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1.
Nature ; 627(8002): 64-66, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38448696

RESUMO

Planetary magnetic fields provide a window into the otherwise largely inaccessible dynamics of a planet's deep interior. In particular, interaction between fluid flow in electrically conducting interior regions and the magnetic field there gives rise to observable secular variation (time dependency) of the externally observed magnetic field. Secular variation of Jupiter's field has recently been revealed1-3 and been shown to arise, in part, from an axisymmetric, equatorial jet2. Whether this jet is time dependent has not previously been addressed, yet it is of critical importance for understanding the dynamics of the planet's interior. If steady, it would probably be a manifestation of deep dynamo convective flow (and jets are anticipated as part of that flow4-9) but if time dependent on a timescale much shorter than the convective turnover timescale of several hundred years, it would probably have a different origin. Here we show that the jet has a wavelike fluctuation with a period of roughly 4 years, strongly suggestive of the presence of a torsional oscillation10 (a cylindrically symmetric oscillating flow about the rotation axis) or a localized Alfvén wave in Jupiter's metallic hydrogen interior. This opens a pathway towards revealing otherwise hidden aspects of the magnetic field within the metallic hydrogen region and hence constraining the dynamo that generates Jupiter's magnetic field.

2.
J Am Chem Soc ; 146(18): 12530-12537, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38664859

RESUMO

Electrocatalytic nitrogen oxide reduction (NOxRR) emerges as an effective way to bring the disrupted nitrogen cycle back into balance. However, efficient and selective NOxRR is still challenging partly due to the complex reaction mechanism, which is influenced by experimental conditions such as pH and electrode potential. Here, we have studied the enzyme-inspired iron single-atom catalysts (Fe-N4-C) and identified that the selectivity roots in the first step of the nitric oxide reduction. Combining the constrained molecular dynamics (MD) simulations with the quasi-equilibrium approximation, the effects of electrode potential and pH on the reaction free energy were considered explicitly and predicted quantitatively. Systematic heat maps for selectivity between single-N and N-N-coupled products in a wide pH-potential space are further developed, which have reproduced the experimental observations of NOxRR. The approach presented in this study allows for a realistic simulation of the electrocatalytic interfaces and a quantitative evaluation of interfacial effects. Our results in this study provide valuable and straightforward guidance for selective NOx reduction toward desired products by precisely designing the experimental conditions.

3.
Bioorg Chem ; 147: 107360, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38604019

RESUMO

HSA (human serum albumin), a most abundant protein in blood serum, plays a key role in maintaining human health. Abnormal HSA level is correlated with many diseases, and thus has been used as an essential biomarker for therapeutic monitoring and biomedical diagnosis. Development of small-molecule fluorescent probes allowing the selective and sensitive recognition of HSA in in vitro and in vivo is of fundamental importance in basic biological research as well as medical diagnosis. Herein, we reported a series of new synthesized fluorescent dyes containing D-π-A constitution, which exhibited different optical properties in solution and solid state. Among them, dye M-H-SO3 with a hydrophilic sulfonate group at electron-acceptor part displayed selectivity for discrimination of HSA from BSA and other enzymes. Upon binding of dye M-H-SO3 with HSA, a significant fluorescence enhancement with a turn-on ratio about 96-fold was triggered. The detection limit was estimated to be âˆ¼ 40 nM. Studies on the interaction mechanism revealed that dye M-H-SO3 could bind to site III of HSA with a 1:1 binding stoichiometry. Furthermore, dye M-H-SO3 has been applied to determine HSA in real urine samples with good recoveries, which provided a useful method for HSA analysis in biological fluids.


Assuntos
Corantes Fluorescentes , Soroalbumina Bovina , Albumina Sérica Humana , Humanos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Estrutura Molecular , Bovinos , Animais , Espectrometria de Fluorescência
4.
Nature ; 561(7721): 76-78, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30185957

RESUMO

The Juno spacecraft, which is in a polar orbit around Jupiter, is providing direct measurements of the planet's magnetic field close to its surface1. A recent analysis of observations of Jupiter's magnetic field from eight (of the first nine) Juno orbits has provided a spherical-harmonic reference model (JRM09)2 of Jupiter's magnetic field outside the planet. This model is of particular interest for understanding processes in Jupiter's magnetosphere, but to study the field within the planet and thus the dynamo mechanism that is responsible for generating Jupiter's main magnetic field, alternative models are preferred. Here we report maps of the magnetic field at a range of depths within Jupiter. We find that Jupiter's magnetic field is different from all other known planetary magnetic fields. Within Jupiter, most of the flux emerges from the dynamo region in a narrow band in the northern hemisphere, some of which returns through an intense, isolated flux patch near the equator. Elsewhere, the field is much weaker. The non-dipolar part of the field is confined almost entirely to the northern hemisphere, so there the field is strongly non-dipolar and in the southern hemisphere it is predominantly dipolar. We suggest that Jupiter's dynamo, unlike Earth's, does not operate in a thick, homogeneous shell, and we propose that this unexpected field morphology arises from radial variations, possibly including layering, in density or electrical conductivity, or both.

5.
Heart Surg Forum ; 27(1): E006-E013, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38286647

RESUMO

Primary heart tumors are rare, with atrial myxomas being the most common type. Atrial myxomas can lead to embolisms, heart obstruction, and systemic symptoms. Herein, we report a case of 72-year-old woman who presented with a left atrial myxoma at the atrial septal defect occluder, a new acute cerebral infarction, and MINOCA (myocardial infarction with no obstructive coronary atherosclerosis). Left atrial myxoma is a common primary cardiac tumor; however, left atrial myxomas arising after percutaneous atrial septal defect occlusion are rare. Additionally, the patient presented with a new case of multiple systemic emboli. The patient underwent surgical resection of a left atrial myxoma, occluder, and left atrium, and atrial septal repair, and was discharged with good recovery for outpatient follow-up. The possibility of a cardiac tumor, especially an atrial myxoma, which can lead to a series of complications, should be considered at the closure site after percutaneous atrial septal closure. Therefore, active surgical treatment and long-term follow-up are warranted in such cases.


Assuntos
Embolia , Neoplasias Cardíacas , Comunicação Interatrial , Embolia Intracraniana , Mixoma , Dispositivo para Oclusão Septal , Feminino , Humanos , Idoso , Dispositivo para Oclusão Septal/efeitos adversos , Embolia Intracraniana/diagnóstico , Embolia Intracraniana/etiologia , Embolia Intracraniana/cirurgia , MINOCA , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/cirurgia , Embolia/diagnóstico , Embolia/etiologia , Embolia/cirurgia , Átrios do Coração/cirurgia , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/cirurgia , Mixoma/complicações , Mixoma/diagnóstico , Mixoma/cirurgia , Cateterismo Cardíaco/efeitos adversos
6.
Zhongguo Zhong Yao Za Zhi ; 49(8): 2076-2087, 2024 Apr.
Artigo em Zh | MEDLINE | ID: mdl-38812224

RESUMO

Raphani Semen, with both edible and medicinal values, is a typical Chinese herbal medicine with different effects before and after processing. The raw helps ascending and the cooked helps descending. This paper comprehensively summarizes the differences in chemical constituents and pharmacological effects between raw and processed Raphani Semen that are reported in recent years. Based on the principle of quality markers(Q-markers) of traditional Chinese medicines, the chemical constituent sources, chemical constituent detection techniques, and correlation between bidirectional regulatory efficacy and chemical constituents are compared between raw and processed Raphani Semen. The results suggest that sulforaphene and glucoraphanin could be used as candidate Q-markers of raw and processed Raphani Semen, respectively. This review is expected to provide a reference for further research on the processing, new drug development, and improvement of safety and effectiveness of Raphani Semen in clinical application.


Assuntos
Medicamentos de Ervas Chinesas , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Controle de Qualidade , Humanos , Biomarcadores/análise
7.
J Am Chem Soc ; 145(24): 13038-13047, 2023 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-37285479

RESUMO

The design of active and low-cost electrocatalyst for hydrogen evolution reaction (HER) is the key to achieving a clean hydrogen energy infrastructure. The most successful design principle of hydrogen electrocatalyst is the activity volcano plot, which is based on Sabatier principle and has been used to understand the exceptional activity of noble metal and design of metal alloy catalysts. However, this application of volcano plot in designing single-atom electrocatalysts (SAEs) on nitrogen doped graphene (TM/N4C catalysts) for HER has been less successful due to the nonmetallic nature of the single metal atom site. Herein, by performing ab initio molecular dynamics simulations and free energy calculations on a series of SAEs systems (TM/N4C with TM = 3d, 4d, or 5d metals), we find that the strong charge-dipole interaction between the negatively charged *H intermediate and the interfacial H2O molecules could alter the transition path of the acidic Volmer reaction and dramatically raise its kinetic barrier, despite its favorable adsorption free energy. Such kinetic hindrance is also experimentally confirmed by electrochemical measurements. By combining the hydrogen adsorption free energy and the physics of competing interfacial interactions, we propose a unifying design principle for engineering the SAEs used for hydrogen energy conversion, which incorporates both thermodynamic and kinetic considerations and allows going beyond the activity volcano model.

8.
Opt Express ; 31(19): 31486-31503, 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37710666

RESUMO

Microbial bacteria play an irreplaceable role in natural and human production and life; thus, determining their activities is an important issue. This study proposed a method to quantitatively determine the activity of microbial materials through extinction property calculation using infrared spectroscopy. Complex refractive indices of different active biomaterials were calculated based on their infrared spectra, and their extinction properties were determined using the discrete dipole approximation method. Using partial least squares (PLS), support vector regression (SVR), and extreme learning machine (ELM) regression, quantitative determination models of microbial materials based on infrared extinction properties were established to predict their activity. The results demonstrated that the model of least angle regression (LAR) combined with PLS exhibited better potential for the determination of biomaterial activity. The coefficient of determination (R2) values acquired by the optimal model for the three biomaterials were 0.9699, 0.9744, and 0.9621, respectively. These findings suggested that a rapid and accurate quantitative determination of microbial activity can be achieved based on extinction property.


Assuntos
Materiais Biocompatíveis , Aprendizagem , Humanos , Luz , Espectrofotometria Infravermelho
9.
Appl Opt ; 62(8): 1907-1914, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-37133073

RESUMO

Spectroscopic technique based on nanophotonic filters can recover spectral information through compressive sensing theory. The spectral information is encoded by nanophotonic response functions and decoded by computational algorithms. They are generally ultracompact, low in cost, and offer single-shot operation with spectral resolution better than 1 nm. Thus, they could be ideally suited for emerging wearable and portable sensing and imaging applications. Previous work has revealed that successful spectral reconstruction relies on well-designed filter response functions with sufficient randomness and low mutual correlation, but no thorough discussion has been performed on the filter array design. Here, instead of blind selection of filter structures, inverse design algorithms are proposed to obtain a photonic crystal filter array with predefined correlation coefficients and array size. Such rational spectrometer design can perform accurate reconstruction for a complex spectrum and maintain the performance under noise perturbation. We also discuss the impact of correlation coefficient and array size on the spectrum reconstruction accuracy. Our filter design method can be extended to different filter structures and suggests a better encoding component for reconstructive spectrometer applications.

10.
Mar Drugs ; 21(4)2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-37103365

RESUMO

Fascaplysin is a planar structure pentacyclic alkaloid isolated from sponges, which can effectively induce the apoptosis of cancer cells. In addition, fascaplysin has diverse biological activities, such as antibacterial, anti-tumor, anti-plasmodium, etc. Unfortunately, the planar structure of fascaplysin can be inserted into DNA and such interaction also limits the further application of fascaplysin, necessitating its structural modification. In this review, the biological activity, total synthesis and structural modification of fascaplysin will be summarized, which will provide useful information for pharmaceutical researchers interested in the exploration of marine alkaloids and for the betterment of fascaplysin in particular.


Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Indóis/farmacologia
11.
Molecules ; 28(4)2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36838867

RESUMO

Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by Pyrethrum cinerariifolium Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.


Assuntos
Furina , Permetrina , Humanos , COVID-19 , Furina/antagonistas & inibidores , Permetrina/farmacologia , Proteínas , SARS-CoV-2
12.
Biochem Biophys Res Commun ; 632: 189-194, 2022 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-36228519

RESUMO

Autoimmune diseases afflict nearly 10% of the world's population and have a serious impact on survival and quality of life. Unfortunately, the specific pathogenesis of almost all autoimmune diseases is still unclear, with more research findings identifying some key pathogenic genes at the genetic level and several pathogenic inflammatory factor phenotypes. ERAP1 has been suggested as a potential therapeutic target for several autoimmune diseases, especially MHC-Ⅰ related. How the structure and antigenic peptide processing function of ERAP1 affect the pathogenesis of these autoimmune diseases needs to be elucidated more clearly. Genetic studies on single nucleotide polymorphism of ERAP1 provide a good bridge to better understand the relationship and pattern between ERAP1 structure, function, and disease. However, existing reviews have focused on the genetic association of ERAP1 SNPs with autoimmune diseases, and no one has specifically addressed how ERAP1 gene polymorphisms embodied at the protein level specifically mediate antigenic peptide editing and the development of multiple autoimmune diseases. In this paper, we present a comprehensive review of these ERAP1 SNPs associated with multiple autoimmune diseases, in particular the polymorphisms affecting their protein structure and enzyme function, and attempt to unravel the underlying structural and biochemical mechanisms by which ERAP1 affects the pathogenesis of multiple autoimmune diseases through the SNP-protein structure-function-disease relationship. This study will provide theoretical help and ideas for understanding the relationship between ERAP1 and autoimmune diseases and for drug design targeting wild-type and mutant proteins with different polymorphisms.


Assuntos
Aminopeptidases , Doenças Autoimunes , Antígenos de Histocompatibilidade Menor , Humanos , Aminopeptidases/química , Aminopeptidases/genética , Aminopeptidases/metabolismo , Doenças Autoimunes/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/química , Proteínas Mutantes/genética , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
13.
BMC Cancer ; 22(1): 521, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534815

RESUMO

BACKGROUND: Tumor resistance is a global challenge for tumor treatment. Cancer stem cells (CSCs) are the main population of tumor cells for drug resistance. We have reported that high aldehyde dehydrogenase (ALDH) activity represents a functional marker for cervical CSCs. Here, we aimed at disulfiram (DSF), an ALDH inhibitor, that has the potential to be used for cervical cancer treatment. METHODS: MTT assay, western blot, vector construction and transfection, cell sorting and in vivo anti-tumor assays were performed using cervical cancer cell lines SiHa and HeLa. Cell cycle distribution and cell apoptosis were carried out by flow cytometry. The cytotoxicity of DSF was detected by MTT assay and cervical cancer xenograft models. RESULTS: DSF was cytotoxic to cervical cancer cell lines in a copper (Cu)-dependent manner. Disulfiram/copper (DSF/Cu) complex induced deregulation of S-phase and inhibited the expression of stemness markers in cervical cancer cells. Furthermore, DSF/Cu could also reduce the cancer stem cell-like LGR5+ cells which lead to cisplatin resistance in cervical cancer cells. DSF/Cu complex had the greater antitumor efficacy on cervical cancer than cisplatin in vitro and in vivo. CONCLUSION: Our findings indicate that the cytotoxicity of DSF/Cu complex may be superior to cisplatin because of targeting LGR5-positive cervical cancer stem-like cells in cervical cancer. Thus, the DSF/Cu complex may represent a potential therapeutic strategy for cervical cancer patients.


Assuntos
Antineoplásicos , Cobre , Dissulfiram , Neoplasias do Colo do Útero , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cobre/farmacologia , Dissulfiram/farmacologia , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias do Colo do Útero/patologia
14.
BMC Cancer ; 22(1): 691, 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35739510

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a third most common tumor of the urinary system. Nowadays, Immunotherapy is a hot topic in the treatment of solid tumors, especially for those tumors with pre-activated immune state. METHODS: In this study, we downloaded genomic and clinical data of RCC samples from The Cancer Genome Atlas (TCGA) database. Four immune-related genetic signatures were used to predict the prognosis of RCC by Cox regression analysis. Then we established a prognostic risk model consisting of the genes most related to prognosis from four signatures to value prognosis of the RCC samples via Kaplan-Meier (KM) survival analysis. An independent data from International Cancer Genome Consortium (ICGC) database were used to test the predictive stability of the model. Furthermore, we performed landscape analysis to assess the difference of gene mutant in the RCC samples from TCGA. Finally, we explored the correlation between the selected genes and the level of tumor immune infiltration via Tumor Immune Estimation Resource (TIMER) platform. RESULTS: We used four genetic signatures to construct prognostic risk models respectively and found that each of the models could divide the RCC samples into high- and low-risk groups with significantly different prognosis, especially in advanced RCC. A comprehensive prognostic risk model was constructed by 8 candidate genes from four signatures (HLA-B, HLA-A, HLA-DRA, IDO1, TAGAP, CIITA, PRF1 and CD8B) dividing the advanced RCC samples from TCGA database into high-risk and low-risk groups with a significant difference in cancer-specific survival (CSS). The stability of the model was verified by independent data from ICGC database. And the classification efficiency of the model was stable for the samples from different subgroups. Landscape analysis showed that mutation ratios of some genes were different between two risk groups. In addition, the expression levels of the selected genes were significantly correlated with the infiltration degree of immune cells in the advanced RCC. CONCLUSIONS: Sum up, eight immune-related genes were screened in our study to construct prognostic risk model with great predictive value for the prognosis of advanced RCC, and the genes were associated with infiltrating immune cells in tumors which have potential to conduct personalized treatment for advanced RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Prognóstico , Fatores de Risco
15.
Artigo em Inglês | MEDLINE | ID: mdl-35502996

RESUMO

A Gram-stain-positive, aerobic, endospore-forming and rod-shaped bacterium (KQ-3T), which grew at 10-45 °C (optimum 35 °C), pH 8.0-10.5 (optimum pH 9.0) and in the presence of 0-16 % (w/v) NaCl (optimum 3.0 %), was isolated from a soda lake and identified as representing a novel species using a polyphasic taxonomic approach. Strain KQ-3T was catalase-positive, oxidase-negative and non-motile. Phylogenetic analysis based on 16S rRNA gene sequence affiliated KQ-3T to the genus Alteribacter and showed the highest similarities to Alteribacter natronophilus M30T (97.90 %), Alteribacter aurantiacus K1-5T (97.84 %) and Alteribacter populi FJAT-45347T (97.22 %). Digital DNA-DNA hybridization and average nucleotide identity analyses revealed that KQ-3T displayed 21.4 and 72.81% genomic DNA relatedness with the most closely related strain, A. natronophilus M30T, respectively. KQ-3T contained all of the conserved signature indels that are specific for members of the genus Alteribacter. The DNA G+C content was 45.03 mol%. The cell-wall peptidoglycan contained meso-diaminopimelic acid and the polar lipids consisted of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and one unidentified phospholipid. The predominant menaquinone was MK-7 (100%) and the major fatty acids (>10 %) comprised anteiso-C15 : 0, iso-C15 : 0 and iso-C16 : 0. Based on the data from the current polyphasic studies, KQ-3T represents a novel species of the genus Alteribacter, for which the name Alteribacter keqinensis sp. nov. is proposed. The type strain is KQ-3T (=ACCC 61799T=KCTC 33933T).


Assuntos
Bacillaceae , Lagos , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/química , Lagos/microbiologia , Fosfolipídeos/química , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
16.
Phys Chem Chem Phys ; 24(21): 13305-13316, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35608012

RESUMO

Two-dimensional MoS2 nanosheets have shown great potential in heavy metal remediation due to their unique properties. MoS2 has two primary phases: 1T and 2H. Each has different physiochemical properties, but the impact of these differences on the overall material's heavy metal removal performance and associated mechanisms is rarely reported. In this study, we synthesized morphologically similar but phase-distinct MoS2 samples via hydrothermal synthesis, which comprised dominantly either a metallic 1T phase or a semiconducting 2H phase. 1T-MoS2 samples exhibited higher removal capacities for Ag+ and Pb2+ cations relative to 2H-MoS2. In particular, an eight-fold increase in the Pb2+ adsorption capacity was observed in the 1T-MoS2 samples (i.e. ∼632.9 mg g-1) compared to the 2H-MoS2 samples (∼81.6 mg g-1). The mechanisms driving the enhanced performance of 1T-MoS2 were investigated through detailed characterization of metal-laden MoS2 samples and DFT modelling. We found that 1T-MoS2 intrinsically had a larger interlayer spacing than 2H-MoS2 because water molecules were retained between the hydrophilic 1T nanosheets during hydrothermal synthesis. The widened interlayer spacing in 1T-MoS2 allowed the diffusion of heavy metal ions into the nanochannels, increasing the number of adsorption sites and total removal capacities. On the other hand, DFT modelling revealed the energy-favorable adsorption complex of Ag+ and Pb2+ for 1T-MoS2, in which each metal atom was bonded with three S atoms leading to much higher adsorption energies relative to 2H-MoS2 for Ag+ and Pb2+. This study unravels the underlying mechanisms of phase-dependent heavy metal remediation by MoS2 nanosheets, providing an important guide for the use of 2D nanomaterials in environmental applications which include heavy metal removal, contaminant sensing, and membrane separation.

17.
J Enzyme Inhib Med Chem ; 37(1): 431-444, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34957906

RESUMO

Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC50 values of 1.83 and 1.90 µM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cromonas/farmacologia , Desenho de Fármacos , Mecloretamina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Mecloretamina/química , Estrutura Molecular , Relação Estrutura-Atividade
18.
Proc Natl Acad Sci U S A ; 116(20): 9723-9728, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31036661

RESUMO

The radii and orbital periods of 4,000+ confirmed/candidate exoplanets have been precisely measured by the Kepler mission. The radii show a bimodal distribution, with two peaks corresponding to smaller planets (likely rocky) and larger intermediate-size planets, respectively. While only the masses of the planets orbiting the brightest stars can be determined by ground-based spectroscopic observations, these observations allow calculation of their average densities placing constraints on the bulk compositions and internal structures. However, an important question about the composition of planets ranging from 2 to 4 Earth radii (R⊕) still remains. They may either have a rocky core enveloped in a H2-He gaseous envelope (gas dwarfs) or contain a significant amount of multicomponent, H2O-dominated ices/fluids (water worlds). Planets in the mass range of 10-15 M⊕, if half-ice and half-rock by mass, have radii of 2.5 R⊕, which exactly match the second peak of the exoplanet radius bimodal distribution. Any planet in the 2- to 4-R⊕ range requires a gas envelope of at most a few mass percentage points, regardless of the core composition. To resolve the ambiguity of internal compositions, we use a growth model and conduct Monte Carlo simulations to demonstrate that many intermediate-size planets are "water worlds."

19.
Bioorg Med Chem Lett ; 40: 127952, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33744443

RESUMO

The cytotoxicity properties of the ß-carboline alkaloids have been broadly investigated. However, the potential application of ß-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty ß-carboline-(phenylsulfonyl)furoxan hybrids (11a-j, 12a-j and 13a-j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 µM) and MDA-MB-231 (IC50 = 0.62 µM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbolinas/farmacologia , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Sulfonas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Carbolinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Doadores de Óxido Nítrico/síntese química , Oxidiazóis/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química
20.
Bioorg Med Chem ; 45: 116341, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34365102

RESUMO

To discover the promising antitumor agents, a series of ß-carboline derivatives with nitrogen mustard moieties were designed and synthesized. Most target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cells. Among them, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate possessed the most potent antiproliferative activity with IC50 values of 1.79 µM and 4.96 µM, respectively, which were significantly higher than that of the parent compounds, and the efficacy was comparable to that of the positive control doxorubicin. More importantly, it showed weak cytotoxicity against human normal breast cell line MCF-10A (IC50 > 20 µM), exhibiting certain selectivity. Subsequently, further mechanism exploration indicated that it induced G2/M phase cell cycle arrest and apoptosis in MDA-MB-231 cells. The DCFH-DA fluorescent probe assay and comet assay showed that this compound could cause intracellular ROS accumulation and DNA damage. In addition, it exerted potent inhibitory effect on the migration, invasion and adhesion of MDA-MB-231 cells in vitro. In short, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate was considered as a promising compound for anti-breast cancer.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Desenho de Fármacos , Mecloretamina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Mecloretamina/química , Estrutura Molecular , Relação Estrutura-Atividade
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