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1.
Bioorg Chem ; 125: 105844, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35594720

RESUMO

A novel series of carbamate-based N-substituted tryptamine derivatives were designed and synthesized based on functional group combination strategy, and possessed both cholinesterase inhibition and neuroprotective effects. After systematically evaluating the cholinesterase inhibitory activity of 24 synthesized compounds, compound 6H6, bearing n-heptyl residue as carbamate moiety, was highlighted due to its great BChE-selective inhibition (eeAChE IC50 > 100 µM; eqBChE IC50 = 7 nM), neuronal protection, antioxidation and anti-neuroinflammation efficacy. Cytotoxicity and acute toxicity assays confirmed the safety-efficacy profiles of compound 6H6. Besides, pharmacokinetic properties and blood-brain barrier (BBB) permeability of compound 6H6 were favorable and suitable for further study in vivo. The behavioral tests revealed that compound 6H6 could remarkably improve the scop-induced ethological changes and memory impairment, suggesting compound 6H6, as an attractive pleiotropic molecule, had great promise in treating Alzheimer's disease.

2.
Bioorg Med Chem ; 60: 116705, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35286954

RESUMO

Isoquinoline alkaloid displays significant anti-gastric cancer effects due to its unique structure, which is attracting more and more attention for the development of anti-gastric cancer drugs. In this study, we explore the active components against gastric cancer from the Tibetan Medicine Corydalis hendersonii Hemsl, which is rich in isoquinoline alkaloids. 14 compounds including 2 previously undescribed natural products were obtained. Interestingly, an new active compound displays potent anti-gastric cancer activity. After accomplishing the total syntheses of the active compound and its derivatives, the anti-gastric cancer activity of the active compound was further investigated. In vitro experiments revealed that the active compound significantly attenuated the proliferative capacity, caused G2/M phase arrest, inhibited the cell migration and invasion, and induced cell apoptosis. Mechanistically, the active compound could increase the Bax/Bcl-2 ratio, elevate cytochrome c in the cytosol, and activate caspase-9/3, along with inactivating the upstream PI3K/Akt/mTOR signaling pathway. In addition, the active compound could also cause gastric cancer cell death by inhibiting topoisomerase I activity. More importantly, the anti-gastric cancer activity of the active compound was confirmed in MGC-803 xenograft nude mice in vivo. This work not only promotes the exploitation of Corydalis hendersonii Hemsl., but also provides some experience for discovering new entities from natural sources.


Assuntos
Alcaloides , Corydalis , Neoplasias Gástricas , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Apoptose , Corydalis/química , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
3.
Int J Mol Sci ; 23(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35055057

RESUMO

Exosomes derived from tumor cells contain various molecular components, such as proteins, RNA, DNA, lipids, and carbohydrates. These components play a crucial role in all stages of tumorigenesis and development. Moreover, they reflect the physiological and pathological status of parental tumor cells. Recently, tumor-derived exosomes have become popular biomarkers for non-invasive liquid biopsy and the diagnosis of numerous cancers. The interdisciplinary significance of exosomes research has also attracted growing enthusiasm. However, the intrinsic nature of tumor-derived exosomes requires advanced methods to detect and evaluate the complex biofluid. This review analyzes the relationship between exosomes and tumors. It also summarizes the exosomal biological origin, composition, and application of molecular markers in clinical cancer diagnosis. Remarkably, this paper constitutes a comprehensive summary of the innovative research on numerous detection strategies for tumor-derived exosomes with the intent of providing a theoretical basis and reference for early diagnosis and clinical treatment of cancer.


Assuntos
Biomarcadores Tumorais , Exossomos/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Suscetibilidade a Doenças , Detecção Precoce de Câncer/métodos , Humanos , Biópsia Líquida/métodos , Técnicas de Diagnóstico Molecular , Neoplasias/etiologia , Proteínas Oncogênicas , Técnica de Seleção de Aptâmeros , Análise Espectral Raman/métodos
4.
Eur J Med Chem ; 228: 113960, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34774339

RESUMO

Gastric cancer represents a significant health burden worldwide. Previously, inspired by the traditional Chinese medicine Wu-Chu-Yu to treat the spleen and stomach system for thousands of years, we identified N14-phenyl substituted evodiamine derivatives as potential antitumor agents with favorable inhibition on Top1. Herein, structural optimization and structure-activity relationship studies (SARs) led us to discovering a highly active evodiamine derivative compound 6t against gastric cancer. Further anti-tumor mechanism studies revealed that compound 6t played as the inhibition of topoisomerase 1 (Top1), effectively induced apoptosis, obviously arrested the cell cycle at the G2/M phase, and significantly inhibited the migration and invasion of SGC-7901 and MGC-803 cell lines in a dose-dependent manner. Moreover, the compound 6t was low toxicity in vivo and exhibited excellent anti-tumor activity (TGI = 70.12%) in the MGC-803 xenograft models. In summary, compound 6t represents a promising candidate as a potential chemotherapeutic agent against gastric cancer.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 228: 113985, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34802836

RESUMO

This article describes the syntheses and biological activity of five 3-arylisoquinoline natural products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC50 = 9.82 µM on Huh7 cells and 6.83 µM on LM9 cells), and arrest cell cycle at G2/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of cancer cells by inhibiting the expression of MMP-9, and induce apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver cancer.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Isoquinolinas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Neoplasias Hepáticas/patologia , Estrutura Molecular , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 227: 113888, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34628244

RESUMO

Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 µM against HGC-27 cell) and T9 (IC50 = 1.84 µM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Eur J Med Chem ; 227: 113908, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656900

RESUMO

Highly efficacious and tolerable agents for the treatment of glioblastoma (GBM), the most common and aggressive primary brain tumor, are urgently needed. Herein, we reveal the design, synthesis and biological evaluation of several piperazine based benzamide derivatives, which are based on the non-classical isostere principle and combination principle for GBM therapy. After structure-activity relationship (SAR) study, compound L19 was demonstrated as the most promising compound with IC50 values of 0.15 µM, 0.29 µM, 1.25 µM against GBM C6, U87-MG, U251 cells, respectively. Moreover, compound L19 could inhibit the proliferation, migration and invasion, as well as induce apoptosis and cell cycle arrest of GBM cell lines in vitro. From mechanism perspective, compound L19 could regulate the cell cycle-related proteins and influence the p16INK4a-CDK4/6-pRb pathway by western blotting experiment. What is worth mentioning is that compound L19 could penetrate the blood-brain barrier (BBB) with an exceptional brain-to-plasma ratio of 1.07 in vivo. Besides, the superior anti-glioblastoma potency in vivo of compound L19 was identified on U87-MG-xenograft model without any apparent host toxicity. Overall, the potential of compound L19 warrants further pre-clinical investigation for GBM therapy.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Piperazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Eur J Med Chem ; 229: 114044, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34923430

RESUMO

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aß1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.


Assuntos
Carbamatos/química , Desenho de Fármacos , Fármacos Neuroprotetores/síntese química , Triptaminas/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Carbamatos/metabolismo , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Agregados Proteicos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 226: 113817, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34537445

RESUMO

Glioblastoma is one of the most lethal brain tumors. The crucial chemotherapy is mainly alkylating agents with modest clinical success. Given this desperate need and inspired by the encouraging results of a phase II trial via concomitant Topo I inhibitor plus COX-2 inhibitor, we designed a series of N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents based on structure modification on 1,5-naphthyridine derivatives (Topo I inhibitors). Notably, the target compounds I-1 (33.61 ± 1.15 µM) and I-8 (45.01 ± 2.37 µM) were confirmed to inhibit COX-2, while a previous reported compound (1,5-naphthyridine derivative) resulted nearly inactive towards COX-2 (IC50 > 150 µM). Besides, I-1 and I-8 exhibited higher anti-proliferation, anti-migration, anti-invasion effects than the parent compound 1,5-naphthyridine derivative, suggesting the success of modification based on the parent. Moreover, I-1 obviously repressed tumor growth in the C6 glioma orthotopic model (TGI = 66.7%) and U87MG xenograft model (TGI = 69.4%). Besides, I-1 downregulated PGE2, VEGF, MMP-9, and STAT3 activation, upregulated E-cadherin in the orthotopic model. More importantly, I-1 showed higher safety than temozolomide and different mechanism from temozolomide in the C6 glioma orthotopic model. All the evidence demonstrated that N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents could be promising for the glioma management.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais Cultivadas
10.
Bioorg Chem ; 115: 105255, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34435574

RESUMO

Alzheimer's disease (AD) has become a serious threat to the developed nations with burgeoning patients and annual costs on health care system in modern society. Neuroinflammation, as one of the specific biochemical factors in the progress of neurodegeneration diseases, performs a crucial role in the pathogenesis and development of AD. Therefore, it is of great significance to develop effective anti-neuroinflammatory strategies for the treatment of AD. N-salicyloyl tryptamine derivatives were previously reported and demonstrated that possessed great potential anti-neuroinflammatory effects and favorable blood-brain barrier (BBB) permeation. Herein, a series of novel N-salicyloyl tryptamine derivatives were synthesized and their anti-AD potential was evaluated both in vitro and in vivo. Among them, L7 performed well anti-neuroinflammatory effects and excellent neuroprotective effects, as well as little toxicity. To lucubrate its potential for the treatment of AD, behavior tests including morris water maze (MWM), eight-arm radial maze, open field test and novel object recognition (NOR) test were carried out and the results showed that L7 could remarkably improve Aß-induced cognitive impairment. Moreover, the mechanism of action of L7 on improving Aß-induced AD was preliminarily investigated, and the results uncovered that the neuroprotective effects of L7 was might exerte via intervening Aß-induced pyroptosis through NLRP3-caspase-1-GSDMD axis and ameliorating neuronal apoptosis by mitochondrial apoptosis pathway. Besides, the distribution of Aß plaques in brain tissues were detected by immunohistochemical (IHC) assay and the results indicated that L7 could significantly attenuate the deposition of Aß plaques in the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Triptaminas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química
11.
Bioorg Chem ; 114: 105154, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34378540

RESUMO

Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-κB, TGF-ß/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G2/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
J Cancer ; 12(16): 5035-5045, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234872

RESUMO

Exosomes carry genetic information originating from their parental cells, raising their possibility as novel noninvasive biomarkers for cancer. Tumor-derived exosomes (TEXs) have a variety of endogenous cargos that reflect the pathophysiology status and information of tumor cells. TEXs are increasingly being recognized as potential biomarkers for cancer diagnosis prognosis, and monitoring. It is important to develop a variety of sensitive methods, including probes and biomaterials to isolate exosomes. A variety of approaches for detecting exosomes have been established. By combining exosome DNA and RNA sequencing tools, exosome proteomics analysis and immunoassay technology, it is expected that exosomes will gain widespread use in the diagnosis and treatment of cancer.

13.
Int J Biol Sci ; 17(10): 2476-2486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326688

RESUMO

Extracellular vesicles (EVs), are membrane-bound vesicles that have many advantages over traditional nanocarriers for drug and gene delivery. Evidence from recent studies indicate that EVs have therapeutic capability with chemical or biological modification. Tumor-derived exosomes (TEXs) were used as a new type of antigens or tumor vaccines in anti-tumor immunotherapy. With superior characteristics, modified EVs were applied to loaded and delivered synthetic drugs, silencing RNA, and microRNA for treatment. Different surface functionalization strategies have been proposed to improve the therapeutic functions of EVs. Appropriately modified EVs for disease intervention provide new avenues for effective clinical treatment strategies. Therefore, this review aimed at elucidating the therapeutic functions of EVs to generate new ideas for treatment and to unlock their hidden potential in translational medicine.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Exossomos/química , Vesículas Extracelulares/química , Neoplasias/terapia , Antineoplásicos/química , Vacinas Anticâncer/química , Vacinas Anticâncer/uso terapêutico , Terapia Genética/métodos , Humanos
14.
Eur J Med Chem ; 222: 113564, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091208

RESUMO

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Glioma/tratamento farmacológico , Triptaminas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/metabolismo , Glioma/patologia , Humanos , Estrutura Molecular , Ratos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Células Tumorais Cultivadas
15.
Artigo em Inglês | MEDLINE | ID: mdl-34149863

RESUMO

This study aims to analyze the targets of the effective active ingredients of Scutellariae radix-Coptidis rhizoma drug pair (SCDP) in ulcerative colitis (UC) by network pharmacology and molecular docking and to explore the associated therapeutic mechanism. The effective active ingredients and targets of SCDP were determined from the TCMSP database, and the drug ingredient-target network was constructed using the Cytoscape software. The disease targets related to UC were searched in GeneCards, DisGeNET, OMIM, and DrugBank databases. Then, the drug ingredient and disease targets were intersected to construct a protein-protein interaction network through the STRING database. The Metascape database was used for the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the predicted targets of SCDP for UC. The Autodock software was used for molecular docking between the main active ingredient and the core target to evaluate the binding ability. SCDP has 43 effective active ingredients and 134 intersection targets. Core targets included AKT1, TP53, IL-6, VEGFA, CASP3, JUN, TNF, MYC, EGFR, and PTGS2. GO functional enrichment analysis showed that biological process was mainly associated with a cytokine-mediated signaling pathway, response to an inorganic substance, response to a toxic substance, response to lipopolysaccharide, reactive oxygen species metabolic process, positive regulation of cell death, apoptotic signaling pathway, and response to wounding. KEGG enrichment analysis showed main pathway concentrations were related to pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, bladder cancer, IL-17 signaling pathway, apoptosis, p53 signaling pathway, and PI3K-Akt signaling pathway. The drug active ingredient-core target-key pathway network contains 41 nodes and 108 edges, of which quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol are important active ingredients; PTGS2, CASP3, TP53, IL-6, TNF, and AKT1 are important targets; and the pathways involved in UC treatment include pathways in cancer, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic, apoptosis, IL-17 signaling pathway and herpes simplex infection. The active ingredient has a good binding capacity to the core target. SCDP key active ingredients are mainly quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol, which function mainly by regulating targets, such as PTGS2, CASP3, TP53, IL-6, TNF, and AKT1, and are associated with multiple signaling pathways as pathways in cancer, PI3K-Akt signaling pathway, apoptosis, IL-17 signaling pathways.

16.
PLoS One ; 16(3): e0247521, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33667249

RESUMO

A tropical storm (TS) Roanu occurred in northern Sri Lanka in 2016, which transported northwards along the west coast of the Bay of Bengal (BoB). During the development of the TS, ocean eddies on its track had an important effect on the intensity of Roanu. The dynamic mechanism was investigated with multisource reanalysis and Argo float data in this study. The results show that ocean eddies were the main reason why Roanu first enhanced, weakened, and then enhanced again. Warm eddy W1 supports the initial development of the TS, cold eddy C1 weakens Roanu, and warm eddy W2 continues to support Roanu. On May 19, 2016, the maximum average latent heat flux over W1 was 260.85 w/m2, while that of C1 was only 200.71 w/m2. After the passage of Roanu, the tropical cyclone heat potential (TCHP) of eddies significantly decreased. The TCHP of W1, W2, C1 and C2 decreased by 20.95 kJ/cm2, 11.07 kJ/cm2, 29.82 kJ/cm2, 9.31 kJ/cm2, respectively. The mixed layer of warm eddies deepened much more than that of cold eddies, supporting Roanu development. In addition, changes in potential vorticity (PV) values caused by the disturbance of eddies may also reflect changes in the TS intensity. This study offers new insights on the influence of ocean eddies in regulating the development of tropical cyclone (TC) in the BoB.


Assuntos
Baías , Tempestades Ciclônicas , Temperatura Alta , Movimentos da Água , Estações do Ano , Água do Mar , Sri Lanka , Vento
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(1): 105-108, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33565411

RESUMO

OBJECTIVE: To explore the predictive value of MB isoenzyme of creatine kinase (CK-MB) and poisoning severity score (PSS) in the clinical prognosis of patients with wasp sting. METHODS: A retrospective study was conducted. The clinical data of patients who were stung by wasps admitted to emergency department of the First Affiliated Hospital of Henan University of Science and Technology from July 2017 to November 2019 were collected. The 24-hour acute physiology and chronic health evaluation II (APACHE II), CK-MB and PSS scores of the patients were collected after admission, and 28-day outcome was recorded. Spearman correlation analysis method was used to analyze the correlation between CK-MB and PSS score. Logistic regression model was used to construct joint predictors, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of various indicators for 28-day prognosis of patients with wasp stings. RESULTS: Finally 90 patients were included in the analysis. There were 67 patients survived at 28 days, and 23 dead with the 28-day mortality of 25.6%. APACHE II score, CK-MB and PSS score in the death group were significantly higher than those in the survival group [APACHE II score: 19.7±2.7 vs. 13.7±2.3, CK-MB (U/L): 183 (151, 243) vs. 36 (21, 75), PSS score: 17.7±2.6 vs. 9.3±4.5, all P < 0.01]. The correlation analysis showed that CK-MB and PSS score were positively correlated (r = 0.843, P < 0.01). Logistic regression model fitted CK-MB and PSS score, and Hosmer-Lemeshow test showed that the model fitted well. ROC curve analysis showed that the area under ROC curve (AUC) of CK-MB for predicting 28-day outcome was 0.957, the sensitivity was 91.3%, and the specificity was 88.1%; the AUC of PSS score was 0.908, the sensitivity was 91.3%, and the specificity was 90.8%. The AUC of CK-MB combined with PSS score was 0.964, the sensitivity was 100%, and the specificity was 79.4%, indicating that CK-MB combined with PSS score had higher predictive value and higher sensitivity for 28-day prognosis of patients with wasp sting. CONCLUSIONS: High CK-MB level and high PSS score in early stage of wasp sting injury indicate poor prognosis. Both CK-MB and PSS score can be used as predictors for predicting the prognosis of patients with wasp stings. In addition, CK-MB combined with PSS score have greater predictive value.


Assuntos
Mordeduras e Picadas , Sepse , Vespas , Animais , Creatina Quinase , Humanos , Isoenzimas , Prognóstico , Curva ROC , Estudos Retrospectivos
18.
Ann Transl Med ; 9(1): 31, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33553324

RESUMO

BACKGROUND: There is a heated debate on whether or not a late-stage cancer patient with bone metastasis should receive primary surgery. The aim was to assess whether primary tumor surgery in cancer patients with bone metastasis was associated with improved survival. METHODS: Cancer patients with bone metastasis were identified in the Surveillance, Epidemiology, and End Results database between 2010 and 2016. Overall survival and cancer-specific survival were compared between patients with and without primary tumor surgery using risk-adjusted Cox proportional hazard regression models and stratified propensity score methods. Further nomograms were constructed to predict personalized survival. RESULTS: Overall, 22,631 cancer patients with synchronous bone metastasis were identified and the surgery rates were 33.3%, 76.3%, 42.0% and 2.0% for breast, bladder, renal and lung cancer, respectively. In Cox regression analysis after propensity score matching, primary cancer surgery was associated with a significantly improved overall survival for breast [hazard ratio (HR) =0.56], bladder (HR =0.69), lung (HR =0.61) and renal carcinoma (HR =0.37), while the prolonged median survival time was 20 months, 3 months, 4months and 21 months, respectively. Nomograms were constructed based on predictive factors, showing good consistency between the actual and predicted outcomes (C-index between 0.697 to 0.750) and feasibility in clinical practice. CONCLUSIONS: This population-based cohort of cancer patients with bone metastasis supports primary tumor surgery as a significant protective factor for cancer patients with bone metastasis, and nomograms hold promise in assisting individualized risk stratification and accurate therapeutic strategy making.

19.
Huan Jing Ke Xue ; 42(1): 305-314, 2021 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-33372482

RESUMO

In this study, sediment incubation experiments were carried out to investigate the efficiency and mechanism of the control of phosphorus (P) release from sediments. The results showed that under anoxic conditions, P could be released from the sediment into the pore water first and then the dissolved P in the pore water could be transported into the overlying water, leading to high concentrations of soluble reactive P (SRP) and diffusive gradient in thin-films (DGT)-labile P in the overlying water. However, the combined use of calcium nitrate (CN) addition and zirconium-modified bentonite (ZB) capping could effectively control the release of P from sediment, resulting in the low concentrations of SRP and DGT-labile P in the overlying water. Furthermore, the combined use of CN addition and ZB capping could significantly decrease the concentrations of SRP and DGT-labile P in the sediment. In addition, the combined utilization of CN addition and ZB capping also could result in a reduction of redox sensitive P (BD-P) in the uppermost sediment layer. The reduction of pore water SRP, DGT-labile P, and BD-P in sediment solids is of great importance to the control of sediment-P liberation by the combined use of CN addition and ZB capping. The reduction efficiency of overlying water SRP by combined CN addition/ZB capping technology was higher than that of single CN addition technology. Compared to that of single CN addition technology, the reduction efficiencies of pore water SRP, SRP diffusion flux across the sediment/overlying water interface (SWI), and BD-P in the sediment by the combined use of CN addition and ZB capping were also higher. The combined technology based on CN addition and ZB capping had a higher reduction efficiency of overlying water SRP during the late stage of sediment remediation than the single technology based on ZB capping, and the former had higher reduction efficiencies of pore water SRP, DGT-labile P, and SRP diffusion flux across the SWI and apparent P diffusion flux through the SWI than the latter. The results of this work indicate that the combined use of CN addition and ZB capping is a very promising method for the control of P release from sediments.

20.
Bioorg Med Chem ; 55: 116595, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34990980

RESUMO

Natural products are important sources for the development of therapeutic medicine, among which evodia fruit has a wide range of medicinal properties in traditional Chinese medicine. Evodiamine, the main active component of evodia fruit, has various anti-cancer effects and has been proved to be a Topo inhibitor. From our previous attempts of modifying evodiamine, we found that the N14 phenyl substituted derivatives had showed great anti-tumor activity, which prompted us to further explore the novel structures and activities of these compounds. Compound 6f, as a N14 3-fluorinated phenyl substituted evodiamine derivative, showed a certain inhibitory activity against Topo I at 200 µM. By studying its anti-tumor effects in vitro, compound 6f could inhibit proliferation and induce apoptosis, as well as arrest the cell cycle of HGC-27 and HT-29 cell lines at G2/M phase in a concentration-dependent manner. Moreover, compound 6f could inhibit the migration and invasion of HGC-27 cell lines. Meanwhile, compound 6f could induce apoptosis of HGC-27 cells by inhibiting PI3K/AKT pathway. Overall, this work demonstrated that the N14 phenyl-substituted evodiamine derivatives had a good inhibitory effect on tumor cells in vitro, providing a promising strategy for developing potential anticancer agents for the treatment of gastrointestinal tumors.

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