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1.
Environ Int ; 136: 105475, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007923

RESUMO

Fine particulate matter (PM2.5) poses a significant risk to human health worldwide, by promoting oxidative stress and inflammation; however, the components responsible for these effects have not been fully evaluated. In this study, we investigated the cellular response of a macrophage cell line exposed to PM2.5 extracts in vitro. We obtained a dataset of chemical components of PM2.5 and determined those associated with the generation of reactive oxygen species (ROS) and secretion of inflammatory cytokines through an orthogonal partial least-squares (OPLS) regression. The results indicated that after water extracts exposure, both ROS and interleukin (IL)-1ß levels were positively correlated with transition metals. In cells exposed to dichloromethane extracts, IL-1ß secretion was significantly correlated with polycyclic aromatic hydrocarbons (PAHs); meanwhile, tumor necrosis factor (TNF)-α secretion was negatively associated with secondary nitrated PAHs, suggesting that atmospheric nitration process might modify the biological effects of PM2.5 components. We also performed source apportionment using a positive matrix factorization (PMF) model to explore the relative influence of different sources of components on cells. It was found that components from vehicle emissions promoted both ROS and TNF-α, while IL-1ß secretion was induced mainly by those from coal combustion. This study provides information regarding PM2.5 components having biological effects, and the sources thereof, which could inform effective measures for controlling this type of air pollution.

2.
FEBS Open Bio ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898405

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors in the digestive system. A greater understanding of the pathogenesis of PDAC may facilitate the search for new therapeutic targets. Guanine nucleotide-binding protein subunit gamma-12 (GNG12) belongs to the G protein family and participates in the modulation of the inflammatory signaling cascade. However, the cancer-related function and clinical relevance of GNG12 in PDAC have not previously been reported. Here, we investigated the clinical significance of GNG12 in PDAC using the Oncomine web tool, the gene expression profiling interactive analysis tool and tissue microarray (TMA). GNG12 expression was observed to be higher in PDAC patient specimens than in nontumor pancreatic tissues, and high expression of GNG12 was associated with poor prognosis. We subsequently show that GNG12 promotes pancreatic cancer cell growth in vivo and in vitro, as evaluated using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assays, colony formation assays and a xenograft mouse model. Furthermore, our results suggest that GNG12 activates nuclear factor-κB signaling and modulates the immune response. Collectively, our findings suggest that GNG12 may be suitable as a new prognosis-related biomarker and a promising target for treatment of pancreatic cancer.

3.
Proc Natl Acad Sci U S A ; 117(3): 1321-1329, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31896586

RESUMO

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.

4.
Sci Total Environ ; 704: 135284, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31806318

RESUMO

The efficient removal of toxic hexavalent chromium (Cr(VI)) is crucial for waste water treatment. Herein, we report a new strategy to couple adsorption and in situ photo-reduction of Cr(VI) to Cr (III) using metal-free, N-doped carbon facilely derived from naturally abundant biomass cellulose. Experimental results exhibited the removal rate of Cr(VI) can be significantly enhanced from 43.25 mg/g to 98.25 mg/g after visible light irradiation under acidic conditions. We demonstrated that toxic Cr(VI) ions were firstly adsorbed on N-doped carbon via electrostatic attraction, and then photo-reduced into Cr(III), followed by re-adsorption through chemical complexation. The carbon sp2-hybridized structures and electro-attracting graphic-N groups (N-(C)3) are proposed to be responsible for this photo-reduction effect. This work reveals the efficient removal of heavy metals through the cooperative adsorption and photo-reduction using the materials synthesized from biomass waste.

5.
Biochim Biophys Acta Mol Basis Dis ; 1866(4): 165431, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898538

RESUMO

Current application of human induced pluripotent stem cells (hiPSCs) technology in patient-specific models of neurodegenerative disorders recapitulate some of key phenotypes of diseases, representing disease-specific cellular modeling and providing a unique platform for therapeutics development. We review recent efforts toward advancing hiPSCs-derived neuronal cell types and highlight their potential use for the development of more complex in vitro models of neurodegenerative diseases by focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. We present evidence from previous works on the important phenotypic changes of various neuronal types in these neurological diseases. We also summarize efforts on conducting low- and high-throughput screening experiments with hiPSCs toward developing potential therapeutics for treatment of neurodegenerative diseases. Lastly, we discuss the limitations of hiPSCs culture system in studying neurodegenerative diseases and alternative strategies to overcome these hurdles.

6.
Ann Transl Med ; 7(20): 533, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807515

RESUMO

Background: Detection of distant metastasis (DM) is important in differentiated thyroid cancer (DTC). This study aimed to investigate the synergic effects of histology subtype, tumor size, and lymph node metastasis (LNM) status on the occurrence of DM in DTC. Methods: We collected data of 96,788 patients with DTC. Univariate and multivariate analyses were conducted to identify the risk factors of DM. Relative excess risk of synergic effect, attributable proportion of synergic effect, and synergy index were then calculated to assess synergic effects. Further, Kaplan-Meier method using the log-rank test and receiver operating characteristic (ROC) curves were utilized. Results: Age at diagnosis (P<0.001), sex (P<0.001), race (P<0.01), tumor size (P<0.001), N stage (P < 0.001), histology subtype (P<0.001), and extrathyroidal extension (P<0.001) were risk factors for DM in both univariate and multivariate analyses. We also found a significant additive synergic effect between histology subtype and LNM, and between tumor size and LNM on DM in the DTC patients. In addition, patients with follicular thyroid cancer and N1 stage had the sharpest decline in cancer-specific survival curves (P<0.001) and all-cause survival curves (P<0.001) compared to patients with other combinations of histology subtype and N stage. Similar results were obtained in patients with larger tumors (≥10 mm) and N1 stage. The areas under the curve of histology subtype, tumor size, and LNM status were 0.569, 0.744, and 0.681, respectively. Conclusions: Age at diagnosis, sex, race, tumor size, N stage, histology subtype, and extrathyroidal extension are risk factors for DM in DTC patients. LNM has a synergic effect with either follicular thyroid histology or larger tumor size for higher risk of DM which is important for diagnosing DM.

7.
Cereb Cortex ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819951

RESUMO

Comprehensive delineation of white matter (WM) microstructural maturation from birth to childhood is critical for understanding spatiotemporally differential circuit formation. Without a relatively large sample of datasets and coverage of critical developmental periods of both infancy and early childhood, differential maturational charts across WM tracts cannot be delineated. With diffusion tensor imaging (DTI) of 118 typically developing (TD) children aged 0-8 years and 31 children with autistic spectrum disorder (ASD) aged 2-7 years, the microstructure of every major WM tract and tract group was measured with DTI metrics to delineate differential WM maturation. The exponential model of microstructural maturation of all WM was identified. The WM developmental curves were separated into fast, intermediate, and slow phases in 0-8 years with distinctive time period of each phase across the tracts. Shorter periods of the fast and intermediate phases in certain tracts, such as the commissural tracts, indicated faster earlier development. With TD WM maturational curves as the reference, higher residual variance of WM microstructure was found in children with ASD. The presented comprehensive and differential charts of TD WM microstructural maturation of all major tracts and tract groups in 0-8 years provide reference standards for biomarker detection of neuropsychiatric disorders.

8.
Front Oncol ; 9: 1093, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681617

RESUMO

Objectives: Since the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis (AJCC/TNM) cancer staging system introduced some significant changes, we investigated whether patients with stage T1-2N1M1 differentiated thyroid cancer (DTC) should be placed in stage IVB, with the goal of providing suggestions for improved survival prediction. Materials and Methods: We divided 30,234 DTC patients aged ≥55 years enrolled from the Surveillance, Epidemiology, and End Results (SEER) database into different stage groups based on the new stage system but in a more thorough manner. Univariate and multivariate Cox regression analyses were conducted to explore the clinicopathological factors associated with cancer-specific survival. Survival of different stage groups was assessed by mortality rates per 1,000 person-years, Cox proportional hazards regression analyses, and Kaplan-Meier analyses with log-rank tests and the propensity score matching method. Results: Univariate and multivariate analyses demonstrated that age at diagnosis, T stage, lymph node metastasis, distant metastasis, histological types, extrathyroidal extension, and radiation therapy were associated with cancer-specific survival. Patients with stage T1-2N1M1 had a lower cancer-specific mortality rate per 1,000 person-years (28.081, 95% confidence interval [CI]: 12.616-62.505) and all-cause mortality rate per 1,000 person-years (70.203, 95% CI: 42.323-116.448) than those with low-level stages such as stage T4aN1M0, stage IVA, and stage T1-2N0M1. Cox proportional hazards regression analyses suggested that patients with stage T4bN1M0 belonging to stage IVA (hazard ratio: 2.529, 95% CI: 1.018-6.278, p = 0.046) had a significantly higher risk of cancer-specific mortality than those with stage T1-2N1M1. Kaplan-Meier analyses with log-rank tests suggested that the cancer-specific survival curve of patients with stage T1-2N1M1 had a more modest decline than that of stage T4bN1M0 (p = 0.0125), and the cancer-specific survival curve and all-cause survival curve of patients with stage T1-2N1M1 were not different from those of stage T3N1M0, stage T4aN0M0, stage T4aN1M0, stage T4bN0M0, and stage T1-2N0M1 (all, p > 0.05). The analysis yielded similar results after propensity score matching for other clinicopathological characteristics. Conclusion: Patients aged ≥55 years with stage T1-2N1M1 DTC according to the eighth edition AJCC/TNM cancer staging system should be downstaged and those with stage T4bN1M0 upstaged accordingly.

10.
Data Brief ; 26: 104459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31667231

RESUMO

In this article we report 5 terrestrial heat flow points along the southern Tan-Lu Fault Zone based on the first systematic deep borehole temperature measurements and thermal conductivities of 128 rock samples. All the temperature logs after 1 m spacing is plotted. The thermal properties test data of all samples have been collated separately, and the thermal conductivity correction data for different depths is presented. In combination with steady state temperature and thermal properties testing, the vertical variation of heat flow is calculated. Detailed interpretation of this data can be found in a research article titled "Heat flow, heat production, thermal structure and its tectonic implication of the southern Tan-Lu Fault Zone, East-Central China" (Wang et al., 2019) [1].

11.
Data Brief ; 27: 104700, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720344

RESUMO

We present 271 detrital single-grain zircon fission track (ZFT) ages obtained for eight sandstones, which were sampled from the southwestern Yangtze Craton, southern China. Accessory minerals were concentrated using standard crushing, sieving, electro-magnetic and heavy liquid mineral separation techniques. Zircon grains were mounted on FEP Teflon and polished to expose their internal surfaces to 4π geometry. Two to three mounts of each sample were etched in KON:NaOH eutectic melt at ∼228 °C for 12-60 hours to reveal spontaneous fission tracks. Etched mounts were covered with a uranium-free muscovite external detector for the irradiation with thermal neutrons. CN2 standard uranium glasses were embedded with the age standards (Fish Canyon Tuff zircons). After irradiation, external mica detectors were removed from sample mounts and then etched in 48% HF at room temperature for 30 min to reveal induced tracks. Fission track counting was performed using a Zeiss Axiotron microscope at a total magnification of 1250 × . Zircon fission-track ages were calculated using the ζ-calibration technique. The central ages (with 1σ error) vary from 144.7 ± 4.9 Ma to 256.7 ± 9.6 Ma, with variable P(χ2) values of 0%-75%. ZFT ages of the five Cambrian to Ordovician samples are younger than their depositional ages, and thus were fully reset by post-depositional heating. ZFT ages of three Jurassic samples are partially reset, as they overlap with or slightly younger than the corresponding depositional ages.

12.
Plant Physiol Biochem ; 144: 413-426, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31634809

RESUMO

Heteromorphic self-incompatibility (HetSI), which is regulated by sporophytes, occurs in some species as a strategy to promote cross-pollination. This research aimed to reveal metabolic changes occurring in HetSI. We used fluorescence microscopy as a tool to compare growth behavior in self-incompatible (SI) and self-compatible (SC) pollination in both pin and thrum flowers of Plumbago auriculata and to identify the ideal timepoint for sample collection for subsequent experiments. We also employed scanning electron microscopy (SEM) to evaluate intermorph structural differences in the pollen grains and stigmas in relation to HetSI. Importantly, UPLC-MS/MS was applied in this study to identify metabolites, compare metabolic differences between pin and thrum styles and monitor metabolic changes in SC and SI pollinations in the two types of flowers. The metabolites mainly included amino acids/peptides, flavonoids, glycosides/sugars, phenols, other organic acids, fatty acids (derivatives)/lipids, amines, aldehydes, alkaloids, alcohols and other compounds. Surprisingly, energy-related nutrients such as amino acids/peptides and tricarboxylic acid cycle-related metabolites were found at higher levels in SI pollinations than in SC pollinations. This result indicates that physiological changes in pollen-stigma interactions differ in pin and thrum styles and SC and SI pollinations and that energy deficiency is not one of the reasons for HetSI.


Assuntos
Flores/metabolismo , Plumbaginaceae/metabolismo , Flores/ultraestrutura , Metabolômica , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Plumbaginaceae/ultraestrutura , Espectrometria de Massas em Tandem
13.
Environ Pollut ; 255(Pt 1): 113087, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541815

RESUMO

Humic-like substances (HULIS) account for a considerable fraction of water-soluble organic matter (WSOM) in ambient fine particulates (PM2.5) over the world. However, systemic studies regarding the chemical characteristics, sources and redox activity of HULIS are still limited. In this study, the mass concentration, optical properties, and reactive oxygen species (ROS)-generation potential of HULIS were investigated in PM2.5 samples collected in Hong Kong during 2011-2012, and they all showed higher levels on days under regional pollution than on days under long range transport (LRT) pollution and local emissions. Positive matrix factorization (PMF) analysis was conducted regarding the mass concentration and dithiothreitol (DTT) activity of HULIS. Four primary sources (i.e. marine vessels, industrial exhaust, biomass burning, and vehicle emissions), and two secondary sources (i.e. secondary organic aerosol formation and secondary sulfate) were identified. Most sources showed higher contributions to both the mass concentration and DTT activity of HULIS on regional days than on LRT and local days, except that marine vessels had a higher contribution on local days than the other two synoptic conditions. Secondary processes were the major contributor to HULIS (54.9%) throughout the year, followed by biomass burning (27.4%) and industrial exhaust (14.7%). As for the DTT activity of HULIS, biomass burning (62.9%) and secondary processes (25.4%) were found to be the top two contributors. Intrinsic ROS-generation potential of HULIS was also investigated by normalizing the DTT activity by HULIS mass in each source. HULIS from biomass burning were the most DTT-active, followed by marine vessels; while HULIS formed through secondary processes were the least DTT-active. For the optical properties of HULIS, multiple linear regression model was adopted to evaluate the contributions of various sources to the light absorbing ability of HULIS. Biomass burning was found to be the only source significantly associated with the light absorbing property of HULIS.


Assuntos
Poluentes Atmosféricos/química , Monitoramento Ambiental/métodos , Substâncias Húmicas/análise , Material Particulado/química , Emissões de Veículos/análise , Aerossóis , Poluentes Atmosféricos/análise , Carvão Mineral/análise , Poeira/análise , Hong Kong , Oxirredução , Material Particulado/análise , Solubilidade , Água/química
14.
World J Clin Cases ; 7(17): 2587-2596, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31559297

RESUMO

BACKGROUND: The history of allogenic tooth transplantation can be traced back to the 16th century. Although there have been many successful cases, much needs to be better understood and researched prior to the technique being translated to everyday clinical practice. CASE SUMMARY: In the present report, we describe a case of allogenic tooth transplantation between a mother and her daughter. The first left maxillary molar of the mother was diagnosed with residual root resorption and needed to be extracted. The 3rd molar of the daughter was used as a donor tooth. Prior to transplantation, a 3D printing system was introduced to fabricate an individualized reamer drill specifically designed utilizing the donor's tooth as a template. The specific design of our 3D printed bur allowed for the recipient site to better match the donor tooth. With the ability to 3D print in layers, even the protuberance of the root can be matched and 3D printed, thereby minimizing unnecessary bone loss. CONCLUSION: Our study is a pioneering case combining 3D printing with allogenic tooth transplantation, which could be able to minimize unnecessary bone loss and improve the implant stability. This article aims to enhance our understanding of allogenic tooth transplantation and 3D printing, and may potentially lead to tooth transplantation being utilized more frequently - especially since transplantations are so commonly utilized in many other fields of medicine with high success rates.

15.
Sci Rep ; 9(1): 12481, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462667

RESUMO

CT has become a routine imaging modality based on its excellent ability of displaying lung structures and diseases. But, how to reduce radiation dose of routine CT examination is a concern for radiologists. Our study aimed to evaluate the feasibility of using 80kVp and a model-based iterative reconstruction (MBIR) algorithm to achieve one-tenth mSv dose chest CT in infants and young children. Thirty-two cases (study group, average age 1.71 ± 1.01 years) underwent non-contrast chest CT examination at low dose with 80 kV, 4mAs and was reconstructed with MBIR (LD-MBIR) and the standard adaptive statistical iterative reconstruction (ASIR) algorithm (LD-ASIR); another group (control group) of 32 children underwent routine-dose chest CT with 100 kV and was reconstructed with ASIR only (RD-ASIR). The subjective and objective image quality of the three groups were measured and statistically compared. The radiation dose for the low dose scan was 0.09 ± 0.02 mSv, 6% of the routine dose. All LD-MBIR images were diagnostically acceptable. Compared with the RD-ASIR images, the LD-MBIR images were similar in noise in the left ventricle, muscles, lung field, on-par in displaying large airways, lung lucency and mediastinum, but were inferior in displaying lung marking, small airways and mediastinum. Thus, MBIR images with low dose in pediatric chest CT can be used in the diagnosis for lung field and air way disorders in infants and young children.

16.
Nanoscale ; 11(33): 15519-15529, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31393491

RESUMO

Herein, a series of wrinkled silica nanoparticles with hierarchical pore (HPWSNs) supports were successfully prepared by dual-templating, and the special wrinkle pore structures in the monodisperse HPWSN samples were found to be beneficial for reducing the diffusion resistance of macromolecular aromatic compounds and achieving high dispersion of Ni2P active phases. Moreover, the distance between wrinkles in silica nanoparticles could be easily tuned by changing the ratios of SDS/CTAB through charge-reversed interactions. It was found that the Ni2P/HPWSNs-0.13 catalyst with smallest Ni2P particles had highest surface area and biggest pore volume. Furthermore, the Ni2P/HPWSNs-0.13 catalyst exhibited highest naphthalene hydrogenation conversion as well as 99.9% selectivity to decalin at 320 °C. To correlate the internal relationship between the macroscopic catalytic performance in the experiment and the atomic chemistry in the microscopic point of view, DFT calculations were performed, and the results showed that stronger adsorptions of naphthalene and tetralin occurred over the Ni(2) sites than those over the Ni(1) sites. Therefore, it can be concluded that the superior catalytic activity of the Ni2P/HPWSNs-0.13 catalyst is due to the synergistic effect of the center-radical framework structure and the small sizes of Ni2P particles, which are conducive to exposing more Ni(2) sites on the support surface, thus inducing more H for the naphthalene hydrogenation reaction.

17.
PLoS One ; 14(6): e0218171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31199822

RESUMO

Minimal extrathyroidal extension (ETE) is defined as tumor cells extending to the sternothyroid muscle or perithyroidal soft tissue. However, there is controversy regarding whether the magnitude of ETE (minimal or gross) should be considered in assigning a precise TNM stage to patients with thyroid cancer in the seventh/eighth editions of the AJCC system. The present study evaluated Surveillance, Epidemiology, and End Results data from 107,114 patients with differentiated thyroid cancer (2004-2013) to determine whether the magnitude of ETE (thyroid confinement, minimal, or gross) influenced the ability to predict cancer-specific survival (CSS) and overall survival (OS). Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The cancer-specific mortality rates per 1,000 person-years were 1.407 for the thyroid confinement group (95% CI: 1.288-1.536), 5.133 for the minimal ETE group (95% CI: 4.301-6.124), and 29.735 for the gross ETE group (95% CI: 28.147-31.412). Relative to the thyroid confinement group, patients with minimal ETE and gross ETE had significantly poorer CSS and OS in the univariate and multivariate analyses (both P<0.001). After propensity-score matching according to age, sex, and race, we found that thyroid confinement was associated with better CSS and OS rates than minimal ETE (P<0.001) and gross ETE (P<0.001). These results from a population-based cohort provide a reference for precise personalized treatment and management of patients with minimal ETE. Furthermore, it may be prudent to revisit the magnitude of ETE as advocated by the AJCC and currently used for treatment recommendation by the American Thyroid Association.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Musculares , Músculos do Pescoço , Neoplasias da Glândula Tireoide , Adulto , Fatores Etários , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/classificação , Neoplasias Musculares/mortalidade , Neoplasias Musculares/terapia , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/terapia
18.
Angew Chem Int Ed Engl ; 58(32): 10914-10918, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165553

RESUMO

New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor PtII complex targeting a tumor-associated protein, rather than DNA, under cellular conditions. Complex [(bis-NHC)Pt(bt)]PF6 (1 a; Hbt=1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis-NHC-ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active-site cysteine of ASNS.

19.
Nat Commun ; 10(1): 1703, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979871

RESUMO

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium.


Assuntos
Polaridade Celular , Citoesqueleto/fisiologia , Mandíbula/embriologia , Mandíbula/fisiologia , Proteína Wnt-5a/fisiologia , Citoesqueleto de Actina , Actomiosina/metabolismo , Animais , Cálcio/metabolismo , Ciclo Celular , Citosol/metabolismo , Elasticidade , Células Epiteliais/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Mutação , Oscilometria , Transdução de Sinais , Estresse Mecânico , Vinculina/metabolismo , Viscosidade
20.
Acta Neuropathol ; 137(6): 939-960, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30877431

RESUMO

Both α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that αSyn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which αSyn and mitochondrial proteins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Here, we show that the protein level of ClpP is selectively decreased in αSyn-expressing cell culture and neurons derived from iPS cells of PD patient carrying αSyn A53T mutant, and in dopaminergic (DA) neurons of αSyn A53T mice and PD patient postmortem brains. Deficiency in ClpP induces an overload of mitochondrial misfolded/unfolded proteins, suppresses mitochondrial respiratory activity, increases mitochondrial oxidative damage and causes cell death. Overexpression of ClpP reduces αSyn-induced mitochondrial oxidative stress through enhancing the level of Superoxide Dismutase-2 (SOD2), and suppresses the accumulation of αSyn S129 phosphorylation and promotes neuronal morphology in neurons derived from PD patient iPS cells carrying αSyn A53T mutant. Moreover, we find that αSyn WT and A53T mutant interact with ClpP and suppress its peptidase activity. The binding of αSyn to ClpP further promotes a distribution of ClpP from soluble to insoluble cellular fraction in vitro and in vivo, leading to reduced solubility of ClpP. Compensating for the loss of ClpP in the substantia nigra of αSyn A53T mice by viral expression of ClpP suppresses mitochondrial oxidative damage, and reduces αSyn pathology and behavioral deficits of mice. Our findings provide novel insights into the mechanism underlying αSyn-induced neuronal pathology, and they suggest that ClpP might be a useful therapeutic target for PD and other synucleinopathies.

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