Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 159
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Death Dis ; 11(5): 327, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382019

RESUMO

Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase ß-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and ß-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/ß-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.

2.
Eur J Ophthalmol ; : 1120672120922447, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32370622

RESUMO

PURPOSE: To report a case with neurofibromatosis type 1 presenting as prominent enophthalmos and abnormal infraorbital artery. CASE DESCRIPTION: A 19-year-old man with a family history of neurofibromatosis presented with prominent right enophthalmos. Computed tomography showed orbital dysplasia and enlarged inferior orbital fissure but no plexiform neurofibroma. Prominent intraoperative hemorrhage originated from several abnormal arteries in the infraorbital region during orbital reconstruction. A tortuous and dysplastic infraorbital artery was verified postoperatively by computed tomography angiography. The bleeding vessels were supposed to be the orbital branches of the dysplastic infraorbital artery. CONCLUSIONS: The orbital malformation and enlargement of inferior orbital fissure probably resulted in an abnormal infraorbital artery. Selective artery embolization may be chosen as a preceding treatment before orbital reconstruction surgery.

3.
Medicine (Baltimore) ; 99(16): e19747, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311970

RESUMO

The objective of this retrospective study was to evaluate the efficacy of high-energy focused extracorporeal shock wave therapy (HF-ESWT) on painful bone marrow edema syndrome (BMES) of the hip and shorten the natural course of disease.Thirty-four consecutive patients with BMES of the hip were treated with HF-ESWT in our department between August 2017and July 2018. The progression and treatment results of BMES were evaluated by imaging examination and clinical outcomes. The clinical outcomes include hip pain and function which were measured using the visual analog scale (VAS) and Harris hip score (HHS), respectively, and the VAS and HHS of all patients were calculated and evaluated before treatment (s0), at 1 month (s1), 3 months (s2), 6 months (s3)post-treatment. Imaging examination including Pelvic radiographs and frog views and double hip magnetic resonance imaging (MRI) were also obtained and scheduled before treatment, at 1, 3, 6, and the final follow-up post-treatment to exclude avascular necrosis and other pathology.All patients successfully completed the treatment and follow-up. Compared with pretherapy, the pain was alleviated to varying degrees and the HHS was significantly improved, and the VAS was significantly reduced at S1-2 (1- and 3-months post-treatment) after therapeutic intervention (P < .05). The mean improvements were strongly statistically significant between S0 and S1 and between S1 andS2 (P < .0001) and less significant between S2 and S3 (P < .01). The mean improvement between 6 months (S3) and final follow-up (more than 12 months) was not statistically significant. The MRI findings demonstrated that the diffuse BMES in the femoral head and neck disappeared completely.HF-ESWT is a safe, effective, reliable, and noninvasive treatment in patients with painful BMES of the hip, and it can accelerate the recovery of BMES of the hip, shorten the treatment time and course of disease, improve hip joint function and the quality of life of patients.


Assuntos
Doenças da Medula Óssea/terapia , Edema/terapia , Tratamento por Ondas de Choque Extracorpóreas , Articulação do Quadril , Adulto , Feminino , Humanos , Masculino , Estudos Retrospectivos
4.
J Phys Chem Lett ; : 2053-2061, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32105076

RESUMO

Highly efficient blue-emitting three-dimensional (3D) lead-free halide perovskites with excellent stability have attracted worldwide attention. Herein, a doping route was adopted to incorporate Sb3+ ions into the Cs2NaInCl6 for decorating the electronic band structure. Due to the moderate electron-phonon coupling, the Sb3+-doped Cs2NaInCl6 double perovskites showed a narrow and relatively unusual blue emission of self-trapped excitons (STEs). Density functional theory (DFT) calculation indicated that the doped Sb3+ ions could break the parity-forbidden transition rule and modulate the density of state (DOS) population effectively to boost the PLQY of STEs drastically. The optimized Sb3+:Cs2NaInCl6 exhibited a PLQY of up to 75.89% and excellent stability under the consecutive illumination of 365 nm UV light for 1000 h. This kind of highly efficient lead-free Sb3+-doped Cs2NaInCl6 double perovskites may overcome the bottlenecks of severe toxicity and insufficient stability and therefore have an extensive application in the scarce blue photonic and optoelectronic fields.

5.
J Cell Physiol ; 235(7-8): 5511-5524, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32017075

RESUMO

There is now increasing evidence which suggests a key role for osteoblast apoptosis in the pathogenesis of postmenopausal osteoporosis. Here, we evaluated the role and mechanism of proteasome 26S subunit, ATPase (PSMC) 6, a protein that is highly expressed in bone. Gene expression pattern had been extracted based on database of Gene Expression Omnibus (GEO). GEO2R was employed for analyses, while the DAVID database was adopted to further analyze the gene ontology (GO) as well as Kyoto Encyclopedia of Genomes pathway (KEGG) enrichment. Then, the Search Tool Retrieval of Interacting Genes (STRING) was utilized to carry out interaction regulatory network for the top 200 differentially expressed genes (DEGs). A key gene, called PSMC6, was identified by Cytoscape 3.6.0. The OVX osteoporosis model was established in female C57BL/6 mice by full bilateral ovariectomy. According to our findings, PSMC6 gene knockout would elevate bone mineral density (BMD) and the phosphorylation level of PI3K protein and increased the protein level of cleaved caspase-3/-9 in OVX osteoporosis mice. Further, MTT, bromodeoxyuridine, and flow cytometry assays revealed that PSMC6 inhibition promoted the progression of cell cycle and cell proliferation, whereas, PSMC6 overexpression promoted the apoptosis and inhibited cell cycle progression and cell proliferation in vitro. Besides, we found that PI3K activation significantly decreased PSMC6-induced osteoblast apoptosis and promoted cell proliferation through regulating the protein levels of p53, cyclinD1, and cleaved caspase-3/9. In conclusion, PSMC6 aggravated the degree of OVX-induced osteoporosis by inhibiting the PI3K/AKT signal transduction pathway, thereby promoting the apoptosis of osteoblasts.

6.
Chem Commun (Camb) ; 56(17): 2550-2553, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32022017

RESUMO

A novel versatile thermally activated delayed fluorescence (TADF) nanoprobe, AI-Cz-NP, was designed and fabricated through self-assembly of a single-component amphiphilic monomer for potential applications in confocal imaging and time-resolved fluorescence imaging.


Assuntos
Corantes Fluorescentes/química , Nanoestruturas , Microscopia Confocal , Imagem Óptica , Temperatura
7.
Cell Death Dis ; 11(1): 1, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31911576

RESUMO

Cubosomes, a product of nanobioengineering, are self-structured lipid nanoparticles that act like drug-loaded theranostic probes. Here, we describe a simple method for the preparation of combinatorial drug-loaded cubosomes with, proof-of-principle, therapeutic effect against cancer cells, along with diagnostic capabilities. Anticancer drugs cisplatin and paclitaxel were loaded in the cubosomes in combination. The cubosomes were coated with a layer of poly-Ɛ-lysine, which helped avoid the initial burst release of drug and allowed for a slow and sustained release for better efficacy. Cubosomes were imaged by transmission electron microscope, and their dispersion analyzed in vitro by differential scanning calorimetric and X-ray diffractogram studies. The microscopic images depicted spherical polyangular structures, which are easily distinguishable. The analyses revealed that the drug is uniformly dispersed all through the cubosomes. Further characterization was carried out by zeta-potential measurement, in vitro release, and entrapment efficiency studies. The in vitro studies established that the coating of cubosomes successfully reduced the burst release of drugs initially and confirmed a slow, sustained release over increased time. Comparative cytotoxicity of coated, uncoated, and blank cubosomes was evaluated, using human hepatoma HepG2 cell line, and the formulations were found to be entirely nontoxic, similar to the blank ones. The therapeutic efficiency of the cubosomes against HeLa cells was confirmed by the impedance measurement and fluorescent imaging. Furthermore, the reduction in impedance in cells treated with coated combinatorial cubosomes proved the impairment of HeLa cells, as confirmed by fluorescence microscopy.

8.
Chem Rev ; 120(2): 683-733, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31549814

RESUMO

Selective catalytic hydrogenation has wide applications in both petrochemical and fine chemical industries, however, it remains challenging when two or multiple functional groups coexist in the substrate. To tackle this challenge, the "active site isolation" strategy has been proved effective, and various approaches to the site isolation have been developed. In this review, we have summarized these approaches, including adsorption/grafting of N/S-containing organic molecules on the metal surface, partial covering of active metal surface by metal oxides either via doping or through strong metal-support interaction, confinement of active metal nanoparticles in micro- or mesopores of the supports, formation of bimetallic alloys or intermetallics or core@shell structures with a relatively inert metal (IB and IIB) or nonmetal element (B, C, S, etc.), and construction of single-atom catalysts on reducible oxides or inert metals. Both advantages and disadvantages of each approach toward the site isolation have been discussed for three types of chemoselective hydrogenation reactions, including alkynes/dienes to monoenes, α,ß-unsaturated aldehydes/ketones to the unsaturated alcohols, and substituted nitroarenes to the corresponding anilines. The key factors affecting the catalytic activity/selectivity, in particular, the geometric and electronic structure of the active sites, are discussed with the aim to extract fundamental principles for the development of efficient and selective catalysts in hydrogenation as well as other transformations.

9.
Biochem Biophys Res Commun ; 521(2): 383-388, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31668924

RESUMO

The NADPH oxidase Nox4 is a multi-pass membrane protein responsible for the generation of reactive oxygen species that are implicated in cellular signaling but may also cause pathological situations when dysregulated. Although topological organization of integral membrane protein dictates its function, only limited experimental data describing Nox4's topology are available. To provide deeper insight on Nox4 structural organization, we developed a novel method to determinate membrane protein topology in their cellular environment, named Topological Determination by Ubiquitin Fusion Assay (ToDUFA). It is based on the proteolytic capacity of the deubiquitinase enzymes to process ubiquitin fusion proteins. This straightforward method, validated on two well-known protein's topologies (IL1RI and Nox2), allowed us to discriminate rapidly the topological orientation of protein's domains facing either the nucleocytosolic or the exterior/luminal compartments. Using this method, we were able for the first time to determine experimentally the topology of Nox4 which consists of 6 transmembrane domains with its N- and C-terminus moieties facing the cytosol. While the first, third and fifth loops of Nox4 protein are extracellular; the second and fourth loops are located in the cytosolic side. This approach can be easily extended to characterize the topology of all others members of the NADPH oxidase family or any multi-pass membrane proteins. Considering the importance of protein topology knowledge in cell biology research and pharmacological development, we believe that this novel method will represent a widely useful technique to easily uncover complex membrane protein's topology.

10.
J Cell Mol Med ; 24(1): 521-529, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657882

RESUMO

Mesenchymal stem cells (MSCs) are previously found to have potential capacity to differentiate into osteocytes when exposed to specific stimuli. However, the detailed molecular mechanism during this progress remains largely unknown. In the current study, we characterized the lncRNA NKILA as a crucial positive regulator for osteogenesis of MSCs. NKILA attenuation significantly inhibits the calcium deposition and alkaline phosphatase activity of MSCs. More interestingly, we defined that NKILA is functionally involved in the regulation of RXFP1/PI3K-AKT and NF-κB signalling. Knockdown of NKILA dramatically down-regulates the expression of RXFP1 and then reduces the activity of AKT, a downstream regulator of RXFP1 signalling which is widely accepted as an activator of osteogenesis. Moreover, we identify NF-κB as another critical regulator implicated in NKILA-mediated osteogenic differentiation. Inhibition of NF-κB can induce the expression of RUNX2, a master transcription factor of osteogenesis, in a HDAC2-mediated deacetylation manner. Thus, this study illustrates the regulatory function of NKILA in osteogenesis through distinct signalling pathways, therefore providing a new insight into searching for new molecular targets for bone tissue repair and regeneration.

11.
Cells ; 8(11)2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671755

RESUMO

Centriolar satellites are non-membrane cytoplasmic granules that deliver proteins to centrosome during centrosome biogenesis and ciliogenesis. Centriolar satellites are highly dynamic during cell cycle or ciliogenesis and how they are regulated remains largely unknown. We report here that sorting nexin 17 (SNX17) regulates the homeostasis of a subset of centriolar satellite proteins including PCM1, CEP131, and OFD1 during serum-starvation-induced ciliogenesis. Mechanistically, SNX17 recruits the deubiquitinating enzyme USP9X to antagonize the mindbomb 1 (MIB1)-induced ubiquitination and degradation of PCM1. SNX17 deficiency leads to enhanced degradation of USP9X as well as PCM1 and disrupts ciliogenesis upon serum starvation. On the other hand, SNX17 is dispensable for the homeostasis of PCM1 and USP9X in serum-containing media. These findings reveal a SNX17/USP9X mediated pathway essential for the homeostasis of centriolar satellites under serum starvation, and provide insight into the mechanism of USP9X in ciliogenesis, which may lead to a better understating of USP9X-deficiency-related human diseases such as X-linked mental retardation and neurodegenerative diseases.

12.
Nat Commun ; 10(1): 4500, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582748

RESUMO

Heterogeneous single-atom catalyst (SAC) opens a unique entry to establishing structure-performance relationship at the molecular level similar to that in homogeneous catalysis. The challenge lies in manipulating the coordination chemistry of single atoms without changing single-atom dispersion. Here, we develop an efficient synthetic method for SACs by using ethanediamine to chelate Pt cations and then removing the ethanediamine by a rapid thermal treatment (RTT) in inert atmosphere. The coordination chemistry of Pt single atoms on a Fe2O3 support is finely tuned by merely adjusting the RTT temperature. With the decrease in Pt-O coordination number, the oxidation state of Pt decreases, and consequently the hydrogenation activity increases to a record level without loss of chemoselectivity. The tunability of the local coordination chemistry, oxidation states of the metal, and the catalytic performance of single atoms reveals the unique role of SACs as a bridge between heterogeneous and homogeneous catalysis.

13.
Sci Rep ; 9(1): 13792, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551460

RESUMO

In biological tissues, radiation causes the formation of reactive oxygen species (ROS), some of which lead to sequential oxidation of certain protein cysteine residues. Resultant cysteinyl radicals are subject to post-translational modification through S-glutathionylation. The present clinical trial was designed to determine if S-glutathionylated serine protease inhibitors (serpins) in blood could be used as biomarkers of exposure to radiation. 56 male prostate cancer patients treated with radiotherapy were enrolled in the trial and levels of S-glutathionylated serpins A1 and A3 were assessed by immunoblotting. Patients were classified into three groups: (1) external beam radiation therapy (EBRT); (2) brachytherapy (BT); (3) both EBRT and BT. Prior to treatment, baseline plasma levels of both unmodified and S-glutathionylated serpins were similar in each group. We identified elevated plasma levels of S-glutathionylated serpin A1 monomer, trimer and serpin A3 monomer in patient blood following radiation. Maximal increased levels of these S-glutathionylated serpins were correlated with increased duration of radiotherapy treatments. We conclude that it is practical to quantify patient plasma S-glutathionylated serpins and that these post-translationally modified proteins are candidate biomarkers for measuring radiation exposure. This provides a platform for use of such biomarkers in trials with the range of drugs that, like radiation, produce ROS.

14.
Int J Oncol ; 55(5): 1077-1089, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545408

RESUMO

Peripheral T­cell lymphomas (PTCLs) are heterogeneous malignancies that are types of non­Hodgkin lymphomas; patients with this disease have poor prognoses. The IL­2­inducible T­cell kinase­spleen tyrosine kinase (ITK­SYK) fusion gene, the first recurrent chromosome translocation in PTCL­not otherwise specified (NOS), can drive cellular transformation and the development of T­cell lymphoma in mouse models. The aim of the current study was to investigate the signal transduction pathways downstream of ITK­SYK. The authors constructed a lentiviral vector to overexpress the ITK­SYK fusion gene in Jurkat cells. By using Signal­Net and cluster analyses of microarray data, the authors identified the tyrosine­protein kinase JAK (JAK)3/STAT5 signalling pathway as a downstream pathway of ITK­SYK, activation of which mediates the effects of ITK­SYK on tumourigenesis. JAK3­selective inhibitor tofacitinib abrogated the phosphorylation of downstream signalling molecule STAT5, supressed cell growth, induced cell apoptosis and arrested the cell cycle at the G1/S phase in ITK­SYK+ Jurkat cells. In a xenograft mouse model, tumour growth was significantly delayed by tofacitinib. Since JAK3 associates with interleukin­2 receptor subunit γ (IL2RG) only, siRNA­specific knockdown of IL2RG showed the same effect as tofacitinib treatment in vitro. These results first demonstrated that the activation of the IL2RG/JAK3/STAT5 signalling pathway contributed greatly to the oncogenic progress regulated by ITK­SYK, supporting further investigation of JAK3 inhibitors for the treatment of PTCLs carrying the ITK­SYK fusion gene.

15.
J Colloid Interface Sci ; 557: 112-123, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518833

RESUMO

Direct assembling 2D zeolitic imidazolate frameworks-derived (ZIFs)-derived Ni-Co oxide on Ni foam (NixCo3-xO4/Ni foam) is a very attractive way to obtain high performance for electrochemical energy storage device. In this work, the highly optimized NixCo3-xO4/Ni foam was prepared via facile co-precipitation, ion-exchange method and subsequently composited with rGO, acting as binder-less electrode for high properties hybrid supercapacitors. As electrode materials, the pure Co3O4/Ni foam shows 94.40 C g-1 (209.78 F g-1) at 1 A g-1, while the highly optimized NixCo3-xO4/Ni foam exhibits a high capacity of 870.3 C g-1 (1934F g-1) at 1 A g-1. Compared with NixCo3-xO4/Ni foam, the reduced graphene oxides (rGO) modified NixCo3-xO4/Ni foam electrodes possess a porous conductive structure, displaying more superior capacity of 1440.99 C g-1 (3202.22F g-1) at 1 A g-1 and a higher cycling stability of 76.10% retention value after 1000 cycles. Subsequently, the NixCo3-xO4/rGO/Ni foam electrodes were assembled as a hybrid supercapacitor, exhibiting a maximum energy density of 36.31 Wh kg-1, a maximum power density of 8000 W kg-1 and a good cycling stability of 76.29% retention value after 3000 cycles. The NixCo3-xO4/rGO/Ni foam also could light the blue LED device. Thereby, it is proved that NixCo3-xO4/rGO/Ni foam is a promising materials for hybrid supercapacitors.

16.
Talanta ; 205: 120133, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450408

RESUMO

Timely and effective detection of bacterial pathogens is of great importance to reduce morbidity rates from bacterial infections. Recently, enzyme-activated fluorogenic probes, which invoke enzymatic catalysis to trigger fluorescence emission, have been superior sensors for bacterial infections needed for accurate diagnoses. Here, a fluorescent sensor for nitroreductase (NTR) detection is described. It is based on a cyanine fluorophore and utilizes photoinduced electron transfer to generate a rapid 10-fold fluorescence response after being catalytically reduced by NTR. It has enabled selective and sensitive visualization of NTR activity in vitro and in living bacterial pathogens. Thus, the probe has great potential to provide a rapid, noninvasive tool to diagnose infections and guide antimicrobial selection.


Assuntos
Nitrorredutases/metabolismo , Imagem Óptica , Processos Fotoquímicos , Espectrometria de Fluorescência/instrumentação , Carbocianinas/química , Transporte de Elétrons , Concentração de Íons de Hidrogênio , Staphylococcus aureus Resistente à Meticilina/metabolismo , Nitrorredutases/antagonistas & inibidores , Temperatura
17.
J Econ Entomol ; 112(4): 1598-1603, 2019 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-31329887

RESUMO

Metarhizium rileyi, a well-known entomopathogenic fungus, could open up new vistas in biological control of insect pests; however, due to its intrinsic shortcomings, such as long pathogenic process, its application is largely limited. To explore which process, the invasion or the following in vivo development, is the main factor responsible for the long pathogenic process, the lethal effect of M. rileyi against Spodoptera litura (Fabricius) was determined by conidial topical application and hyphae body injection, and the host immune response was also monitored. Results showed when larvae were inoculated by conidial topical application, the pathogenicity of M. rileyi varied greatly depending on the larval instar and conidia concentration, and LC50 values ranged from 6.24 × 106 to 6.06 × 109 conidia/ml while LT50 values fluctuated from 4.35 to 9.43 d. However, in vivo study showed when hyphal bodies (Hbs) of M. rileyi were injected into host hemocoel, they would not be recognized by the host's immune system as invaders. There were no significant differences in the hemocytes and phenoloxidase activity between the infected and control larvae at the initial 44 h, indicated that the fungus was able to successfully avoid the attack from the cellular and humoral immune systems, therefore, it could multiply freely in the hemocoel. The in vivo development time of M. rileyi tended to remain constant for 2-3 d regardless of the initial inoculated numbers. Considering no detectable defense response was observed during in vivo development, it can be concluded that host nonself-recognition system does not respond to the hemolymph borne-Hbs.


Assuntos
Metarhizium , Mariposas , Animais , Larva , Spodoptera , Virulência
18.
Chem Commun (Camb) ; 55(61): 9031-9034, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292574

RESUMO

A Cu-NWs paper synthesized by a one-step method is first presented. Owing to its good conductivity, it is an effective framework to interlink TMOs and prevent aggregation. For a practical application, the core-shell Cu NWs@ultrathin CoOx delivers good performance for the catalytic oxidation of glucose and energy storage, with a sensitivity of 396.57 µA mM-1 cm-2 and a capacitance of 797.7 F g-1 (1 A g-1).

19.
Cell Signal ; 62: 109343, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31176746

RESUMO

Plexin-B2 (PLXNB2), a transmembrane protein is found in various tissues. Recent studies have indicated the presence of PLXNB2 in large quantity in the growth plates of Sprague-Dawley rats and are believed to be potentially involved in their skeletal development. This study endeavored to analyze the effect of PLXNB2 on the osteogenic differentiation of BMSCs by using gene overexpression and knockdown assays. The results of our study revealed that PLXNB2 was upregulated during BMSCs differentiation into an osteoblastic lineage. By determining the expression levels of specific markers and mineral deposition, the study established that PLXNB2 promotes the osteogenic differentiation of human BMSCs through the activation of the RhoA signaling pathway. In conclusion, the study identified PLXNB2 as a novel regulator that enhanced the osteogenic differentiation of human BMSCs. The enhancing effect of PLXNB2 on osteogenesis of human BMSCs was mediated through activation of RhoA signaling. The results of our study imply that pharmacological targeting of PLXNB2 may initiate a possible improvement in bone formation.

20.
Cancer Res ; 79(16): 4072-4085, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31227482

RESUMO

ME-344 is a second-generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species and this initiated a nuclear erythroid factor 2-like 2 signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels, were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared with normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected, resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344. SIGNIFICANCE: A novel cytotoxic isoflavone is shown to inhibit heme oxygenase, a desirable yet elusive target that disrupts redox homeostasis causing cell death.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA