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1.
Adv Sci (Weinh) ; : e2200608, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508899

RESUMO

The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.

2.
Chem Commun (Camb) ; 58(39): 5837-5840, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35420089

RESUMO

Rh-catalyzed highly chemo- and enantioselective hydrogenation of chromone-2-carboxylic acids was successfully established for the first time, providing a wide range of enantiopure chromanone-2-carboxylic acids with excellent results (up to 97% yield and 99% ee) and high efficiency (up to 10 000 TON). The carboxylic group in the substrate was demonstrated to play a vital role and an enantio-induction mode was elucidated by DFT calculation. This hydrogenation protocol provided straightforward access to various bioactive chromanoids.

3.
Molecules ; 27(3)2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35164361

RESUMO

A family of novel efficient non-oxime compounds exhibited promising reactivation efficacy for VX and sarin inhibited human acetylcholinesterase was discovered. It was found that aromatic groups coupled to Mannich phenols and the introduction of imidazole to the ortho position of phenols would dramatically enhance reactivation efficiency. Moreover, the in vivo experiment was conducted, and the results demonstrated that Mannich phenol L10R1 (30 mg/kg, ip) could afford 100% 48 h survival for mice of 2*LD50 sarin exposure, which is promising for the development of non-oxime reactivators with central efficiency.


Assuntos
Acetilcolinesterase/metabolismo , Antídotos/farmacologia , Reativadores da Colinesterase/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Compostos de Piridínio/farmacologia , Sarina/toxicidade , Animais , Substâncias para a Guerra Química/toxicidade , Humanos , Camundongos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Oximas
4.
ACS Appl Mater Interfaces ; 14(3): 3675-3684, 2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35020346

RESUMO

Exploiting zeolitic imidazolate framework (ZIF)-based nanoparticles to synergistically enhance starvation-combined chemotherapy strategies remains an urgent demand. Herein, glucose oxidase (GOX) and doxorubicin (DOX) were facilely incorporated into ZIFs for starvation-combined chemotherapy. The as-prepared DOX/GOX-loaded ZIF (DGZ) exhibited uniform size with good dispersity, effective protection of the GOX activity, and stable delivery of the drugs into tumor. Correspondingly, it could achieve the glucose- and pH-responsive degradation and thus the controllable drug release. As a result, the acidification of glucose accompanied with reactive oxygen species (ROS) production was observed for the starvation-enhanced chemotherapy and the improved degradation. Most importantly, adjustable Zn2+ release was achieved with the biodegradation of DGZ, which thus contributed to an augmented therapeutic outcome via the Zn2+-induced mitochondrial dysfunction and antioxidation dyshomeostasis. These findings, synergized with the enhancement of starvation-combined chemotherapy by inhibiting the mitochondrial energy metabolism and boosting the ROS accumulation using pristine ZIF-based nanoparticles, provide a new insight into the metal-organic framework-based nanomedicine for further cancer treatments.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Materiais Biocompatíveis/farmacologia , Doxorrubicina/farmacologia , Estruturas Metalorgânicas/farmacologia , Neoplasias/tratamento farmacológico , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Doxorrubicina/química , Doxorrubicina/metabolismo , Glucose Oxidase/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Teste de Materiais , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias/metabolismo , Zeolitas/química , Zeolitas/metabolismo , Zeolitas/farmacologia
5.
J Cancer ; 12(14): 4240-4246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093824

RESUMO

Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.

6.
Eur J Med Chem ; 215: 113286, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33611189

RESUMO

Covalent drugs have been intensively studied in some very important fields such as anti-tumor and anti-virus, including the currently global-spread SARS-CoV-2. However, these drugs may interact with a variety of biological macromolecules and cause serious toxicology, so how to reactivate the inhibited targets seems to be imperative in the near future. Organophosphate was an extreme example, which could form a covalent bound easily with acetylcholinesterase and irreversibly inhibited the enzyme, causing high toxicology. Some nucleophilic oxime reactivators for organophosphate poisoned acetylcholinesterase had been developed, but the reactivation process was still less understanding. Herein, we proposed there should be a pre-reactivated pose during the reactivating process and compounds whose binding pose was easy to transfer to the pre-reactivated pose might be efficient reactivators. Then we refined the previous reactivators based on the molecular dynamic simulation results, the resulting compounds L7R3 and L7R5 were proven as much more efficient reactivators for organophosphate inhibited acetylcholinesterase than currently used oximes. This work might provide some insights for constructing reactivators of covalently inhibited targets by using computational methods.


Assuntos
Acetilcolinesterase/química , Reativadores da Colinesterase/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Reativadores da Colinesterase/metabolismo , Humanos , Cinética , Simulação de Dinâmica Molecular , Compostos Organofosforados/química , Estudo de Prova de Conceito , Ligação Proteica
7.
Org Lett ; 23(1): 140-144, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351639

RESUMO

An efficient enantioselective hydrogenation of sterically hindered cyclic imines catalyzed by the Ir-tBu-ax-Josiphos complex has been described, producing a series of useful chiral bulky tetrahydroisoquinoline analogs in high isolated yields (85-96%) with good to excellent enantioselectivities (74-99% ee). This transformation provided highly straightforward access to the useful derivatives of tetrahydroisoquinolines, which are of great potential value in drug molecule and natural product research.

8.
Org Lett ; 22(12): 4812-4816, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32519872

RESUMO

The highly chemo- and enantioselective hydrogenation of (E)-2-substituted-4-oxo-2-alkenoic acids was established for the first time using the Rh/JosiPhos complex, affording a series of chiral α-substituted-γ-keto acids with excellent results (up to 99% yield and >99% ee) and high efficiency (up to 3000 TON). In addition, the importance of this methodology was further demonstrated by a concise and gram-scale synthesis of the anti-inflammatory drug (R)-flobufen.

9.
Nat Commun ; 11(1): 243, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913267

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

10.
Nanoscale ; 12(2): 877-887, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31833519

RESUMO

Engineered exosomes have become popular drug delivery carriers for cancer treatment. This is partially due to the interesting property, i.e. exosome organotropism, which plays an important role in organ distribution post systemic administration. Here, we demonstrated that breast cancer (MDA-MB-231) cell-derived exosomes (231-Exo) could be specifically internalized by non-small cell lung cancer cells via a specific interaction between overexpressed integrin ß4 (on exosomes) and surfactant protein C (SPC) on the cancer cells. We showed that 231-Exo was capable of recognizing A549 cells in blood and effectively escaping from the immune surveillance system in vitro. Once loaded with microRNA molecules in the exosome carriers, the resulting, miRNA-126 loaded 231-Exo (miRNA-231-Exo) strongly suppressed A549 lung cancer cell proliferation and migration through the interruption of the PTEN/PI3K/AKT signaling pathway. Intravenous administration of the miRNA-126 laden exosomes led to an effective lung homing effect in mice. When tested in a lung metastasis model, miRNA-231-Exo resulted in an efficacious effect in inhibiting the formulation of lung metastasis in vivo. Collectively, our data demonstrated the possibility of using the organotropism feature of exosomes in exosome carrier design, generating a potent anti-metastasis effect in a mouse model.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Exossomos , Neoplasias Pulmonares/terapia , MicroRNAs/uso terapêutico , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Exossomos/metabolismo , Técnicas de Transferência de Genes , Humanos , Integrina beta4/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Neoplásicas Circulantes/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual
11.
RSC Adv ; 10(29): 16882-16885, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35496927

RESUMO

(S)-5-Methyl-tetrahydropyran-2-one 1 is a by-product in the production of key intermediates of steroidal hormones. Asymmetric synthesis of natural oxacyclododecindione-type macrolactones 2 and 3 has been realized for the first time from (S)-1 in seven and eight steps with 37% and 27% overall yield, respectively.

12.
Nat Commun ; 10(1): 5476, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792209

RESUMO

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi's sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.


Assuntos
Sangue/metabolismo , Exossomos/metabolismo , Intestino Delgado/metabolismo , Nanopartículas/metabolismo , Células A549 , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Análise Química do Sangue , Endocitose , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exossomos/química , Hepatócitos/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Dióxido de Silício/química , Dióxido de Silício/metabolismo
13.
Org Lett ; 21(21): 8641-8645, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603341

RESUMO

Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.

14.
J Exp Clin Cancer Res ; 38(1): 232, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151472

RESUMO

BACKGROUND: Sorafenib is approved as a standard therapy for advanced hepatocellular carcinoma (HCC), but its clinical application is limited due to moderate therapeutic efficacy and high incidence of acquired resistance resulted from elevated levels of SDF-1/CXCR4 axis induced by prolonged sorafenib treatment. We previously demonstrated metapristone (RU486 metabolite) as a cancer metastatic chemopreventive agent targeting SDF-1/CXCR4 axis. Therefore, we hypothesized that combining sorafenib with metapristone could synergistically suppress cell proliferation, enhance anti-cancer activity and repress potential drug resistance. METHODS: Changes in cellular CXCR4 expression by metapristone were analyzed by RT-PCR and western blotting. Effect of combining sorafenib with metapristone on cell viability was examined by MTT assay; combination index value was calculated to evaluate the synergistic effect of combined therapy. To overcome poor pharmacokinetics and reduce off-target toxicity, CXCR4-targeted nanoparticles (NPs) were developed to co-deliver sorafenib and metapristone into CXCR4-expressing HCC in vitro and in vivo; cell proliferation, colony formation and apoptosis assays were conducted; nude mice bearing HCC xenograft were used to examine effects of this therapeutic approach on HCC progression. RESULTS: Here we showed metapristone significantly reduced CXCR4 expression in HCC. Combinatory chemotherapy of sorafenib with metapristone synergistically suppressed HCC proliferation and resistance. CXCR4-targeted PEGylated poly (lactic-co-glycolic acid) NPs conjugated with LFC131 (a peptide inhibitor of CXCR4), could deliver more sorafenib and metapristone into HCC via specific recognition and binding with transmembrane CXCR4, and resulted in the enhanced cytotoxicity, colony inhibition and apoptosis by regulating more Akt/ERK/p38 MAPK/caspase signaling pathways. Co-delivery of sorafenib with metapristone by the LFC131-conjugated NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in a tumor xenograft model. CONCLUSIONS: In conclusion, co-delivery of sorafenib and metapristone via the CXCR4-targeted NPs displays a synergistic therapy against HCC. Our results suggest combinational treatment of chemotherapeutics offer an effective strategy for enhancing the therapeutic efficacy on carcinoma, and highlight the potential application of ligand-modified tumor-targeting nanocarriers in delivering drugs as a promising cancer therapeutic approach.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mifepristona/análogos & derivados , Nanopartículas , Poliésteres , Polietilenoglicóis , Receptores CXCR4/antagonistas & inibidores , Sorafenibe/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fenômenos Químicos , Composição de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Mifepristona/administração & dosagem , Mifepristona/farmacocinética , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Colloid Interface Sci ; 548: 131-144, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991180

RESUMO

The construction of multifunctional theranostic nanoplatforms to integrate accurate imaging and enhanced therapy to treat tumors is highly attractive but remains a challenge. Here, we developed a molybdenum disulfide (MoS2)-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving the targeted co-delivery of the gadolinium (Gd)-based contrast agents (CAs) and the anticancer drug gefitinib (Gef) for magnetic resonance imaging (MRI) and synergetic chemo-photothermal therapy of tumors. Gd3+ ions were coupled to HA-grafted MoS2 nanosheets with diethylenetriaminepentaacetic acid (DTPA) as a linker, followed by the incorporation of Gef. The resulting MoS2-HA-DTPA-Gd/Gef exhibited enhanced relaxivity, 3.3 times greater than that of the commercial CA DTPA-Gd, which facilitated the MRI in vivo. Moreover, the nanoplatform effectively converted the absorbed near-infrared (NIR) light into heat, which not only induced the photothermal ablation of cancer cells but also triggered the release of Gef from MoS2-HA-DTPA-Gd/Gef, enabling the synergetic chemo-photothermal therapy. The results of in vitro and in vivo experiments revealed that MoS2-HA-DTPA-Gd/Gef upon NIR irradiation effectively blocked the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway and activated apoptosis-related proteins to induce cell apoptosis and suppress cell proliferation, thus inhibiting the tumor growth in lung cancer cell-bearing mice. Taken together, this multifunctional theranostic nanoplatform has significant promise for the diagnosis and treatment of cancer.


Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Meios de Contraste/química , Liberação Controlada de Fármacos , Tratamento Farmacológico/métodos , Gadolínio/química , Gefitinibe/química , Gefitinibe/farmacologia , Humanos , Raios Infravermelhos , Imageamento por Ressonância Magnética/métodos , Camundongos , Tamanho da Partícula , Fototerapia/métodos , Transdução de Sinais , Propriedades de Superfície , Nanomedicina Teranóstica
16.
Bioorg Chem ; 81: 681-688, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30265992

RESUMO

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes' binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Desenho de Fármacos , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacologia , Agentes Neurotóxicos/toxicidade , Praguicidas/toxicidade , Ativadores de Enzimas/síntese química , Humanos , Simulação de Acoplamento Molecular , Sarina/toxicidade
17.
Biomaterials ; 145: 56-71, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28843733

RESUMO

Tumor hypoxia is a common feature of the tumor microenvironment and has been regarded as one of the key factors in driving the emergence of drug resistance in solid tumors. To surmount the hypoxia-associated drug resistance, we fabricated the novel multifunctional liposomal complexes (ACLEP) that could co-deliver oxygen and molecular targeted drug to overcome the hypoxia-induced drug resistance in lung cancer. The ACLEP were fabricated with liposomes anchored with anti-EGFR aptamer-conjugated chitosan to co-administrate erlotinib and PFOB to EGFR-overexpressing non-small-cell lung cancer. Our results showed that the ACLEP possessed desired physicochemistry, good biostability and controlled drug release. The entrapped PFOB in nanoparticle facilitated the uptake of ACLEP in either normoxia or hypoxic condition. Comparing to those nanoparticles loading erlotinib alone, our innovative oxygen/therapeutic co-delivery system showed a promising outcome in fighting against hypoxia-evoked erotinib resistance both in vitro and in vivo. Hence, this work presents a potent drug delivery platform to overcome hypoxia-induced chemotherapy resistance.


Assuntos
Aptâmeros de Nucleotídeos/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/uso terapêutico , Hipóxia/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oxigênio/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Humanos , Imuno-Histoquímica , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Nus , Modelos Biológicos , Oxigênio/administração & dosagem , Oxigênio/farmacologia , Distribuição Tecidual/efeitos dos fármacos
18.
Bioorg Med Chem ; 25(16): 4497-4505, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28684009

RESUMO

A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade
19.
AAPS J ; 19(3): 814-826, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28233244

RESUMO

Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target. We loaded erlotinib into Apt-Cs-anchored liposomal complexes (Apt-CL-E) and characterized the physicochemistry of Apt-CL-E. The nanoparticles showed good biostability and a binding specificity for EGFR-mutated cancer cells guided by the Apt. The specific binding facilitated the uptake of Apt-CL-E into EGFR-mutated cancer cells. A cytotoxicity study showed an advantage of Apt-CL-E over their nontargeted liposomal counterparts in delivering erlotinib to EGFR-mutated cancer cells, resulting in cell cycle arrest and apoptosis. These results provide a good platform for future in vivo animal studies with Apt-CL-E.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Cloridrato de Erlotinib/administração & dosagem , Lipossomos/química , Apoptose/efeitos dos fármacos , Aptâmeros de Nucleotídeos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
20.
Neuroreport ; 28(5): 259-267, 2017 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-28240721

RESUMO

Cucurbitacin IIa (CuIIa) is the major active component of the Helmseya amabilis root and is known to have antiviral and anti-inflammatory effects. In this study, we examined the antidepressant-like effects of CuIIa in a mouse model of chronic unpredictable mild stress (CUMS) and investigated the possible underlying mechanisms. To evaluate the antidepressant-like effects of CuIIa on depression-like behaviors, mice were subjected to the open-field test, the elevated plus-maze test, the forced-swimming test, and the tail-suspension test. We found that CuIIa treatment reversed the CUMS-induced behavioral abnormalities. Western blot analyses showed that CUMS significantly decreased brain-derived neurotrophic factor (BDNF) levels, cAMP-response element binding protein (CREB), and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, and N-methyl-D-aspartate receptor subtype GluN2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 expression in the amygdala; in addition, the expression of gamma-aminobutyric acid receptor A subunit α2 was upregulated in CUMS mice. These CUMS-induced changes were all normalized by CuIIa treatment and administration of the BDNF antagonist ANA-12 can block the antidepressant effect of CuIIa. Our findings suggest that the antidepressant-like effects of CuIIa may be exerted by regulation of the CaMKIIα-CREB-BDNF pathway and the balance between excitatory and inhibitory synaptic transmission in the amygdala.


Assuntos
Antidepressivos/uso terapêutico , Cucurbitacinas/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Estresse Psicológico/complicações , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Azepinas/uso terapêutico , Benzamidas/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Elevação dos Membros Posteriores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Psicológico/tratamento farmacológico , Natação/psicologia
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