RESUMO
This study conducted experimental analyses on a 280 Ah single lithium iron phosphate battery using an independently constructed experimental platform to assess the efficacy of compressed nitrogen foam in extinguishing lithium-ion battery fires. Based on theoretical analysis, the fire-extinguishing effects of compressed nitrogen foam at different outlet pressures from foam mixture tanks were analyzed, examining factors such as battery surface temperature, flame temperature, and thermal weight loss. The results indicate that the compressed nitrogen foam can extinguish the open flame of the battery in 14 s at 0.7 MPa, with the battery's surface temperature dropping by approximately 11 % before and after the application of the extinguishing agent. Compared with other commonly used extinguishing agents, the compressed nitrogen foam demonstrates superior extinguishing efficiency, but its cooling efficiency is somewhat lower. At pressures ranging from 0.4 to 0.6 MPa, the foam displays prolonged drainage time and sustained cooling effects, rendering it more suitable for lithium-ion battery fire scenarios. To address the issue of reduced cooling performance during later stages of fire suppression by compressed nitrogen foam, an intermittent injection approach has been proposed to effectively preserve its cooling efficacy.
RESUMO
The molecular chaperone heat shock protein 90 (HSP90) regulates multiple crucial signalling pathways in cancer by driving the maturation of key signalling components, thereby playing a crucial role in tumorigenesis and drug resistance in cancer. Inhibition of HSP90 results in metastable conformational collapse of its client proteins and their proteasomal degradation. Considerable efforts have been devoted to the development of small-molecule inhibitors targeting HSP90, and more than 20 inhibitors have been evaluated in clinical trials for cancer therapy. However, owing to disadvantages such as organ toxicity and drug resistance, only one HSP90 inhibitor has been approved for use in clinical settings. In recent years, HSP90 inhibitors used in combination with other anti-cancer therapies have shown remarkable potential in the treatment of cancer. HSP90 inhibitors work synergistically with various anti-cancer therapies, including chemotherapy, targeted therapy, radiation therapy and immunotherapy. HSP90 inhibitors can improve the pharmacological effects of the above-mentioned therapies and reduce treatment resistance. This review provides an overview of the use of combination therapy with HSP90 inhibitors and other anti-cancer therapies in clinical and preclinical studies reported in the past decade and summarises design strategies and prospects for these combination therapies. Altogether, this review provides a theoretical basis for further research and application of these combination therapies in the treatment of cancer.
Assuntos
Proteínas de Choque Térmico HSP90 , Neoplasias , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia CombinadaRESUMO
Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines. This review summarizes the recent research progress of the regulators of the RIPK3 signaling pathway and discusses the potential role of RIPK3/necroptosis in the aetiopathogenesis of various diseases. An in-depth understanding of the mechanisms and functions of RIPK3 may facilitate the development of novel therapeutic strategies.
RESUMO
Workshop with different fermentation years plays an essential role in the yield and quality of Baijiu. In actual production, the quality of base Baijiu in newly built workshop is inferior to the older one. In this study, the microbiota of workshop environment and fermentation process from two workshops namely N (ferment 2 years) and O (ferment 20 years) and flavor compounds were studied during Xiasha round. Results showed workshop O accumulated more environmental microorganisms and fungi including P. kudriavzevii, Wickerhamomyces anomalus and Saccharomyces sp mainly came from ground. Yeasts including Pichia, Cyberlindnera, Wickerhamomyces and Candida were responsible for flavor substances formation in O while Saccharopolyspora was in N. This study for the first time explored the reasons for the brewing differences among N and O workshop from perspectives of workshop environment, microbial community and flavor substances, providing new ideas for guiding production as well as improvement of Baijiu quality.
RESUMO
Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Farmacóforo , Ligantes , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas de Choque Térmico HSP90 , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
Background: Hepatocellular carcinoma (HCC) represents a prominent gastrointestinal malignancy with a grim clinical outlook. In this regard, the discovery of novel early biomarkers holds substantial promise for ameliorating HCC-associated mortality. Efferocytosis, a vital immunological process, assumes a central position in the elimination of apoptotic cells. However, comprehensive investigations exploring the role of efferocytosis-related genes (EFRGs) in HCC are sparse, and their regulatory influence on HCC immunotherapy and targeted drug interventions remain poorly understood. Methods: RNA sequencing data and clinical characteristics of HCC patients were acquired from the TCGA database. To identify prognostically significant genes in HCC, we performed the limma package and conducted univariate Cox regression analysis. Subsequently, machine learning algorithms were employed to identify hub genes. To assess the immunological landscape of different HCC subtypes, we employed the CIBERSORT algorithm. Furthermore, single-cell RNA sequencing (scRNA-seq) was utilized to investigate the expression levels of ERFGs in immune cells and to explore intercellular communication within HCC tissues. The migratory capacity of HCC cells was evaluated using CCK-8 assays, while drug sensitivity prediction reliability was determined through wound-healing assays. Results: We have successfully identified a set of nine genes, termed EFRGs, that hold significant potential for the establishment of a hepatocellular carcinoma-specific prognostic model. Furthermore, leveraging the individual risk scores derived from this model, we were able to stratify patients into two distinct risk groups, unveiling notable disparities in terms of immune infiltration patterns and response to immunotherapy. Notably, the model's capacity to accurately predict drug responses was substantiated through comprehensive experimental investigations, encompassing wound-healing assay, and CCK8 experiments conducted on the HepG2 and Huh7 cell lines. Conclusions: We constructed an EFRGs model that serves as valuable tools for prognostic assessment and decision-making support in the context of immunotherapy and chemotherapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Reprodutibilidade dos Testes , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Prognóstico , Análise de Célula ÚnicaRESUMO
Due to the complicacy of asphalt fumes, the analytical methods for investigating volatile organic compounds (VOCs) are very limited. In this study, a direct and real-time analysis method based on carbon fiber ionization mass spectrometry (CFI-MS), an ambient mass spectrometric technique, was established and successfully applied in the analysis of asphalt VOCs. The asphalt VOCs can be directly detected in the open atmosphere without the collection step of asphalt fumes, and the mass spectra of one asphalt sample can be obtained in a few seconds in both positive and negative ion modes. By investigating the mass spectral changes of asphalt fumes at different heating temperatures ranging from 50 to 200 °C, the temperature factor of asphalt fume emission was demonstrated in this work. The research results demonstrate that the complexity of asphalt fumes is positively related to the applied temperature. Moreover, the VOCs of saturates, aromatics, resins, and asphaltenes fractions were also analyzed by the direct analysis method. The result shows that aromatics contribute most to the emission of VOCs. In addition, the obtained mass spectra combined with the principal component analysis method show the great potential to quickly screen VOC inhibitors of asphalt materials.
RESUMO
Two-dimensional (2D) half-metal and topological states have been the current research focus in condensed matter physics. Herein, we report a novel 2D material named EuOBr monolayer, which can simultaneously show 2D half-metal and topological fermions. This material shows a metallic state in the spin-up channel but a large insulating gap of 4.38 eV in the spin-down channel. In the conducting spin channel, the EuOBr monolayer shows the coexistence of Weyl points and nodal-lines near the Fermi level. These nodal-lines are classified by type-I, hybrid, closed, and open nodal-lines. The symmetry analysis suggests these nodal-lines are protected by the mirror symmetry, which cannot be broken even spin-orbit coupling is included because the ground magnetization direction in the material is out-of-plane [001]. The topological fermions in the EuOBr monolayer are fully spin-polarized, which can be meaningful for future applications in topological spintronic nano-devices.
RESUMO
PURPOSE: To obtain the relative volume by measuring the tongue volume and the lesion volume, and further explore its relationship with the prognosis of patients, hoping to supplement the TNM staging with a new index. METHODS: ITK-SANP software was used to outline the patients' MRI. After MRI reconstruction and measurement, slicer software was used to estimate tumor volume. RESULTS: A total of 64 patients with tongue cancer who met the inclusion criteria were included in the study. The estimated tumor volume after MRI reconstruction revealed a significant and robust correlation with tumor stage (p < 0.05, Rs = 0.6207) and a substantial and medium correlation with early lymph node metastasis (p < 0.05, Rs = 0.4873). CONCLUSIONS: We classified tongue cancer into three grades based on tumor volume (Stage I, tumors smaller than 1500 mm³; Stage II, tumors 1500-9000 mm³; and Stage III, tumors larger than 9000 mm³), and such grading could be used as a reference for tumor staging, lymph node metastasis, and patient prognosis to a certain extent.
Assuntos
Neoplasias da Língua , Humanos , Neoplasias da Língua/diagnóstico por imagem , Neoplasias da Língua/cirurgia , Neoplasias da Língua/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Estudos Retrospectivos , Prognóstico , Estadiamento de Neoplasias , Imageamento por Ressonância Magnética , Língua , Linfonodos/patologiaRESUMO
COVID-19, referred to as new coronary pneumonia, is an acute infectious disease caused by a new type of coronavirus SARS-CoV-2. To evaluate the effect of integrated Chinese medicine and Western medicine in patients with COVID-19 from overseas. Data were collected from 178 COVID-19 patients overseas at First Affiliated Hospital of Xiamen University from April 1, 2021 to July 31, 2021. These patients received therapy of integrated Chinese medicine and western medicine. Demographic data and clinical characteristics were extracted and analyzed. In addition, the prescription which induced less length of PCR positive days and hospitalization days than the median value was obtained. The top 4 frequently used Chinese medicine and virus-related genes were analyzed by network pharmacology and bioinformatics analysis. According to the chest computed tomography (CT) measurement, abnormal lung findings were observed in 145 subjects. The median length of positive PCR/hospitalization days was 7/7 days for asymptomatic subjects, 14/24 days for mild subjects, 10/15 days for moderate subjects, and 14/20 days for severe subjects. The most frequently used Chinese medicine were Scutellaria baicalensis (Huangqin), Glycyrrhiza uralensis (Gancao), Bupleurum chinense (Chaihu), and Pinellia ternata (Banxia). The putative active ingredients were baicalin, stigmasterol, sigmoidin-B, cubebin, and troxerutin. ACE, SARS-CoV-2 3CL, SARS-CoV-2 Spike, SARS-CoV-2 ORF7a, and caspase-6 showed good binding properties to active ingredients. In conclusion, the clinical results showed that integrated Chinese medicine and Western medicine are effective in treating COVID-19 patients from overseas. Based on the clinical outcomes, the putative ingredients from Chinese medicine and the potential targets of SARS-CoV-2 were provided, which could provide a reference for the clinical application of Chinese medicine in treating COVID-19 worldwide.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Estudos Retrospectivos , Medicina Tradicional Chinesa , HospitalizaçãoRESUMO
The ecological environment of quarry mining area is fragile, and the vegetation restoration cycle is long and difficult, so scientific and appropriate artificial vegetation is of great significance to ecological restoration. The purpose of this study was to evaluate the herbaceous and woody vegetation restoration, including Medicago sativa (Me), artificial miscellaneous grass (Mg), Rhus typhina (Rh), fruit orchard (Or) and Pinus tabulaeformis (Pi), to investigate the soil physicochemical properties and the structure of the microbial communities, and to reveal the correlation between them. The results addressed that Medicago sativa and artificial miscellaneous grass had significant effect on soil remediation, which were conducive to scientific and efficient ecological restoration, and could promote ecological restoration in the damaged ecosystems. While, the modes of Rh and Pi were not suitable for ecological restoration in this study area because they had strong allelopathy. Another arborous restoration mode of Or showed a better improvement effect (including soil nutrients, soil microbial diversity, etc.) than that of Rh and Pi. The findings also indicated that the herbaceous vegetation restoration modes of Me and Mg significantly increased the relative abundance of Proteobacteria, Acidobacteria, Actinobacteria bacteria, Ascomycota and Mortierllomycota fungi, and reduced the relative abundance of Firmicutes bacteria and Basidiomycota fungi. This study also revealed that the trend of bacterial localization in the fruit orchard, artificial miscellaneous grass and Medicago sativa was more obvious. Among many soil abiotic factors, the contents of organic matter, available nitrogen and pH were the most important factors affecting soil microbial community.
Assuntos
Ascomicetos , Microbiota , Solo/química , Bactérias , Proteobactérias , PoaceaeRESUMO
Circulating and tissue-resident extracellular vesicles (EVs) represent promising targets as novel theranostic biomarkers, and they emerge as important players in the maintenance of organismal homeostasis and the progression of a wide spectrum of diseases. While the current research focuses on the characterization of endogenous exosomes with the endosomal origin, microvesicles blebbing from the plasma membrane have gained increasing attention in health and sickness, which are featured by an abundance of surface molecules recapitulating the membrane signature of parent cells. Here, a reproducible procedure is presented based on differential centrifugation for extracting and characterizing EVs from the plasma and solid tissues, such as the bone. The protocol further describes subsequent profiling of surface antigens and protein cargos of EVs, which are thus traceable for their derivations and identified with components related to potential function. This method will be useful for correlative, functional, and mechanistic analysis of EVs in biological, physiological, and pathological studies.
Assuntos
Micropartículas Derivadas de Células , Exossomos , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Exossomos/metabolismo , Micropartículas Derivadas de Células/metabolismo , Biomarcadores/metabolismo , Plasma/metabolismoRESUMO
The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC50 values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC50 value of 0.21 µM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.
Assuntos
Antineoplásicos , Imidazolidinas , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas , Proteínas de Choque Térmico HSP90 , Humanos , Lactamas Macrocíclicas , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-aktRESUMO
Recently, long noncoding RNAs (lncRNA) have been reported as tumor suppressors or oncogenes in colorectal cancer. This study aims to discover functional role of a novel lncRNA in colorectal cancer tumorigenesis. Expression profile of fibronectin type III domain containing 1 antisense RNA 1 (ELFN1-AS1) in colorectal cancer samples was displayed on TCGA database. Expression level of ELFN1-AS1 was tested in colorectal cancer tissues and cell lines via qRT-PCR. Functional role of ELFN1-AS1 was assessed by loss-of-function assays. Mechanism experiments, such as chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay, were done to analyze the molecular mechanism of ELFN1-AS1 in colorectal cancer. ELFN1-AS1 knockdown inhibited colorectal cancer tumor growth through restricting cell proliferation and facilitating cell apoptosis. ELFN1-AS1 was transcriptionally activated by MYC. Moreover, ELFN1-AS1 led to transcriptional silencing of tropomyosin 1 (TPM1) via recruiting enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and forkhead box P1 (FOXP1). Collectively, MYC-upregulated ELFN1-AS1 recruited EZH2 and FOXP1 to restrain TPM1 expression, thereby promoting colorectal cancer tumor growth. IMPLICATIONS: This study revealed a novel molecular pathway in colorectal cancer progression, which may provide new method for early diagnosis and treatment of colorectal cancer.
Assuntos
Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , MicroRNAs/genética , Tropomiosina/genética , Tropomiosina/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição Forkhead/genéticaRESUMO
Warburg effect is considered to be related to the malignancy of tumor cells under hypoxic conditions, but the underlying mechanism remains unknown. In this article, it has been reported that lncRNA LINC00525 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. It was found that LINC00525 was up-regulated, and promoted cell proliferation in colorectal cancer in vitro and in vivo. In colorectal cancer cells, hypoxia increasedLINC00525 expression, whereas knocking down LINC00525 reduced hypoxia-enhanced glycolysis. For specific molecular mechanisms, it was found that LINC00525 promoted UBE2Q1 expression by binding miR-338-3p, and UBE2Q1-stabilized ß-catenin enhances hypoxia-enhanced glycolysis by activating HIF-1α. In conclusion, these findings showed that LINC00525 was essential for hypoxia-enhanced glycolysis; its mechanism was related to activating HIF-1α through miR-338-3p/UBE2Q1/ß-catenin axis in colorectal cancer cells.
Assuntos
Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/genética , RNA Longo não Codificante/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , beta Catenina/metabolismoRESUMO
The objective of this experimental study was to examine the effects of the Chinese herbal medicines Patchouli and Elsholtzia on the follicular granulosa cells of hens undergoing heat stress conditions. In the current investigation, hen follicular granulosa cells were isolated from the prehierarchical follicles of layer hens and then cultured in-vitro. The cells were randomly divided into the 6 groups. Following the completion of this study's experiments using different heat stress and medicinal treatments, the cell activities of each group were measured using an MTT method. The levels of the heat shock protein 70 (HSP70) were detected using ELISA. The expressions of the steroidogenic acute regulatory protein (StAR) mRNA; cytochrome P450 family 11, subfamily A, member 1 (CYP11A1) mRNA; proliferating cell nuclear antigen (PCNA) mRNA; and the follicle stimulating hormone receptor (FSHR) were detected using the real-time quantitative polymerase chain reactions. The concentration levels of estrogen and progesterone in the cell supernatant of each group were measured using ELISA. The results showed that cell activity had significantly decreased following the heat stress treatments at 43â, 44â, and 45â (P < 0.01), respectively. Meanwhile, cell activities observed in Patchouli and Elsholtzia were found to be much better than those of heat stress group (P < 0.05). In addition, the expression levels of HSP70 in the follicular granulosa cells of Patchouli and Elsholtzia groups were lower than those of heat stress group. Patchouli and Elsholtzia can maintain expressions of the receptor at 43â. This study determined that the estrogen and progesterone in the supernatant fluid of Patchouli and Elsholtzia were higher than those observed in heat stress. Therefore, the results obtained in this study indicated that the Patchouli and Elsholtzia treatments administered prior the heat stress experiments had successfully protected the follicular granulosa cells from heat damages while maintaining the normal secretory functions of the granulosa cells.
Assuntos
Galinhas , Pogostemon , Animais , Células Cultivadas , Feminino , Células da Granulosa , Resposta ao Choque Térmico , ProgesteronaRESUMO
Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that certain of the flow cytometric data featured in Fig. 4C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 44: 11391150, 2019; DOI: 10.3892/ijmm.2019.4245].
RESUMO
BACKGROUND: HSP90 has been considered an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance. METHODS: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In view of rare examples of structure-based identification of HSP90 C-terminal inhibitors, we report a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products. RESULTS & DISCUSSION: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics simulation. CONCLUSION: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90. A structure based virtual screening strategy was established for the discovery of HSP90 Cterminal inhibitors.
Assuntos
Antineoplásicos , Produtos Biológicos , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90 , Simulação de Dinâmica MolecularRESUMO
The molecular chaperone HSP90 facilitates the maturation of newly synthesized and unfolded proteins. The client proteins of HSP90 are involved in many processes of cancer occurrence and development, and therefore, HSP90 is considered as a promising target for the development of anticancer drugs. In contrast to N-terminal inhibitor, C-terminal inhibitor does not induce the pro-survival heat shock response. In order to get novel HSP90 C-terminal inhibitors and more evidences that HSP90 inhibitors could be applied in the therapy of cancer, we conducted a virtual screening toward HSP90 C-terminus from FDA-approved drugs. In this study, miltefosine and octenidine were identified as new HSP90 inhibitors. Miltefosine and octenidine exhibited strong and broad-spectrum anticancer activity and inhibited the proliferation of cancer cell by promoting apoptosis. Western blotting analysis revealed that miltefosine and octenidine significantly down-regulated the expression levels of HSP90 client proteins including p-AKT, CDK6, and ERK, and did not induce overexpression of heat shock proteins including HSP70 and HSP90 in MCF-7 cells. These results were in accordance with the characteristics of HSP90 C-terminal inhibitor. In conclusion, miltefosine and octenidine could disrupt the molecular chaperone function of HSP90, and thus, their strong and broad-spectrum anticancer activity is at least in part attributed to the inhibition activity against HSP90.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Iminas/farmacologia , Fosforilcolina/análogos & derivados , Piridinas/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células MCF-7 , Neoplasias/tratamento farmacológico , Fosforilcolina/farmacologiaRESUMO
Long noncoding RNAs play a role in a variety of malignancies, such as thyroid cancer (TC). However, the effects and function of lincRNA HOTAIRM1 (LINC HOTAIRM1) in TC remains obscure. In the present study, the expression of HOTAIRM1 was evaluated in TC tissues and cells by RTqPCR and the association between the lncRNA and disease progression was assessed. In vitro, the biological function of HOTAIRM1 was assessed in TC. Moreover, changes in the expression of Wnt10b were measured by western blot analysis. In addition, MTT assay, bioinformatics analysis and luciferase assays were performed to determine the target binding effect between LINC HOTAIRM1 and miR148a, as well as that between Wnt10b and miR148a. The changes in the metastatic ability of TPC1 and BCPAP cells were evaluated by Transwell assay. The pronounced upregulated expression of HOTAIRM1 was evident in TC cells and tissues, and was associated with TNM stage and lymph node metastasis. When HOTAIRM1 was knocked down, this inhibited the proliferative and invasive abilities of TPC1 and BCPAP cells in vitro. The knockdown of this lncRNA also increased the expression of microRNA148a (miR148a) and decreased Wnt10b expression in these cells, whereas transfection with miR148a inhibitor was sufficient to overcome this Wnt10b downregulation. In line with these results, the overexpression of miR148a markedly suppressed Wnt10b expression, whereas miR148a inhibition resulted in the opposite effects. The overexpression of Wnt10b was also sufficient to overcome the effects of miR148a mimics on TPC1 and BCPAP cells. Taken together, these results suggest that miR148a and Wnt10b are downstream effectors of the HOTAIRM1 signaling pathway in TC. This HOTAIRM1/miR148a/Wnt10 axis may thus be amenable to therapeutic targeting in order to improve disease outcomes in patients with TC.