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1.
J Neurosci Methods ; 328: 108441, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574288

RESUMO

BACKGROUND: Recombinant adeno-associated virus (rAAV) is increasingly applied in neuroscience research or gene therapy. However, there is no simple and efficient tool for specific transfection of rAAV into cerebrovascular tissues. It has been reported that fluorescent tracers or beta-amyloid protein can enter the brain through perivascular spaces, named as "glymphatic system". The purpose of this study was to explore whether rAAV could transduce the cerebral vasculature through the glymphatic pathway. NEW METHOD: An AAV1-GFP vector suspension (15 µL) was injected into the intracisternal space of anesthetized mice (n = 2) and 5 µl was injected into the bulbus medullae (n = 2). As controls, 15 µl of artificial cerebrospinal fluid (aCSF) was injected into the cisterna magna. The endothelial specific transduction was verified by Glut1 or PDGFRß immunofluorescent staining. Immunofluorescence images for all groups were captured with a laser microscope. RESULTS: It was observed that infection with rAAV1 vectors encoding green fluorescence protein resulted in a successful cerebrovascular transduction when injected into cisterna magna, compared to aCSF or intra-parenchymal injection at 30 days post-transduction in adult mice. In addition, GFP was co-localized with Glut1 based on immuno-fluorescence. These results indicate that glymphatic system delivery enhances the transduction efficiency of AAV1 to brain endothelial cells. COMPARISON WITH EXISTING METHODS: The AAV1 vector can simply and efficiently transduce the cerebral endothelial cells through the glymphatic pathway. CONCLUSION: The findings of this study reveal that rAAV1-based vectors have high application potential for endothelial-targeted neurologic disease research or gene-based therapies.

3.
Int J Oncol ; 55(2): 488-498, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268159

RESUMO

Fascin­1 is an actin­bundling protein, which specifically interacts with F­actin to form parallel actin bundles, and participates in the regulation of cell adhesion, interactions and migration. However, the expression and regulatory mechanisms of fascin­1 in hypopharyngeal squamous cell carcinoma (HSCC) remain poorly understood. The present study investigated the effects and underlying molecular mechanism of fascin­1 on the invasion and metastasis of HSCC. The results demonstrated that fascin­1 was overexpressed and correlated with lymph node metastasis and tumor­node­metastasis stage in HSCC tissues. Further in vitro study revealed that fascin­1 promoted cell morphology polarization to increase the motility of FaDu cells. In addition, fascin­1 significantly promoted the migration and invasion of FaDu cells. At the molecular level, fascin­1 promoted cell invasion and migration by upregulating matrix metalloproteinase­2 (MMP­2) expression in FaDu cells. Immunohistochemical analysis revealed that a correlation existed between hypoxia inducible factor (HIF)­1α and fascin­1 expression in the HSCC tissues. Furthermore, the results from a cobalt chloride­induced hypoxia model demonstrated that fascin­1 may be upregulated by HIF­1α in FaDu cells. Further analysis revealed that fascin­1 knockdown significantly decreased the invasion of cells under hypoxia and partially reversed hypoxia­induced MMP­2 expression under hypoxia in FaDu cells. In conclusion, fascin­1 was upregulated by HIF­1α, and promoted the invasion and migration of HSCC cells; therefore, fascin­1 may provide a potential target for the treatment of invasion and metastasis in HSCC.

5.
Circ Res ; 125(3): 343-355, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31185811

RESUMO

RATIONALE: The developing heart is composed of cardiomyocytes and noncardiomyocytes since the early stage. It is generally believed that noncardiomyocytes including the cardiac progenitors contribute to new cardiomyocytes of the looping heart. However, it remains unclear what the cellular dynamics of nonmyocyte to cardiomyocyte conversion are and when the lineage segregation occurs during development. It also remains unknown whether nonmyocyte to cardiomyocyte conversion contributes to neonatal heart regeneration. OBJECTIVE: We quantify the lineage conversion of noncardiomyocytes to cardiomyocytes in the embryonic and neonatal hearts and determine when the 2 cell lineages segregate during heart development. Moreover, we directly test if nonmyocyte to cardiomyocyte conversion contributes to neonatal heart regeneration. METHODS AND RESULTS: We generated a dual genetic lineage tracing strategy in which cardiomyocytes and noncardiomyocytes of the developing heart could be simultaneously labeled by 2 orthogonal recombination systems. Genetic fate mapping showed that nonmyocyte to cardiomyocyte conversion peaks at E8.0 (embryonic day) to E8.5 and gradually declines at E9.5 and E10.5. Noncardiomyocytes do not generate any cardiomyocyte at and beyond E11.5 to E12.5. In the neonatal heart, noncardiomyocytes also do not contribute to any new cardiomyocyte in homeostasis or after injury. CONCLUSIONS: Noncardiomyocytes contribute to new cardiomyocytes of the developing heart at early embryonic stage before E11.5. The noncardiomyocyte and cardiomyocyte lineage segregation occurs between E10.5 and E11.5, which is maintained afterward even during neonatal heart regeneration.

6.
Biomed Pharmacother ; 114: 108831, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986623

RESUMO

USP13 is emerging as a potential target in cancer therapy. However, the effect of USP13 on tumor progression is controversial. Here we focused on non-small cell lung cancer (NSCLC), a common cancer with high mortality, and studied the role of USP13 in tumor growth. By analysis of multi-level genetic database, we found USP13 is high expressed in heart among healthy primary tissues and is most amplified in lung cancer. Clinical samples of NSCLC showed tumor exhibited high USP13 level compared with adjacent normal tissues. We further utilized lung adenocarcinoma A549 and squamous carcinoma H226 cells as cell model and investigated USP13 effect by USP13 knockdown. As a results, downregulation of USP13 dramatically inhibited A549 and H226 cell proliferation by AKT/MAPK signaling and suppressed tumor growth in nude mice. Collectively, we identified USP13 as a tumor promoter in NSCLC and provide a promising target in cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Endopeptidases/genética , Neoplasias Pulmonares/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Mol Psychiatry ; 24(10): 1461-1477, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30886335

RESUMO

Anxiety disorders are the most prevalent psychiatric disorders, but their pathogenic mechanism remains poorly understood. Here, we report that transmembrane protein 74 (TMEM74), which contains two putative transmembrane domains and exhibits high levels of mRNA in the brain, is closely associated with the pathogenesis of anxiety disorders. TMEM74 was decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus (BLA) in chronic stress mice. Furthermore, genetic deletion of Tmem74 or selective knockdown of Tmem74 in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current (Ih) and greater input resistance and excitability in Tmem74-/- neurons than in wild-type neurons. Accordingly, surface expression of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels was also lower in the BLA of Tmem74-/- mice. The Ih current blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not in Tmem74-/- mice. Consistent with the improvement in anxiety-like behaviors, Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA of Tmem74-/- and chronic stress mice. Mechanistically, we demonstrate that interactions between Tmem74 and HCN1 are physiologically relevant and that transmembrane domain 1 (TM1) is essential for the cellular membrane localization of Tmem74 to enhance Ih. Together, our findings suggest that Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and is a potential target for new treatments of anxiety disorders.

8.
Stem Cell Reports ; 12(3): 624-638, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30773487

RESUMO

Elucidation of the role of different cell lineages in the liver could offer avenues to drive liver regeneration. Previous studies showed that SOX9+ hepatocytes can differentiate into ductal cells after liver injuries. It is unclear whether SOX9+ hepatocytes are uni- or bipotent progenitors at a single-cell level during liver injury. Here, we developed a genetic tracing system to delineate the lineage potential of SOX9+ hepatocytes during liver homeostasis and regeneration. Fate-mapping data showed that these SOX9+ hepatocytes respond specifically to different liver injuries, with some contributing to a substantial number of ductal cells. Clonal analysis demonstrated that a single SOX9+ hepatocyte gives rise to both hepatocytes and ductal cells after liver injury. This study provides direct evidence that SOX9+ hepatocytes can serve as bipotent progenitors after liver injury, producing both hepatocytes and ductal cells for liver repair and regeneration.

9.
PLoS One ; 14(2): e0212574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785930

RESUMO

Diabetic peripheral neuropathy (DPN), the most common chronic complication of diabetes, has become an important public health crisis worldwide. Given that DPN is extremely difficult to treat, determining its risk factors and controlling it at an early stage is critical to preventing its serious consequences and the burden of social disease. Current studies suggest that the risk factors for diabetic peripheral neuropathy are the duration of diabetes, age, glycosylated hemoglobin A1c (HbA1c), diabetic retinopathy (DR), smoking, and body mass Index (BMI). However, most of the aforementioned studies are cross-sectional, and the sample sizes are very limited, so the strength of causal reasoning is relatively low. The current study systematically evaluated DPN's influencing factors in patients with type 2 diabetes using evidence-based medicine. Overall, 16 included studies (14 cross-sectional studies and 2 case-control studies including 12,116 cases) that conformed to the present criteria were included in the final analysis. The results suggested that the duration of diabetes (MD 2.5, 95% CI 1.71~3.29), age (MD 4.00, 95% CI 3.05~4.95), HbA1c (MD 0.48, 95% CI 0.33~0.64), and DR (OR 2.34, 95% CI 1.74~3.16) are associated with significantly increased risks of DPN among diabetic patients, while BMI, smoking, total triglyceride (TG), and total cholesterol (TC) did not indicate any risks of increasing DPN. The findings provide a scientific basis for a further understanding of the causes of type 2 diabetes complicated with peripheral neuropathy and the improvement of preventive strategies. The next step is to conduct further high-quality prospective cohort studies to validate this paper's findings.

10.
Onco Targets Ther ; 11: 7395-7405, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425527

RESUMO

Objective: Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in head and neck. Notch1 has been validated to play prominent roles in the occurrence and development of various types of cancer. The aim of this study was to explore the function and underlying mechanism of Notch1 in HSCC. Patients and methods: Seventy-one cancer tissue samples and adjacent noncancerous formalin-fixed paraffin embedded tissue specimens were analyzed by immunohistochemistry. As Notch1 is overexpressed in HSCC, we further questioned whether there was a relationship between Notch1 and the clinicopathological characteristics. After confirming the successful knockdown of Notch1 by siRNA, the migration and invasion after gene knockdown were investigated by Transwell chambers. We then tried to identify YBX1 and EGFR expression using real-time PCR (RT-PCR) and Western blot analyses. To further determine whether the downexpression of EGFR was caused by YBX1 and the overexpression of YBX1 was caused by gene amplification, the expression of EGFR was detected by RT-PCR and Western blot assays. Results: We found that the expression of Notch1 and EGFR in HSCC tissues was upregulated compared with those in the adjacent noncancerous tissues. Further clinicopathological characteristics analysis revealed that the expression of Notch1 was positively correlated with distant metastasis (P=0.003) and tumor differentiation (P=0.031). The high expression of Notch1 is an independent prognostic factor for a poor overall survival in patients with HSCC (P=0.015, χ 2=10.403). Knocking down of Notch1 significantly inhibits the migration and invasion of FaDu cells in vitro. Mechanistic investigation reveals that Notch1 knockdown is found suppressing the expression of EGFR at transcriptional level. Interestingly, we further found that Notch1 knockdown also decreased the expression of YBX1, which is a transcription factor of EGFR. Moreover, the upregulation of YBX1 reverses the suppression of Notch1 on EGFR. Furthermore, forced overexpression of YBX1 induced the invasion of FaDu cells. Conclusion: Taken together, we found a positively cross-linked role of Notch1 signaling in the outcome of HSCC, providing a novel valuable prognostic marker and potential therapeutic target for the treatment of HSCC patients. Notch1 is a core signaling molecule for regulating migration and invasion via interplaying with EGFR in HSCC cells.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30361788

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of Chinese medicine in the treatment of adenoid hypertrophy in children. METHOD: Screening standard articles, extracting relevant data from meta-analysis, were analyzed by Revman5.1 software, by searching PubMed, Medline, VIP, Wan Fang and Chinese HowNet database 2006-2016 in traditional Chinese medicine treatment of children with adenoid literature. RESULTS: 206 articles met the inclusion criteria, of which ten were selected and included in the meta-analysis, and there were 803 patients. The results showed that the remission rate of the Chinese medicine treatment group was better than that of the Western medicine group. The combined effect of the amount of OR 2.06, 95% Cl (1.45, 2.96) and the combined effect of the amount of the test Z = 4.12, P < 0.00001 showed the recurrence of the disease was lower in traditional Chinese medicine treatment group than the Western medicine group. The combined effect of the amount of OR 3.05, 95% Cl (2.11, 4.56) and the combined effect of the amount of the test Z = 5.86, P < 0.00001 showed the total effective rate is high in the traditional Chinese medicine treatment group than the Western medicine group. The difference between the combined effect of the amount of OR 2.79, 95% Cl (1.78, 5.03) and the combined effect of the amount of the test of Z = 4.54, P < 0.00001 was statistically significant, which showed the treatment effect of Chinese medicine group is obviously better than the Western medicine group. CONCLUSION: The use of Chinese medicine for the treatment of children with adenoid hypertrophy has good clinical efficacy.

12.
Development ; 145(18)2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30111655

RESUMO

In vivo genomic engineering is instrumental for studying developmental biology and regenerative medicine. Development of novel systems with more site-specific recombinases (SSRs) that complement with the commonly used Cre-loxP would be valuable for more precise lineage tracing and genome editing. Here, we introduce a new SSR system via Nigri-nox. By generating tissue-specific Nigri knock-in and its responding nox reporter mice, we show that the Nigri-nox system works efficiently in vivo by targeting specific tissues. As a new orthogonal system to Cre-loxP, Nigri-nox provides an additional control of genetic manipulation. We also demonstrate how the two orthogonal systems Nigri-nox and Cre-loxP could be used simultaneously to map the cell fate of two distinct developmental origins of cardiac valve mesenchyme in the mouse heart, providing dynamics of cellular contribution from different origins for cardiac valve mesenchyme during development. This work provides a proof-of-principle application of the Nigri-nox system for in vivo mouse genomic engineering. Coupled with other SSR systems, Nigri-nox would be valuable for more precise delineation of origins and cell fates during development, diseases and regeneration.

13.
Cell Res ; 28(8): 871, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29959400

RESUMO

The authors apologized for the spelling mistake of author name for Zhengyu Ju. The correct form is Zhenyu Ju. We apologize for any hassle that may have been caused by our mistake.

14.
Cell Commun Signal ; 16(1): 40, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976202

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) is closely implicated in cancer, and sequencing analyses have revealed a high mutation rate of EGFR in lung cancer. Recent advances have provided novel insights into the endocytic regulation of wild-type EGFR, but that of mutated EGFR remains elusive. In the present study, we aim to investigate the endocytic degradation of a frequently occurred exon 19-deleted mutant in lung cancer. METHODS: The EGF-induced endocytic degradation of EGFR was examined in a panel of lung cancer cells using immunoblotting. The subcellular distribution of internalized EGFR was investigated using immunofluorescence and confocal microscopy. The effects of dynamin were assessed using its small molecule inhibitors, while the influence of RTN3 was tested using shRNA-mediated knockdown. Finally the ubiquitylation status of EGFR mutant was studied using immunoprecipitation under steady state and tyrosine kinase inhibitor-treated conditions. RESULTS: EGF induced various rates of EGFR endocytic degradation in lung cancer cells. Interestingly, the exon 19 deletion mutant is constantly internalized and sorted to lysosome for degradation, and this process is independent of dynamin activity. EGF stimulation and HSP90 inhibition further enhance the endocytic degradation of the exon 19 deletion mutant, in a dynamin activity-dependent and -independent manner, respectively. Albeit with different modes of internalization, the uptake of the exon 19-deleted EGFR is mediated through receptor ubiquitylation. CONCLUSIONS: The internalized EGFR mutant is constantly routed through endosome to lysosome for degradation. The endocytosis of EGFR mutant occurs through both dynamin activity-dependent and -independent mechanisms. Our findings gain novel insights into the endocytic regulation of mutated EGFR and may have potential clinical implications.

15.
Cell Physiol Biochem ; 47(5): 2018-2030, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29969783

RESUMO

BACKGROUND/AIMS: Peptidyl-prolyl cis-trans isomerase FKBP25 is a member of the FK506-binding proteins family which has peptidyl-prolyl cis/trans isomerase domain. The biological function and pathophysiologic role of FKBP25 remain elusive. METHODS: The spatio-temporal changes in expression of endothelial FKBP25 upon oxygen-glucose deprivation (OGD) treatment were examined by Western blot and immunofluorescence. The immunoprecipitation and fluorescence resonance energy transfer (FRET) were used to address the interacting proteins with FKBP25. RESULTS: In the present study, nuclear translocation of FKBP25 was observed following OGD in cultured endothelial cells. Intriguingly, FKBP25 nuclear translocation was further validated in peroxynitrite (ONOO-)-treated endothelial cells. Coimmunoprecipitation and FRET data indicated that FKBP25 translocated into the nucleus, in which it interacted with 60S ribosomal protein L7a, while overexpression FKBP25 protect endothelial cells against OGD injury. CONCLUSION: Our findings reveal that the nuclear import of FKBP25 and binding with 60S ribosomal protein L7a are protective stress responses to ischemia/nitrosaive stress injury.


Assuntos
Núcleo Celular/metabolismo , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Transdução de Sinais , Estresse Fisiológico , Proteínas de Ligação a Tacrolimo/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Hipóxia Celular , Camundongos
16.
Mol Med Rep ; 18(2): 1820-1825, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901180

RESUMO

Multidrug resistance (MDR) is a major impediment to cancer therapy. MG­132 has been identified to be effective against MDR in several types of cancer. However, the mechanism of MG­132 in head and neck squamous cell carcinomas remains unknown. Based on our previous study, the present detected P­gp and P­gp expression in hypopharyngeal carcinoma FaDu cells, revealing that their expression was lower than that observed in the MDR cell line FaDu/T. To reverse the MDR of FaDu/T cells, the present study introduced MG­132 and demonstrated that the high expression of P­gp/P­gp in FaDu/T cells was attenuated in a time­dependent manner. MG­132 also strengthened the sensitivity of FaDu/T cells to multidrugs. c­Jun N­terminal kinase (JNK) activation was further observed in FaDu/T cells. However, P­gp/P­gp did not decrease when FaDu/T cells were pretreated with SP600125. These results indicated that MG­132 reversed the MDR of hypopharyngeal carcinoma by downregulating P­gp/P­gp, and the underlying mechanism may be associated with the activation the of the JNK signaling pathway.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hipofaríngeas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/patologia , Leupeptinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Linfócitos T/efeitos dos fármacos
18.
Circulation ; 138(8): 793-805, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-29700121

RESUMO

BACKGROUND: Whether the adult mammalian heart harbors cardiac stem cells for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers, such as the cardiosphere-derived cells, or with markers such as Sca1+, Bmi1+, Isl1+, or Abcg2+ cardiac stem cells have been reported. Moreover, it remains unclear whether putative cardiac stem cells with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart. METHODS: To address this question without relying on a particular stem cell marker, we developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, we assessed whether nonmyocytes generated any new myocytes during embryonic development, during adult homeostasis, and after myocardial infarction. Skeletal muscle was also examined after injury for internal control of new myocyte generation from nonmyocytes. RESULTS: By this stem cell marker-free and dual recombinases-mediated cell tracking approach, our fate mapping data show that new myocytes arise from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive control, our lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. CONCLUSIONS: This study provides in vivo genetic evidence for nonmyocyte to myocyte conversion in embryonic but not adult heart, arguing again the myogenic potential of putative stem cell populations for cardiac regeneration in the adult stage. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.

19.
Bioorg Med Chem Lett ; 28(6): 1149-1153, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29496368

RESUMO

A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among them, eight compounds showed the higher activity with median lethal concentrations (LC50) of 0.36-1.07mM (60.4-192.1µg/mL) and great potential for the development of novel acaricidal agent. Compound 40 showed both the lowest LC50 value of 0.36mM (60.4µg/mL) and the smallest median lethal time (LT50) of 2.6h at 4.5mM, comparable with ivermectin [LC50=0.28mM (247.4µg/mL), LT50=8.9h], an acaricidal drug standard. SAR analysis showed that the carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester moiety and the steric hindrance near the ester group significantly influence the activity. The esters were more active than the corresponding thiol esters, amides, ketones or acids. Replacement of the phenyl group of cinnamic esters with α-pyridyl or α-furanyl significantly increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with excellent acaricidal activity emerged.


Assuntos
Acaricidas/farmacologia , Cinamatos/farmacologia , Psoroptidae/efeitos dos fármacos , Acaricidas/síntese química , Acaricidas/química , Animais , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade
20.
Sci Rep ; 8(1): 1559, 2018 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-29367595

RESUMO

A series of 2-aryl-9-methyl-ß-carbolinium bromides (B) were synthesized and explored for anti-acetylcholinesterase (AChE) activities in vitro, action mechanism and structure-activity relationship. All the compounds B along with their respective 3,4-dihydro intermediates (A) presented anti-AChE activity at 10 µM. Thirteen compounds B showed the excellent activity with IC50 values of 0.11-0.76 µM and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50 = 0.79 µM), a selective AChE inhibitor drug. Kinetic analysis showed that the action mechanisms of both compounds B and A are a competitive inhibition model. Structure-activity relationship analyses showed that the C = N+ moiety is a determinant for the activity. Substituents at 6, 7 or 4' site, the indole-N-alkyl and the aromatization of the C-ring can significantly improve the activity. Molecular docking studies showed that the compounds could combine with the active site of AChE by the π-π or cation-π action between the carboline ring and the phenyl rings of the residues, and the ß-carboline moiety is embedded in a cavity surrounded by four aromatic residues of Trp86, Tyr337, Trp439 and Tyr449. The present results strongly suggest that the para-position of the D-ring should be a preferred modification site for further structural optimization design. Thus, 2-aryl-9-methyl-ß-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents.

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