphilicity, while the capillary forces caused a wicking action. The synergy of the two effects gave rise to the super-wetting property. The special amphiphilic feature of the porous PCL had a positive effect on its biocompatibility and the material can be considered as a promising candidate for tissue engineering applications.


Assuntos
Materiais Biocompatíveis/síntese química , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Teste de Materiais , Poliésteres/síntese química , Ácidos Esteáricos/química , Materiais Biocompatíveis/farmacologia , Adesão Celular , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Poliésteres/farmacologia , Porosidade , Molhabilidade
13.
J Cell Biol ; 219(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31868888

RESUMO

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore-microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.


Assuntos
Aurora Quinase B/genética , Centrômero/genética , Histonas/genética , Mitose/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Células HeLa , Humanos , Cinetocoros/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/genética , Microtúbulos/genética , Fosforilação/genética
14.
J Med Chem ; 62(23): 10630-10644, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31693353

RESUMO

It is a great challenge to design drugs that penetrate the blood-brain barrier to inhibit brain tumor growth by acting against multiple targets and also improve their delivery efficacy and targeting ability to cancer cells. To overcome the above problems, we designed a multitarget metal agent for treating brain tumors based on an human serum albumin (HSA)-cell penetrating peptide conjugate. Thus, we rationally screened copper (Cu) and 2-acetyl-3-ethylpyrazine thiosemicarbazones to synthesize six compounds, and we investigated their structure-activity relationships and confirmed multiple mechanisms for brain glioma cells. The HSA-6b complex structure indicated that 6b binds to the IIA subdomain of HSA and His242 replaces the Br ligand in 6b in coordination with Cu2+. In vivo data suggested that both 6b and the HSA-6b-peptide conjugate penetrate the blood-brain barrier and inhibit brain tumor growth with few side effects. Furthermore, the HSA-peptide conjugate also improved the delivery efficacy and targeting ability of 6b in vivo.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Cobre/química , Peptídeos/química , Albumina Sérica/química , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Neoplasias Experimentais , Relação Estrutura-Atividade
15.
Metallomics ; 11(11): 1847-1863, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553341

RESUMO

To develop new anti-tumour Pt(ii) agents, we designed and synthesized five Pt(ii) complexes. These Pt(ii) complexes were modified benzene rings of 2-hydroxybenzylidene with a hydrocarbyl or halogen group. The five Pt(ii) complexes possessed remarkable cytotoxicity against tumour cells in vitro. In particular, we investigated chemotherapeutic mechanisms of the complexes against A549cisR cells. The Pt(ii) complexes could bind to and cleave DNA, while also inducing arrest of the cell cycle in S phase, leading to down-regulation of the levels of cyclin-dependent kinases and cyclin and up-regulation of the expression of p21. The selected complex, C3, changed the mitochondrial membrane potential and induced apoptosis. C3 also inhibited the expression of the c-myc gene and downstream proteins, thereby inhibiting telomerase activity.


Assuntos
Hidrazonas/síntese química , Hidrazonas/farmacologia , Platina/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Cristalografia por Raios X , DNA/metabolismo , Humanos , Concentração Inibidora 50 , Ligantes , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Telomerase/antagonistas & inibidores , Telomerase/metabolismo
16.
Eur J Med Chem ; 182: 111616, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425907

RESUMO

On the one hand, the multi-target agents have been promising for overcoming the deficiency of the single targeted anticancer metal agents, on the other hand, bismuth (Bi) complexes have shown significant antiproliferative activity and minimal side effects. Therefore, to develop the next-generation anticancer metal agents, we designed and synthesized four novel binuclear Bi(III) complexes by modifying the N-4 position of a series of 2-Acetyl-3-ethylpyrazine thiosemicarbazides, and then investigated their structure-activity relationships to human cancer cell lines, obtaining a lead Bi drug (C4) with significant antiproliferative activity to human bladder cancer cells (T24). C4 arrested the cell cycle in the S-phase by regulation of cyclin and cyclin-dependent kinases, and exerted a chemotherapeutic effect via multi-target mechanism including the activation of apoptotic and autophagic cell signaling pathways. Besides, C4 effectively inhibited metastasis of T24 cell. Our results suggested that C4 can be developed as a potential multi-target anticancer candidate.


Assuntos
Antineoplásicos/farmacologia , Bismuto/farmacologia , Complexos de Coordenação/farmacologia , Semicarbazidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bismuto/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Semicarbazidas/química , Relação Estrutura-Atividade
17.
Metallomics ; 11(8): 1372-1386, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267119

RESUMO

Herein, to develop a multi-target anticancer metal agent and achieve a "1 + 1 > 2" pharmaceutical effect, we rationally designed and synthesized five complexes (C1-C5) by synergistically exploiting the properties of Zn(ii) and a series of modified 2,6-diacetylpyridine bis(thiosemicarbazone) ligands. By investigating the structure-activity relationships, we found that the binuclear Zn(ii) complex (C5) acts against human bladder cancer cells (T-24) with significant cytotoxicity. We subsequently determined the multiple anticancer mechanisms of C5 to T-24 cells, including inhibiting the activity of topoisomerase I (Topo I), blocking the cell cycle in the S phase, and inducing apoptosis and autophagy in T-24 cells. Furthermore, C5 inhibited the migration of T-24 cells and showed a significant cytostatic effect in the T-24 3D spheroid model.


Assuntos
Antineoplásicos/farmacologia , Tiossemicarbazonas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Zinco/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Humanos , Modelos Moleculares , Tiossemicarbazonas/química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Zinco/química
18.
J Biol Chem ; 294(5): 1437-1450, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30498087

RESUMO

The inner centromere region of a mitotic chromosome critically regulates sister chromatid cohesion and kinetochore-microtubule attachments. However, the molecular mechanism underlying inner centromere assembly remains elusive. Here, using CRISPR/Cas9-based gene editing in HeLa cells, we disrupted the interaction of Shugoshin 1 (Sgo1) with histone H2A phosphorylated on Thr-120 (H2ApT120) to selectively release Sgo1 from mitotic centromeres. Interestingly, cells expressing the H2ApT120-binding defective mutant of Sgo1 have an elevated rate of chromosome missegregation accompanied by weakened centromeric cohesion and decreased centromere accumulation of the chromosomal passenger complex (CPC), an integral part of the inner centromere and a key player in the correction of erroneous kinetochore-microtubule attachments. When artificially tethered to centromeres, a Sgo1 mutant defective in binding protein phosphatase 2A (PP2A) is not able to support proper centromeric cohesion and CPC accumulation, indicating that the Sgo1-PP2A interaction is essential for the integrity of mitotic centromeres. We further provide evidence indicating that Sgo1 protects centromeric cohesin to create a binding site for the histone H3-associated protein kinase Haspin, which not only inhibits the cohesin release factor Wapl and thereby strengthens centromeric cohesion but also phosphorylates histone H3 at Thr-3 to position CPC at inner centromeres. Taken together, our findings reveal a positive feedback-based mechanism that ensures proper assembly of the functional inner centromere during mitosis. They further suggest a causal link between centromeric cohesion defects and chromosomal instability in cancer cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Centrômero/metabolismo , Retroalimentação Fisiológica , Histonas/metabolismo , Mitose , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Segregação de Cromossomos , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinetocoros/metabolismo , Microtúbulos/metabolismo , Fosforilação , Proteína Fosfatase 2/metabolismo , /metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30195183

RESUMO

Developing high performance fluorescent chemo-sensors for in vitro and in vivo Al3+ detection is highly desirable, because Al3+ accumulation has been involved to various diseases. Herein, we report a highly selective and sensitive Schiff base fluorescent probe, H3L, based on 2-hydroxynaphthalene, which can recognize aluminum ions and exhibit an "off-on" mode with high selectivity in methanol solutions. The detection limit of the probe for Al3+ is as low as 10-7 M which was determined by fluorescent titration. The high selectivity and high sensitivity of H3L for Al3+ are attributed to the inhibition of ESIPT. Additionally, the distribution of intracellular Al3+ ions could be observed under confocal fluorescence microscopy. Moreover, we also applied H3L for in vivo detection of Al3+ ions in living zebrafish larvae.


Assuntos
Alumínio/análise , Corantes Fluorescentes/química , Naftóis/química , Imagem Óptica/métodos , Bases de Schiff/química , Animais , Cátions/análise , Feminino , Fluorescência , Células HeLa , Humanos , Masculino , Microscopia de Fluorescência/métodos , Modelos Moleculares , Espectrometria de Fluorescência/métodos , Peixe-Zebra
20.
Eur J Med Chem ; 158: 442-452, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30241011

RESUMO

To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cobre/química , Cobre/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Desenho de Fármacos , Humanos , Ligantes , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Piridinas/química , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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