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BACKGROUND: Indocyanine green (ICG) fluorescence played an important role in tumor localization and margin delineation in hepatobiliary surgery. However, the preoperative regimen of ICG administration was still controversial. Factors associated with tumor fluorescence staining effect were unclear. AIM: To investigate the preoperative laboratory indexes corelated with ICG fluorescence staining effect and establish a novel laboratory scoring system to screen specifical patients who need ICG dose adjustment. METHODS: To investigate the predictive indicators of ICG fluorescence characteristics in patients undergoing laparoscopic hepatectomy from January 2018 to January 2021 were included. Blood laboratory tests were completed within 1 wk before surgery. All patients received 5 mg ICG injection 24 h before surgery for preliminary tumor imaging. ImageJ software was used to measure the fluorescence intensity values of regions of interest. Correlation analysis was used to identify risk factors. A laboratory risk model was established to identify individuals at high risk for high liver background fluorescence. RESULTS: There were 110 patients who were enrolled in this study from January 2019 to January 2021. The mean values of fluorescence intensity of liver background (FI-LB), fluorescence intensity of gallbladder, and fluorescence intensity of target area were 18.87 ± 17.06, 54.84 ± 33.29, and 68.56 ± 36.11, respectively. The receiver operating characteristic (ROC) curve showed that FI-LB was a good indicator for liver clearance ability [area under the ROC curve (AUC) = 0.984]. Correlation analysis found pre-operative aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, adenosine deaminase, and lactate dehydrogenase were positively associated with FI-LB and red blood cell, cholinesterase, and were negatively associated with FI-LB. Total laboratory risk score (TLRS) was calculated according to ROC curve (AUC = 0.848, sensitivity = 0.773, specificity = 0.885). When TLRS was greater than 6.5, the liver clearance ability of ICG was considered as poor. CONCLUSION: Preoperative laboratory blood indicators can predict hepatic ICG clearance ability. Surgeons can adjust the dose and timing of ICG preoperatively to achieve better liver fluorescent staining.
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Background: Gallbladder carcinosarcoma (GBCS) is a rare and aggressive malignancy with extremely poor prognosis. Although surgery is regarded as the primary therapy for GBCS, the effective therapeutic strategies for unresected lesions have been poorly defined. Case Presentation: We presented a case of a 74-year-old male who underwent radical resection of gallbladder carcinoma at a local hospital. Seven months later, he was admitted to our hospital due to right upper abdominal discomfort. Postoperative radiological examinations showed multiple hepatic lesions, hilar lymph node metastasis, and main portal vein tumor thrombus. The pathological consultation results confirmed GBCS and immunohistochemical examinations revealed PD-L1 expression in 20% of tumor cells. Then, the patient received chemotherapy (Gemcitabine plus Oxaliplatin, GEMOX) in combination with anti-PD-1 therapy. After nine courses of the combination therapy, complete regression of the tumors was achieved with no evidence of relapse till now. Conclusions: We, for the first time, reported a patient with recurrent GBCS who benefited from the combined chemotherapy and immunotherapy, providing a potential effective management strategy for the refractory malignant tumor.
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Zi Cao is an important traditional medicinal plant resource in China. Shikonin and its derivatives, as the purple-red naphthoquinones among natural products of its roots, are commonly used clinically in the treatment of sores and skin inflammations. Over the past few decades, due to their highly effective multiple biological activities, pharmacological effects, good clinical efficacy and high utilization value, shikonin and its derivatives have attracted increasing attention of domestic and foreign researchers. For this reason, the wild plant germplasm resources have been suffering a grievous exploitation, leading to a serious threat to the habitat. With the development of the biosynthesis, molecular metabolism and biotechnology, as well as the continuous innovation of research methods on the biological activities and pharmacological effects of plant natural products, significant progress has been made in the research on the biosynthetic pathways and related regulatory genes of shikonin. The pharmacological action and its mechanism of shikonin have also been deeply elucidated, which greatly promoted the basic research and clinical application development of shikonin. In this review, we briefly introduce and analyze the classification of Zi Cao, structure and composition of natural shikonin and its biosynthesis pathway, functional genes related to the regulation of shikonin biosynthesis, and biological activities and pharmacological functions of shikonin. Finally, we address possible prospective for the trend on the future research and development of natural shikonin and its derivatives, hoping to provide a useful reference for the deep mining and development of medicinal natural products from important Chinese medicinal materials, and to promote the modern development of traditional Chinese medicine.
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Produtos Biológicos , Plantas Medicinais , China , Raízes de Plantas , Estudos ProspectivosRESUMO
Low pH with aluminum (Al) toxicity are the main limiting factors affecting crop production in acidic soil. Selection of legume crops with acid tolerance and nitrogen-fixation ability should be one of the effective measures to improve soil quality and promote agricultural production. The role of the rhizosphere microorganisms in this process has raised concerns among the research community. In this study, BX10 (Al-tolerant soybean) and BD2 (Al-sensitive soybean) were selected as plant materials. Acidic soil was used as growth medium. The soil layers from the outside to the inside of the root are bulk soil (BS), rhizosphere soil at two sides (SRH), rhizosphere soil after brushing (BRH) and rhizosphere soil after washing (WRH), respectively. High-throughput sequencing of 16S rDNA amplicons of the V4 region using the Illumina MiSeq platform was performed to compare the differences of structure, function and molecular genetic diversity of rhizosphere bacterial community of different genotypes of soybean. The results showed that there was no significant difference in alpha diversity and beta diversity in rhizosphere bacterial community among the treatments. PCA and PCoA analysis showed that BRH and WRH had similar species composition, while BS and SRH also had similar species composition, which indicated that plant mainly affected the rhizosphere bacterial community on sampling compartments BRH and WRH. The composition and abundance of rhizosphere bacterial community among the treatments were then compared at different taxonomic levels. The ternary diagram of phylum level showed that Cyanobacteria were enriched in WRH. Statistical analysis showed that the roots of Al-tolerant soybean BX10 had an enrichment effect on plant growth promoting rhizobacteria (PGPR), which included Cyanobacteria, Bacteroides, Proteobacteria and some genera and species related to the function of nitrogen fixation and aluminum tolerance. The rhizosphere bacterial community from different sampling compartments of the same genotype soybean also were selectively enriched in different PGPR. In addition, the functional prediction analysis showed that there was no significant difference in the classification and abundance of COG (clusters of orthologous groups of proteins) function among different treatments. Several COGs might be directly related to nitrogen fixation, including COG0347, COG1348, COG1433, COG2710, COG3870, COG4656, COG5420, COG5456 and COG5554. Al-sensitive soybean BD2 was more likely to be enriched in these COGs than BX10 in BRH and WRH, and the possible reason remains to be further investigated in the future.
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Rizosfera , Solo , Alumínio , Raízes de Plantas , Microbiologia do Solo , Glycine maxRESUMO
BACKGROUND: Liver cancer is a malignant tumor with a high incidence. At present, the most effective treatment is laparoscopic hepatectomy (LH). Indocyanine green fluorescence imaging (ICG-FI) has become an important tool in LH, and the most common fluorescent types of tumors are total fluorescence, partial fluorescence, and rim fluorescence. CASE SUMMARY: We presented four cases of LH guided by ICG-FI in which we also observed the fourth special fluorescent type. When the tumor or intrahepatic stone compresses the adjacent bile duct to cause local cholestasis, the liver segment or subsegment with obstructed bile drainage will show strong fluorescence. Complete removal of the lesion together with the fluorescent liver parenchyma may help reduce the risk of tumor or stone recurrence. CONCLUSION: This type of partial fluorescence can indicate local biliary compression, and the resection method is related to bile drainage, which may be called functional anatomical hepatectomy and ensures radical resection of the lesion.
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Aim: Alzheimer's disease (AD) is the most frequent cause of dementia and characterized by the accumulation of ß-amyloid peptides in plaques and vessel walls. This study proposed a hypothesis of an inhibitory role of miR-96-5p in AD via regulating Foxo1. Methods & methods: AD mouse models were established by injecting with 1% pentobarbital. Results: Knockdown of miR-96-5p in the presence of naringin was shown to reduce the expression of Foxo1 and contents of superoxide dismutase, catalase and glutathione peroxidase, yet increase lipocalin-2 expression as well as hydroxyproline and malondialdehyde contents. Also, Foxo1-mediated lipocalin-2 inhibition attenuated AD. Conclusion: Our study shows downregulating miR-96-5p limited AD progression, highlighting miR-96-5p a potential therapeutic target in treating AD.
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Doença de Alzheimer/genética , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Lipocalina-2/genética , MicroRNAs/genética , Osteoblastos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Lipocalina-2/metabolismo , Camundongos , Interferência de RNARESUMO
An anoxic membrane bioreactor-microalgae membrane reactor coupling system (anoxic MBR-MMR) was used to deal with mariculture wastewater. Pre-anoxic MBR was used for the degradation of organic matter, NO3--N and NO2--N, and the released NH4+-N entered MMR for microalgae growth and was removed. Meanwhile, the treatment efficiency and the microalgae recovery were studied, and the membrane fouling behavior was investigated. After running for 91 days, the removal rates of the system toward NO3--N and NH4+-N were stable at above 90.0% and 88.0%, respectively. Furthermore, the average removal rates of PO43--P and TOC were 49.4% and 84.7%, respectively. Under the condition that the microalgae were harvested continuously, the biomass can be stably operated at an average concentration of 9×107 cells·mL-1 and good removal efficiency and resource utilization could be achieved. Through infrared spectrum and three-dimensional fluorescence spectrum analysis, the main substances causing membrane fouling in MMR were tryptophan proteins and humic acids. The membrane fouling in MMR was lighter than that in anoxic MBR.
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BACKGROUND: Tamoxifen (TAM) is a cell type-specific anti-estrogen and is applied to improve the survival of patients with estrogen receptor positive (ER +) breast cancer. However, long-term TAM use can induce serious drug resistance, leading to breast cancer recurrence and death in patients. Further, it is almost useless among patients with estrogen receptor negative (ER -) breast cancer. Shikonin (SK) is a natural product broadly explored in cancer therapy. Some studies have demonstrated the combined treatment of SK and clinical anticancer drugs including TAM on various tumors. However, the combined effect of SK and 4-hydroxytamoxifen (4-OHT) on ER- breast cancer is not known. The current study aimed to assess the combination effects of SK and 4-OHT on human breast cancer cells, MCF-7 (ER +) and MDA-MB-435S (ER -), in vitro and in vivo and to investigate the underlying mechanisms. METHODS: CCK-8 assays and flow cytometry were conducted to determine the cell viability and apoptotic profiles of human breast cancer cell lines (MCF-7 and MDA-MB-435S) treated with SK, 4-OHT, and the combination. ROS and JC-1 assays were used to determine ROS level and mitochondrial membrane potential. Western blot analysis was performed to investigate proteins that are associated with apoptosis. Haematoxylin & Eosin (HE) staining was used to detect the tumor and kidney morphology of mice. TUNEL and immunohistochemical staining were performed to detect Ki67 expression level and cell apoptotic profile in tumor tissues. RESULTS: SK and 4-OHT synergistically inhibited MCF-7 and MDA-MB-435S cell proliferation and promoted apoptosis by reducing mitochondrial membrane potential and increasing the intracellular ROS level. The combination of SK and 4-OHT activated the mitochondrial-dependent apoptosis and the death receptor pathways, significantly regulating the PI3K/AKT/Caspase 9 signaling pathway. Compared with SK and 4-OHT alone, the combination of SK and 4-OHT could better inhibit tumor growth in mice. CONCLUSION: The combination of SK and 4-OHT shows highly efficient anticancer effects on breast cancer therapy. SK may be a promising candidate as an adjuvant to 4-OHT for breast cancer treatments, especially for ER- breast cancer.
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In this study, a series of shikonin derivatives combined with benzoylacrylic had been designed and synthesized, which showed an inhibitory effect on both tubulin and the epidermal growth factor receptor (EGFR). In vitro EGFR and cell growth inhibition assay demonstrated that compound PMMB-317 exhibited the most potent anti-EGFR (IC50â¯=â¯22.7â¯nM) and anti-proliferation activity (IC50â¯=â¯4.37⯵M) against A549 cell line, which was comparable to that of Afatinib (EGFR, IC50â¯=â¯15.4â¯nM; A549, IC50â¯=â¯6.32⯵M). Our results on mechanism research suggested that, PMMB-317 could induce the apoptosis of A549 cells in a dose- and time-dependent manner, along with decrease in mitochondrial membrane potential (MMP), production of ROS and alterations in apoptosis-related protein levels. Also, PMMB-317 could arrest cell cycle at G2/M phase to induce cell apoptosis, and inhibit the EGFR activity through blocking the signal transduction downstream of the mitogen-activated protein MAPK pathway and the anti-apoptotic kinase AKT pathway; typically, such results were comparable to those of afatinib. In addition, PMMB-317 could suppress A549 cell migration through the Wnt/ß-catenin signaling pathway in a dose-dependent manner. Additionally, molecular docking simulation revealed that, PMMB-317 could simultaneously combine with EGFR protein (5HG8) and tubulin (1SA0) through various forces. Moreover, 3D-QSAR study was also carried out, which could optimize our compound through the structure-activity relationship analysis. Furthermore, the in vitro and in vivo results had collectively confirmed that PMMB-317 might serve as a promising lead compound to further develop the potential therapeutic anticancer agents.
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Acrilatos/farmacologia , Antineoplásicos/farmacologia , Benzoatos/farmacologia , Naftoquinonas/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Acrilatos/química , Acrilatos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzoatos/química , Benzoatos/uso terapêutico , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Naftoquinonas/química , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêuticoRESUMO
A number of podophyllotoxin derivatives (3A-3J) had been designed and synthesized, and their biological activities were evaluated in this study. Moreover, the antiproliferation activities of these compounds against four human cancer cell lines (HepG2, HeLa, A549, and MCF-7) were also tested. The results indicated that the most promising compound 3D displayed potent inhibitory activity over the four human cancer cell lines and was further demonstrated to have potent tubulin polymerization inhibitory effects without damaging the non-cancer cells. Additionally, 3D was verified to effectively interfere with tubulin and could prevent the mitosis of cancer cells, leading to cell cycle arrest and eventually inducing apoptosis in a dose- and time-dependent manner. Moreover, the Western blotting and siRNA results showed that Bcl-2 was downregulated in HepG2 cells treated with 3D. Finally, the molecular docking simulation results revealed that 3D could fit well in the colchicine-binding pocket. Taken together, this study has provided certain novel antitubulin agents for possible cancer chemotherapy.
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Antineoplásicos Fitogênicos/farmacologia , Podofilotoxina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Podofilotoxina/síntese química , Podofilotoxina/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In current study, a series of shikonin derivatives were synthesized and its anticancer activity was evaluated. As a result, PMMB232 showed the best antiproliferation activity with an IC50 value of 3.25±0.35µM. Further, treatment of HeLa cells with a variety of concentrations of target drug resulted in dose-dependent event marked by apoptosis. What's more, the mitochondrial potential (Δym) analysis was consistent with the apoptosis result. In addition, PARP was involved in the progress of apoptosis revealed by western blotting. To identify the detailed role and mechanism of PMMB232 in the progression of human cervical cancer, we detected the expression of HIF-1α and E-cadherin in HeLa cells. Results showed that expression of HIF-1α was downregulated, while E-cadherin protein was upregulated. Meanwhile, glycolysis related protein PDK1 was decreased in HeLa cells. Conversely, the expression of PDH-E1α was upregulated. Docking simulation results further indicate that PMMB232 could be well bound to HIF-1α. Taken together, our data indicate that compound PMMB232 could be developed as a potential anticancer agent.
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Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Ácidos Carboxílicos/uso terapêutico , Cumarínicos/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Naftoquinonas/uso terapêutico , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Cumarínicos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células HeLa , Humanos , Simulação de Acoplamento Molecular/métodos , Naftoquinonas/síntese química , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismoRESUMO
Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, α-lipoic acid, the naturally-occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of α-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, 1c displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC50 value of 3.14 ± 0.58 µM and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Desenho de Fármacos , Glicólise/efeitos dos fármacos , Células HeLa , Humanos , Mitose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Tubulina (Proteína)/metabolismoRESUMO
The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.
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Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Naftoquinonas/química , Naftoquinonas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/síntese química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC50=2.78±0.15µM). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption. Moreover, regarding the expression of cell cycle relative proteins CDK1, a protein required for mitotic initiation was up-regulated. Besides, Cyclin A, Cyclin B1 and Cyclin D1 proteins were down-regulated. Meanwhile, it seems that the effect of C5 on MCF-7 cells apoptosis inducing was observed to be not obvious enough. In addition, docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.
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Acetatos/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Ésteres/farmacologia , Piperazinas/farmacologia , Podofilotoxina/farmacologia , Tubulina (Proteína)/metabolismo , Acetatos/síntese química , Acetatos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Células MCF-7 , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/química , Podofilotoxina/síntese química , Podofilotoxina/química , Polimerização/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
In this study, we designed and synthesized eighteen podophyllotoxin-norcantharidin hybrid drugs which could exhibit more potent anti-cancer activity than the parent drugs. Through the anti-proliferation assay, the most potent anti-cancer agent was screened out, namely Q9 (IC50=0.88±0.18µM against MCF-7 cell line), and it showed lower cytotoxicity against non-cancer cells, human embryonic kidney cells (293T) (IC50=54.38±3.78µM). Additionally, based on the flow cytometry analysis result, it can cause a remarkable cell cycle arrest at G2/M phase and induce apoptosis in MCF-7 cells more significantly than podophyllotoxin or norcantharidin per se. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while a protein required for mitotic initiation, Cyclin B1 was down regulated. Furthermore, according to the confocal microscopy observation results, it was shown that Q9 was a potent tubulin polymerization inhibitor and the effect is comparable to that of colchicine. For further investigation on the aforementioned mechanisms, we performed western blot experiments, thus finding the increase of the cleavage of PARP. Consistent with these new findings, molecular docking observations suggested that compound Q9 could be developed as a potential anticancer agent.
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Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desenho de Fármacos , Podofilotoxina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Estrutura Molecular , Podofilotoxina/química , Relação Estrutura-AtividadeRESUMO
A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 4l exhibited the most potent and selective activity for PI3Kα, with the value of 0.014 µM, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound 4l into the PI3Kα active site and the result showed that compound 4l could bind well at the PI3Kα active site and it indicated that compound 4l could be a potential inhibitor of PI3Kα.
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Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores de Fosfoinositídeo-3 Quinase , Compostos Alílicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Galactosídeos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Morfolinas/farmacologia , Pirazóis/química , Quercetina/análogos & derivados , Quercetina/químicaRESUMO
In this study, we report the identification of a new shikonin-phenoxyacetic acid derivative, as an inhibitor of tubulin. A series of compounds were prepared; among them, compound 16 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(4- phenoxyphenyl) acetate] potently inhibited the function of microtubules, inducing cell growth inhibition, apoptosis of cancer cell lines in a concentration and time-dependent manner. Molecular docking involving 16 at the vinblastine binding site of tubulin indicated that a phenoxy moiety interacted with tubulin via hydrogen bonding with asparaginate (Asn) and tyrosine (Tyr). Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density. Cell cycle assay further proved that HepG2 cells were blocked in G2/M phase. Our study provides a new, promising compound for the development of tubulin inhibitors by proposing a new target for the anticancer activity of shikonin.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Naftoquinonas/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Relação Dose-Resposta a Droga , Células Hep G2/efeitos dos fármacos , Humanos , Ligação de Hidrogênio , Microtúbulos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Vimblastina/metabolismoRESUMO
OBJECTIVE: To explore the effect of anhydroicaritin phytosomes (AIP) in preventing and treating bone loss and enhancing bone quality in ovariectomized osteoporosis rats. METHOD: Seventy-two SD female rats were randomly divided into 6 groups: the sham group, the model group, the estrogen group and AIP groups (low, middle, high). The sham group was only sham operated, and the remaining five groups were ovariectomized. One week after the ovariectomy, the rats were given 17 beta-estrogen and AIP (15, 30, 60 mg x kg(-1)) for consecutively three months, during which period their serum calcium (s-Ca), serum phosphorus(s-P), alkaline phosphate (ALP), urine calcium (u-Ca), urine phosphorus(u-P), urinary deoxypyridinoline (D-Pyr) and creatinine (Cr) were detected. Subsequently, rats were sacrificed, and their thighbone, second lumbar vertebrate and forth lumbar vertebrate were collected to detect bone mineral density (BMD), bone calcium (b-Ca) and phosphorus (b-P), biomechanical properties and bone histomorphometric parameters. RESULT: Compared with the sham group, the model group showed a significant increase in serum ALP, u-Ca and D-Pyr /Cr, and reduction in BMD of femur, b-Ca and b-P, biomechanical properties (elastic load, maximum load, break load, stiffness), static parameters (total tissue area, trabecular area, trabecular perimeter) and dynamic parameters (% L Pm, BFR/BV and BFR/ TV), with metratrophia. Compared with the model group, ALP high and middle-dose groups and the estrogen group showed a decrease in serum ALP, u-Ca and D-Pyr/Cr, and growth in BMD of femur, b-Ca and b-P, biomechanical properties of the forth lumbar vertebrae (elastic load, maximum load, break load, stiffness), static parameters (total tissue area, trabecular area, trabecular perimeter) and dynamic parameters (% L Pm, BFR/BV and BFR/TV). The beta-estrogen group showed endometrial hyperplasia, whereas AIP groups showed no hyperplastic change. CONCLUSION: AIP could inhibit enhanced bone turnover induced by ovariectomy, improve BMD the biomechanical properties of vertebrae, without any stimulation on uterus.
Assuntos
Benzopiranos/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose/prevenção & controle , Fosfolipídeos/uso terapêutico , Animais , Cálcio/sangue , Feminino , Osteoporose/tratamento farmacológico , Ovariectomia , Fósforo/sangue , Ratos , Ratos Sprague-DawleyRESUMO
CdPbS quantum dots-sensitized TiO2 photoelectrode was prepared using chemical bath codeposition technique by dipping TiO2 film into a 0.5 M Cd(NO3)2-Pb(NO3)2 solution (molar ratio 9:1) and a 0.5 M Na2S methanol solution. The CdPbS quantum dots have the size about 4 to 6 nm and distribute homogeneously in the TiO2 film. The as-prepared electrode showed improved absorption spectra. The assembled quantum dots-sensitized solar cell (QDSSC) yielded a power conversion efficiency (nu) of 1.88% and a short-circuit current of 15.28 mA/cm2 under AM 1.5 illumination of 100 mW/cm2, far outperformed the single PbS, CdS QDSSC and the nu increased 49.2% than coupled PbS/CdS QDSSC. The solar cell presented IPCE peak value of 45.7% and the effective photovoltaic range covers the visible region and near infrared region.