RESUMO
The development of an efficient adsorbent for the simultaneous capture of large amounts of benzene, toluene, ethylbenzene, and xylene isomers (BTEX) is an important and challenging issue. Here, through a stepwise screening of 10,142 metal-organic framework (MOF) structures from the computation-ready, experimental (CoRE) MOF database, 65 MOFs are proposed as promising adsorbent candidates for BTEX capture by considering the structures with accessible pore sizes for BTEX adsorption, sufficient hydrophobicity, high benzene selectivity (>0.2), and large total BTEX uptake (>3 mmol/g). Among the top-performing MOFs in terms of the BTEXmatrix (total BTEX uptake × benzene selectivity), EGUELUY01 was synthesized, and it exhibited large uptakes (≈5 mmol/g) for all BTEX components at concentrations of 1200-1500 ppm, which are superior to the BTEX uptake of the benchmark adsorbent, activated carbon. Moreover, some structure-property relationships required for BTEX adsorbents are provided through the obtained large-scale simulation data and machine learning analysis. The determined relationships will be useful for the future development of efficient BTEX adsorbents.
RESUMO
Colorectal cancer (CRC) displays noticeable resistance to chemotherapeutic drugs or innovative tumor cell apoptosis-inducing agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, sensitizers are needed to enhance the effects of TRAIL-based cancer therapies. Elevated tumor cell death has been reported when various HDAC inhibitors are administered with TRAIL in various human cancers; however, SB939-TRAIL combined treatment has not been reported. In this study, we determined the ability of SB939 and TRAIL, as single agents or in combination, to inhibit the growth and survival of colorectal cancer cells. Our results demonstrated the effects of SB939 and TRAIL on cell viability, apoptosis, and morphological changes in HT-29 cells. SB939 treatment induces hyper-acetylation of histones and death receptors (DR) by activating MAPK proteins in a dose- and time-dependent manner. The ability of SB939 to sensitize HT-29 cells suggests that SB939 can induce essential changes in cell signaling pathways. Thus, the pan-HDAC inhibitor SB939 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and SB939-TRAIL combined treatment may target the MAPK pathways and serve as an effective therapeutic strategy against CRC.
Assuntos
Neoplasias Colorretais , Inibidores de Histona Desacetilases , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Ligantes , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
Lipocalin 2 (LCN2) is highly expressed in several infectious and inflammatory disorders. However, the expression level and underlying mechanism of LCN2 in inflammatory bowel disease (IBD) are poorly understood. The current study used murine IBD models and LPSactivated macrophages to elucidate the role of LCN2 in IBD pathogenesis. The levels of LCN2 protein and concentration were confirmed to be much higher in the colons of colitisinduced mice compared with healthy mice using immunohistochemistry, western blotting and ELISA assay. In vitro, the level of LCN2 in RAW264.7 macrophages increased significantly following LPS stimulation and diminished markedly upon using NFκBspecific inhibitors. Assembly of the NOD, LRR, and pyrin domaincontaining protein 3 (NLRP3) inflammasome was inhibited when LCN2 expression was knocked down, as evidenced by decreased NLRP3, ASC1 and caspase1 activation. Furthermore, secretion and maturation of IL1ß was attenuated when LCN2 was silenced in LPSstimulated macrophages. Together, these results suggested that LCN2 directly upregulated the NLRP3 inflammasome complex via NFκB activation in response to stimulating macrophages with LPS, and that it acted as a proinflammatory regulator in macrophage activation modulated by NFκB activation. Overall, LCN2 may serve as a promising target for the prevention and treatment of IBD.
Assuntos
Inflamassomos , Doenças Inflamatórias Intestinais , Camundongos , Animais , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/farmacologia , Lipocalina-2/genética , Lipocalina-2/metabolismo , Camundongos Endogâmicos NOD , Macrófagos/metabolismo , Caspases/metabolismo , Doenças Inflamatórias Intestinais/metabolismoRESUMO
Liquefied natural gas (LNG) gasification coupled with adsorbed natural gas (ANG) charging (LNG-ANG coupling) is an emerging strategy for efficient delivery of natural gas. However, the potential of LNG-ANG to attain the advanced research projects agency-energy (ARPA-E) target for onboard methane storage has not been fully investigated. In this work, large-scale computational screening is performed for 5446 metal-organic frameworks (MOFs), and over 193 MOFs whose methane working capacities exceed the target (315 cm3 (STP) cm-3 ) are identified. Furthermore, structure-performance relationships are realized under the LNG-ANG condition using a machine learning method. Additional molecular dynamics simulations are conducted to investigate the effects of the structural changes during temperature and pressure swings, further narrowing down the materials, and two synthetic targets are identified. The synthesized DUT-23(Cu) and DUT-23(Co) show higher working capacities (≈373 cm3 (STP) cm-3 ) than that of any other porous material under ANG or LNG-ANG conditions, and excellent stability during cyclic LNG-ANG operation.
Assuntos
Estruturas Metalorgânicas , Gás Natural , Ensaios de Triagem em Larga Escala , Aprendizado de Máquina , Metano/químicaRESUMO
Lipocalin (LCN) 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the role of LCN2 in inflammation-associated cancer remains unknown. Here, we explored the functional role and mechanisms of LCN2 in tumorigenesis using murine colitis-associated cancer (CAC) models and human colorectal cancer (CRC) cells. Using murine CAC models, we found that LCN2 was preferentially expressed in colonic tissues from CAC models compared with tissues from normal mice. In vitro results demonstrated that the levels of LCN2 mRNA and protein were markedly up-regulated by interleukin (IL) 6 (IL-6) in human CRC cells. Interestingly, we found LCN2 up-regulation by IL-6 is diminished by nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition using specific inhibitors and small interfering RNA (siRNA). Reporter assay results determined that IL-6 induces LCN2 gene promoter activity under control of NF-κB/STAT3 activation. IL-6-induced LCN2 regulated cell survival and susceptibility of developmental factors to the NF-κB/STAT3 pathway. Taken together, our results highlight the unknown role of LCN2 in CAC progression and suggest that increased LCN2 may serve as an indicator of CRC development in the setting of chronic inflammation.
Assuntos
Colite , Lipocalina-2 , NF-kappa B , Animais , Transformação Celular Neoplásica/genética , Colite/induzido quimicamente , Colite/genética , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-tumor agent. However, resistance to TRAIL has been reported in a number of clinical trials. In this study, we investigated the molecular mechanisms by which a novel histone deacetylase (HDAC) inhibitor, CBUD-1001, sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. MATERIALS AND METHODS: Apoptotic cell death induced by CBUD-1001 and/or TRAIL was assessed on human CRC cells using the MTT assay, FACS analysis and nuclei staining. The involved molecular mechanisms were explored through western blotting analysis. RESULTS: We demonstrated that combined with CBUD-1001, TRAIL significantly enhanced TRAIL-induced apoptosis in CRC cells via mitochondria-mediated pathways. We also found that hyper-acetylation of histone by CBUD-1001 treatment leads to up-regulation of death receptor (DR) 5 in a dose- and time-dependent manner. Furthermore, we identified that enhanced sensitivity to TRAIL by combination with CBUD-1001 depends on the MAPK/CHOP axis, being a key mediator of DR5. CONCLUSION: A novel HDAC inhibitor CBUD-1001 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and that CBUD-1001 and TRAIL combination treatment offers an effective strategy to overcome TRAIL resistance in CRC cells.
Assuntos
Neoplasias Colorretais/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , HumanosRESUMO
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and is a leading cause of cancerrelated mortality worldwide. Histone deacetylases (HDACs) are a class of enzymes responsible for the epigenetic regulation of gene expression. Some HDAC inhibitors have been shown to be efficient agents for cancer treatment. The aim of the present study was to discover a novel, potent HDAC inhibitor and demonstrate its anticancer effect and molecular mechanisms in CRC cells. A novel fluorinated aminophenylbenzamidebased compound, CBUD1001, was designed to specifically target HDAC1, and it was then synthesized and evaluated. CBUD1001 exerted a potent inhibitory effect on HDAC enzyme activity and exhibited anticancer potency against CRC cell lines. Molecular docking analysis rationalized the high potency of CBUD1001 by validating its conformation in the HDAC active site. Further investigation using CRC cells demonstrated that CBUD1001 inhibited HDAC activity by hyperacetylating histones H3 and H4, and it exerted an apoptotic effect by activating a mitochondrialdependent pathway. Of note, it was found that CBUD1001 attenuates the cell motility of CRC cells by downregulating the EMT signaling pathway. Thus, CBUD1001 may prove to be a promising novel drug candidate for CRC therapy.
Assuntos
Benzamidas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Cicloexanos/farmacologia , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Simulação de Acoplamento Molecular/métodos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Epigênese Genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , HumanosRESUMO
OBJECTIVE: To evaluate the feasibility of angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular liver tumors abutting abdominal wall, in order to traverse normal liver parenchyma, and thereby, obtain favorable configuration of ablation margin. MATERIALS AND METHODS: In this study, we retrospectively analyzed 15 small superficial subcapsular liver tumors abutting abdominal wall in 15 patients, treated with radiofrequency ablation from March 2013 to June 2015 using a cool-tip electrode manually modified to create 25-35° angle at the junction between exposed and insulated segments. The tumors were hepatocellular carcinoma (n = 13) and metastases (n = 2: cholangiocellular carcinoma and rectosigmoid cancer), with maximum diameter of 10-26 mm (mean, 15.68 ± 5.29 mm). Under ultrasonographic guidance, the electrode tip was advanced to the depth of the tumors' epicenter about 1 cm from the margin. The tip was re-directed to penetrate the tumor for radiofrequency ablation. Minimal ablation margin was measured at immediate post-treatment CT. Radiological images and medical records were evaluated for success rate, length of minimal ablation margin and complications. RESULTS: Technical success rate of obtaining complete necrosis of the tumors was 100%, with no procedure-related complication. Minimal ablation margin ranged from 3-12 mm (mean, 7.07 ± 2.23 mm). CT/MRI follow-up at 21-1022 days (mean, 519.47 ± 304.51 days) revealed no local recurrence, but distant recurrence in 9 patients. CONCLUSION: Using an angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors abutting abdominal wall may be a feasible technique for obtaining adequate ablation margin and lower complication rate.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter/instrumentação , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/secundário , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Eletrodos , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Neuropeptide Y (NPY) is an orexigenic and hypothermic peptide. To understand its role in hypothermic conditions, male rats were placed in a 24 degrees C or 4 degrees C air chamber for 1.5 h. The expression of c-Fos protein, and NPY mRNA and protein, was analyzed in the hypothalamus 1 h-2 h later. The cold treatment increased the number of c-Fos-immunoreactive cells in the paraventricular hypothalamic nucleus (PVN) and arcuate nucleus (ARC). At the same time it decreased the density of NPY-immunoreactive components in the PVN, dorsomedial hypothalamic nucleus and ARC, as well as of NPY transcripts in the PVN and ARC. No colocalization of c-Fos with NPY was detected. These results suggest that short-term cold exposure should reduce indirectly NPY production in some hypothalamic nuclei to facilitate thermogenesis without inducing feeding behavior.