共查询到20条相似文献,搜索用时 15 毫秒
1.
Elisa Bertoli Elisa De Carlo Alessandro Del Conte Brigida Stanzione Alberto Revelant Kelly Fassetta Michele Spina Alessandra Bearz 《International journal of molecular sciences》2022,23(13)
Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications. 相似文献
2.
Dong-Hu Zhou Xuemin Wang Mingmin Yang Xiaoyan Shi Wenbin Huang Qing Feng 《International journal of molecular sciences》2013,14(6):12023-12036
(−)-Epigallocatechin gallate (EGCG) and curcumin are two naturally derived agents that have been widely investigated worldwide. They exhibit their anti-tumor effects in many types of cancers. In the current study, the effect of the combination of the two agents on non-small cell lung cancer (NSCLC) cells was investigated. The results revealed that at low concentrations, the combination of the EGCG and curcumin strongly enhanced cell cycle arrest. Flow cytometry analysis showed that the cells were arrested at G1 and S/G2 phases. Two main cell cycle related proteins cyclin D1 and cyclin B1 were significantly inhibited at the present of EGCG and curcumin. EdU (5-ethynyl-2′-deoxyuridine) fluorescence staining showed that the DNA replication was significantly blocked. A clonal growth assay also confirmed a marked repression of cell growth. In a lung cancer xenograft node mice model, combination of EGCG and curcumin exhibited protective effect against weight loss due to tumor burden. Tumor growth was strongly repressed by the combination of the two agents, without causing any serious side-effect. Overall, these results strongly suggest that EGCG in combination with curcumin could be a candidate for chemoprevention agent of NSCLC. 相似文献
3.
Umberto Malapelle Paola Parente Francesco Pepe Martina Concetta Di Micco Alessandro Russo Celeste Clemente Paolo Graziano Antonio Rossi 《International journal of molecular sciences》2022,23(24)
The striking clinical outcomes of antibody-based immunotherapy, through the inhibitors of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) axis, have driven research aimed at identifying further clinically relevant tumor antigens that can serve as targets in solid tumors. B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family overexpressed in tumor tissues, including non-small cell lung cancer (NSCLC), while showing limited expression in normal tissues, becoming an attractive and promising target for cancer immunotherapy. B7-H3 expression in tumors has been demonstrated to be associated with poor prognosis. In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC. 相似文献
4.
Said AbdAlla Andreas Langer Xuebin Fu Ursula Quitterer 《International journal of molecular sciences》2013,14(8):16917-16942
Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. 相似文献
5.
Stephan Kruck Christian Eyrich Marcus Scharpf Karl-Dietrich Sievert Falco Fend Arnulf Stenzl Jens Bedke 《International journal of molecular sciences》2013,14(6):10944-10957
In renal cell carcinoma (RCC), single members of the Wnt/β-catenin signaling cascade were recently identified to contribute to cancer progression. However, the role of Wnt1, one of the key ligands in β-catenin regulation, is currently unknown in RCC. Therefore, alterations of the Wnt1/β-catenin axis in clear cell RCC (ccRCC) were examined with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS). Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and β-catenin expression by immunohistochemistry in tissue microarrays. Expression scores, including intensity and percentage of stained cells, were compared between normal kidney and ccRCCs. Data was categorized according to mean expression scores and correlated to tumor and patients’ characteristics. Survival was analyzed according to the Kaplan-Meier and log-rank test. Univariable and multivariable Cox proportional hazard regression models were used to explore the independent prognostic value of Wnt1 and β-catenin. In ccRCCs, high Wnt1 was associated with increased tumor diameter, stage and vascular invasion (p ≤ 0.02). High membranous β-catenin was associated with advanced stage, vascular invasion and tumor necrosis (p ≤ 0.01). Higher diameter, stage, node involvement, grade, vascular invasion and sarcomatoid differentiation (p ≤ 0.01) were found in patients with high cytoplasmic β-catenin. Patients with a high cytoplasmic β-catenin had a significantly reduced OS (hazard ratio (HR) 1.75) and CSS (HR 2.26), which was not independently associated with OS and CSS after adjustment in the multivariable model. Increased ccRCC aggressiveness was reflected by an altered Wnt1/β-catenin signaling. Cytoplasmic β-catenin was identified as the most promising candidate associated with unfavorable clinicopathology and impaired survival. Nevertheless, the shift of membranous β-catenin to the cytoplasm with a subsequently increased nuclear expression, as shown for other malignancies, could not be demonstrated to be present in ccRCC. 相似文献
6.
Y Fan S Jin J He Z Shao J Yan T Feng H Li 《International journal of molecular sciences》2012,13(7):9184-9193
In traditional Chinese medicine, shikonin and its derivatives, has been used in East Asia for several years for the prevention and treatment of several diseases, including cancer. We previously identified that β,β-dimethylacrylshikonin (DA) could inhibit hepatocellular carcinoma growth. In the present study, we investigated the inhibitory effects of DA on human colorectal cancer (CRC) cell line HCT-116 in vitro and in vivo. A viability assay showed that DA could inhibit tumor cell growth in a time- and dose-dependent manner. Flow cytometry showed that DA blocks the cell cycle at G(0)/G(1) phase. Western blotting results demonstrated that the induction of apoptosis by DA correlated with the induction of pro-apoptotic proteins Bax, and Bid, and a decrease in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. Furthermore, treatment of HCT-116 bearing nude mice with DA significantly retarded the growth of xenografts. Consistent with the results in vitro, the DA-mediated suppression of HCT-116 xenografts correlated with Bax and Bcl-2. Taken together, these results suggest that DA could be a novel and promising approach to the treatment of CRC. 相似文献
7.
Yutaka Kishida Naohiko Imaizumi Hirohisa Tanimura Shinichiro Kashiwamura Toru Kashiwagi 《International journal of molecular sciences》2016,17(3)
The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and IT with a protease inhibitor (PI) (simeprevir or vaniprevir)/PR (group B, n = 13) in CHC patients with genotype 1b and high viral loads. During IT with nIFN-β, virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4, 30% and 16% (p = 0.6989) at week 12 and 47% and 20% (p = 0.0887) at week 24 respectively. During and after the treatment with PR alone or PI/PR, virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4, 53% and 91% (p = 0.006745) at week 8, 57% and 91% (p = 0.001126) at week 12, 57% and 100% (p < 0.001845) at the end of the treatment and 57% and 80% (p < 0.005166) after treatment cessation. IT with PI/PR linked to the restoration of innate immune response was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in difficult-to-treat CHC patients. IT with PI/PR is beneficial for treating difficult-to-treat CHC patients. 相似文献
8.
9.
《Carbon》2013
We present a simple and fast approach for the synthesis of a graphene–TiO2 hybrid nanostructure using a microwave-assisted technique. The microstructure, composition, and morphology were characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, Raman microscopy, X-ray photoelectron spectroscopy, and field-emission scanning electron microscopy. The electrochemical properties were evaluated using cyclic voltammetry, electrochemical impedance spectroscopy, and galvanostatic charge–discharge tests. Structural analysis revealed a homogeneous distribution of nanosized TiO2 particles on graphene nanosheets. The material exhibited a high specific capacitance of 165 F g−1 at a scan rate of 5 mV s−1 in 1 M Na2SO4 electrolyte solution. Theenhanced supercapacitance property of these materials could be ascribed to the increased conductivity of TiO2 and better utilization of graphene. Moreover, the material exhibited long-term cycle stability, retaining ∼90% specific capacitance after 5000 cycles, which suggests that it has potential as an electrode material for high-performance electrochemical supercapacitors. 相似文献
10.
Ruizhi Geng Niklas Harland Ivonne A. Montes-Mojarro Falko Fend Wilhelm K. Aicher Arnulf Stenzl Bastian Amend 《International journal of molecular sciences》2022,23(10)
Background: Bladder cancer is the most cost-intensive cancer due to high recurrence rates and long follow-up times. Bladder cancer organoids were considered interesting tools for investigating better methods for the detection and treatment of this cancer. Methods: Organoids were generated from urothelial carcinoma tissue samples, then expanded and characterized; the expression of immune modulatory antigens and tumor stem cells markers CD24 and CD44 was explored in early (P ≤ 3) and later (P ≥ 5) passages (P) by immunofluorescence and by quantitative PCR of cDNA. The expression of these factors was investigated in the corresponding cancer tissue samples by immunohistochemistry. Results: The expression of the PD-L1 was detected on some but not all organoids. CD276 and CD47 were observed on organoids in all passages investigated. Organoids growing beyond passage 8 expressed both CD24 and CD44 at elevated levels in early and late cultures. Organoids proliferating to the eighth passage initially expressed both CD24 and CD44, but lost CD24 expression over time, while CD44 remained. Organoids growing only up to the 6th passage failed to express CD24 but expressed CD44. Conclusions: The data indicate that the expression of CD24 in urothelial cancer cell organoids may serve as an indicator for the prolonged proliferation potential of the cells. 相似文献
11.
12.
D. Seifzadeh V. Valizadeh-Pashabeigh A. Bezaatpour 《Chemical Engineering Communications》2016,203(10):1279-1287
5-CM-Salophen Schiff base was examined as an inhibitor for corrosion of mild steel in 0.5 M hydrochloric acid (HCl). The gravimetric data revealed corrosion inhibition effectiveness of the Schiff base even at low concentrations. Polarization measurements showed that the Schiff base is a mixed-type corrosion inhibitor. The polarization resistance (Rp) increased with increasing the Schiff base concentration. Also, the values of the double-layer capacitance decreased after addition of the inhibitor due to adsorption of the Schiff base on the surface. The inhibition mechanism was investigated by plotting the Langmuir adsorption isotherm and calculating the potential of zero charge (EPZC) for mild steel samples. Scanning electron microscopy (SEM) analysis confirmed the results of the corrosion tests. 相似文献
13.
14.
The radical copolymerization of -terpineol with methyl-methacrylate in xylene at 80±0.1C for 50 minutes in the presence of azobisisobutyronitrile (AIBN) follows ideal kinetics and results in the formation of a functional and random copolymer. The activation energy is 33 KJ/mole. The IR spectrum and NMR spectra of the copolymer(s) shows the bands at 1750 and 3400 cm–1 for ester group of methylmethacrylate and alcoholic group of -terpineol and peaks at 3 to 4 for methoxy group and at 6.5 to 7.5 due to alcoholic group of methylmethacrylate and -terpineol repectively. The values of reactivity ratios, calculated by Kelen–Tüdos method, are r
1 (MMA) = 0.18 and r
2 (-terpineol) = 0.046. The Alfrey-Price; Q–e parameters for -terpineol has been calculated as 0.149 and 2.486. The mechanism of copolymerization has been elucidated and it is concluded that the double bond present in the monocyclic ring of -terpineol is an active site for copolymerization and the alcoholic group of -terpineol remain to give functional copolymer. 相似文献
15.
Yurong Lai Po-Chang Chiang Jason D. Blom Na Li Kimberly Shevlin Timothy G. Brayman Yiding Hu Jon G. Selbo Liangbiao George Hu 《Nanoscale research letters》2008,3(9):321-329
In present study, the potential drug delivery of nanoformulations was validated via the comparison of cellular uptake of nanoparticles
in various cell lines and in vivo pulmonary cellular uptake in intratracheally (IT) dosed rat model. Nanoparticles were prepared
by a bench scale wet milling device and incubated with a series of cell lines, including Caco-2, RAW, MDCK and MDCK transfected
MDR1 cells. IT dosed rats were examined for the pulmonary cellular uptake of nanoparticles. The processes of nanoparticle
preparation did not alter the crystalline state of the material. The uptake of nanoparticles was observed most extensively
in RAW cells and the least in Caco-2 cells. Efflux transporter P-gp did not prevent cell from nanoparticles uptake. The cellular
uptake of nanoparticles was also confirmed in bronchoalveolar lavage (BAL) fluid cells and in bronchiolar epithelial cells,
type II alveolar epithelial cells in the intratracheally administrated rats. The nanoparticles uptake in MDCK, RAW cells and
in vivo lung epithelial cells indicated the potential applications of nanoformulation for poorly soluble compounds. The observed
limited direct uptake of nanoparticles in Caco-2 cells suggests that the improvement in oral bioavailability by particle size
reduction is via increased dissolution rate rather than direct uptake. 相似文献
16.
María G. Flores-Sánchez Atlántida M. Raya-Rivera Diego R. Esquiliano-Rendon Patricia G. Ontiveros-Nevares Nancy C. Islas-Arteaga Juan Morales-Corona 《国际聚合物材料杂志》2018,67(7):427-437
This paper presents the study scaffolds of polylactic acid (PLA) and hydroxyapatite (HA) processed by electrospinning and covered with polypyrrole with iodine (PPy-I) synthetized by plasma polymerization. Two kinds of samples were prepared: PLA/HA and PLA/HA/PPy-I, each with two different HA concentrations (18.1 and 35.7%). 7-day in vitro test with osteoblasts of autologous mesenchymal stem cells was performed. In vivo test was done in the back of a rabbit for 30 days. After extraction, cell viability, immunohistochemistry, histological, and tension tests were performed. Scaffolds PLA/HA (35.7%)/PPy-I showed higher cell viability. Tension test showed better integration in high HA samples. 相似文献
17.
Katarina Kalavska Zuzana Sestakova Andrea Mlcakova Katarína Kozics Paulina Gronesova Lenka Hurbanova Viera Miskovska Katarina Rejlekova Daniela Svetlovska Zuzana Sycova-Mila Jana Obertova Patrik Palacka Jozef Mardiak Michal Chovanec Miroslav Chovanec Michal Mego 《International journal of molecular sciences》2021,22(15)
Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs. 相似文献
18.
Mesoporous Ni?CP amorphous alloy nanospheres with controllable sizes and compositions were synthesized by chemical reduction of Ni(OH)2 colloidal particles co-assembling with surfactant hexadecyl-trimethyl-ammonium bromide in liquid crystal mesophase using hypophosphite as reductant. The effects of the synthesis conditions on the particle size, composition and mesostructure of the mesoporous Ni?CP nanospheres were systematically studied. It was found that the size of the mesoporous Ni?CP nanospheres could be tuned from 35 to 90?nm by changing the reduction temperature, and the phosphorus content of the Ni?CP products could be adjusted in the range of 20.1 to 27.6?% by changing the molar ratio of H2PO2 ?/Ni2+. The active surface area and the thermal stability of the mesoporous Ni?CP nanosphere catalyst are much higher than those for the conventional nonporous Ni?CP amorphous alloy. In the liquid phase hydrogenation of nitrobenzene, the typical mesoporous Ni?CP nanosphere catalyst exhibits much higher activity and better selectivity than the conventional nonporous Ni?CP. The correlation between the catalytic performance and the structural properties is discussed based on the results of detailed characterization. 相似文献
19.
Keil S Matter H Schönafinger K Glien M Mathieu M Marquette JP Michot N Haag-Diergarten S Urmann M Wendler W 《ChemMedChem》2011,6(4):633-653
Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type?II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20?a, displayed EC?? values of 1.6 and 336?nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20?a clearly displayed in?vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome. 相似文献
20.
Filip Michniewicz Dr. Federica Saletta Jourdin R. C. Rouaen Dr. Rehana V. Hewavisenti Dr. Daniele Mercatelli Dr. Giuseppe Cirillo Dr. Federico M. Giorgi Dr. Toby Trahair Assoc. Prof. David Ziegler Dr. Orazio Vittorio 《ChemMedChem》2021,16(15):2315-2329
Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy. 相似文献