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1.
Phytomedicine ; 91: 153671, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34425471

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of Hua Shi Bai Du Granule (Q-14) plus standard care compared with standard care alone in adults with coronavirus disease (COVID-19). STUDY DESIGN: A single-center, open-label, randomized controlled trial. SETTING: Wuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020. PARTICIPANTS: A total of 204 patients with laboratory-confirmed COVID-19 were randomized into the treatment group and control group, consisting of 102 patients in each group. INTERVENTIONS: In the treatment group, Q-14 was administered at 10 g (granules) twice daily for 14 days, plus standard care. In the control group, patients were provided standard care alone for 14 days. MAIN OUTCOME MEASURE: The primary outcome was the conversion time for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral assay. Adverse events were analyzed in the safety population. RESULTS: Among the 204 patients, 195 were analyzed according to the intention-to-treat principle. A total of 149 patients (71 vs. 78 in the treatment and control groups, respectively) tested negative via the SARS-CoV-2 viral assay. There was no statistical significance in the conversion time between the treatment group and control group (Full analysis set: Median [interquartile range]: 10.00 [9.00-11.00] vs. 10.00 [9.00-11.00]; Mean rank: 67.92 vs. 81.44; P = 0.051). The recovery time for fever was shorter in the treatment group than in the control group. The disappearance rate of symptoms like cough, fatigue, and chest discomfort was significantly higher in the treatment group. In chest computed tomography (CT) examinations, the overall evaluation of chest CT examination after treatment compared with baseline showed that more patients improved in the treatment group. There were no significant differences in the other outcomes. CONCLUSION: The combination of Q-14 and standard care for COVID-19 was useful for the improvement of symptoms (such as fever, cough, fatigue, and chest discomfort), but did not result in a significantly higher probability of negative conversion in the SARS-CoV-2 viral assay. No serious adverse events were observed. TRIAL REGISTRATION: ChiCTR2000030288.


Assuntos
COVID-19 , Medicamentos de Ervas Chinesas/uso terapêutico , COVID-19/terapia , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Ecotoxicol Environ Saf ; 222: 112514, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280841

RESUMO

Pendimethalin (PND) is one of the best sellers of selective herbicide in the world and has been frequently detected in the water. However, little is known about its effects on cardiac development. In this study, we used zebrafish to investigate the developmental and cardiac toxicity of PND. We exposed the zebrafish embryos with a serial of concentrations at 3, 4, and 5 mg/L at 5.5-72 h post-fertilization (hpf). We found that PND exposure can reduce the heart rate, survival rate, and body length of zebrafish embryos. Furthermore, we identified many malformations including pericardial and yolk sac edema, spinal deformity, and cardiac looping abnormality. In addition, PND increased the expression of reactive oxygen species and malondialdehyde and reduced the activity of superoxide dismutase (Antioxidant enzymes); We examined the expression of cardiac development-related genes and the apoptosis markers, and found changes of the following marker: vmhc, nppa, tbx5a, nkx2.5, gata4, tbx2b and FoxO1, bax, bcl-2, p53, casp-9, casp-3. Our data showed that activation of Wnt pathway can rescue the cardiac abnormalities caused by PND. Our results provided new evidence for the toxicity of PND and suggested that the PND residual should be treated as a hazard in the environment.


Assuntos
Embrião não Mamífero , Peixe-Zebra , Compostos de Anilina , Animais , Apoptose , Cardiotoxicidade/metabolismo , Embrião não Mamífero/metabolismo , Estresse Oxidativo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
Cancer Genet ; 258-259: 18-22, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34233240

RESUMO

The anaplastic lymphoma kinase (ALK) fusions/rearrangements in non-small cell lung cancer (NSCLC) act as oncogenic driver mutations. ALK tyrosine kinase inhibitors have anti-tumor activities in ALK-positive NSCLC. Although the EML4-ALK fusion is common in NSCLC, concomitance of an additional ALK fusion together with an EML4-ALK fusion is not common. Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies.

4.
Adv Healthc Mater ; 10(16): e2100695, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34176235

RESUMO

Electrical stimulation is regarded pivotal to promote repair of nerve injuries, however, failed to get extensive application in vivo due to the challenges in noninvasive electrical loading accompanying with construction of biomimetic cell niche. Herein, a new concept of magneto responsive electric 3D matrix for remote and wireless electrical stimulation is demonstrated. By the preparation of magnetoelectric core/shell structured Fe3 O4 @BaTiO3 NPs-loaded hyaluronan/collagen hydrogels, which recapitulate considerable magneto-electricity and vital features of native neural extracellular matrix, the enhancement of neurogenesis both in cellular level and spinal cord injury in vivo with external pulsed magnetic field applied is proved. The findings pave the way for a novel class of remote controlling and delivering electricity through extracellular niches-mimicked hydrogel network, arising prospects not only in neurogenesis but also in human-computer interaction with higher resolution.


Assuntos
Biomimética , Nanopartículas , Estimulação Elétrica , Humanos , Hidrogéis , Regeneração Nervosa
5.
ACS Appl Mater Interfaces ; 13(21): 24463-24476, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34024102

RESUMO

Viscoelasticity, a time-scale mechanical feature of the native extracellular matrix (ECM), is reported to play crucial roles in plentiful cellular behaviors, whereas its effects on neuronal behavior and the underlying molecular mechanism still remain obscure. Challenges are faced in the biocompatible synthesis of neural ECM-mimicked scaffolds solely controlled with viscoelasticity and due to the lack of suitable models for neurons-viscoelastic matrix interaction. Herein, we report difunctional hyaluronan-collagen hydrogels prepared by a static-dynamic strategy. The hydrogels show aldehyde concentration-dependent viscoelasticity and similar initial elastic modulus, fibrillar morphology, swelling as well as degradability. Utilizing the resulting hydrogels, for the first time, we demonstrate matrix viscoelasticity-dependent neuronal responses, including neurite elongation and expression of neurogenic proteins. Then, a motor-clutch model modified with a tension dissipation component is developed to account for the molecular mechanism for viscoelasticity-sensitive neuronal responses. Moreover, we prove enhanced recovery of rat spinal cord injury by implanting cell-free viscoelastic grafts. As a pioneer finding on neurons-viscoelastic matrix interaction both in vitro and in vivo, this work provides intriguing insights not only into nerve repair but also into neuroscience and tissue engineering.


Assuntos
Elasticidade , Hidrogéis , Neurogênese , Viscosidade , Animais , Células PC12 , Ratos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Frações Subcelulares/metabolismo , Engenharia Tecidual/métodos
6.
J Mater Chem B ; 9(7): 1846-1857, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33527969

RESUMO

Based on widely used photoacoustic imaging (PAI) and photothermal properties of polydopamine (PDA), a multifunctional Gd-PDA-Ce6@Gd-MOF (GPCG) nanosystem with a core-shell structure and strong imaging ability was constructed. Benefitting from the metal-organic framework (MOF) structure, GPCG nanoparticles (NPs) showed enhanced magnetic resonance imaging (MRI) ability with high relaxation rates (r1 = 13.72 mM-1 s-1 and r2 = 216.14 mM-1 s-1). The MRI effect of Gd ions combined with the PAI effect of PDA, giving GPCG NPs a dual-modal imaging ability. The core, mainly composed of PDA and photodynamic photosensitizer chlorin e6 (Ce6), achieved photothermal/photodynamic therapy (PTT/PDT) synergistic performance. Besides, to overcome the unexpected release of Ce6, the MOF shell realized pH-sensitive release and a high local concentration. Through in vivo studies, we concluded that GPCG NPs show a good inhibitory effect on tumor growth. In conclusion, we successfully obtained a GPCG theranostic nanoplatform and paved the way for subsequent design of imaging guided therapeutic nanostructures based on metal-doped PDA.


Assuntos
Antineoplásicos/farmacologia , Estruturas Metalorgânicas/farmacologia , Técnicas Fotoacústicas , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Nanomedicina Teranóstica , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Gadolínio/química , Gadolínio/farmacologia , Indóis/química , Indóis/farmacologia , Imageamento por Ressonância Magnética , Estruturas Metalorgânicas/química , Camundongos , Nanopartículas/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Polímeros/química , Polímeros/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Propriedades de Superfície , Células Tumorais Cultivadas
7.
Phytomedicine ; 81: 153367, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33260064

RESUMO

BACKGROUND: Treatments for coronavirus disease 2019 (COVID-19) are limited by suboptimal efficacy. METHODS: From January 30, 2020 to March 23, 2020, we conducted a non-randomised controlled trial, in which all adult patients with laboratory-confirmed COVID-19 were assigned to three groups non-randomly and given supportive treatments: Group A, Lopinavir-Ritonavir; Group B, Huashi Baidu Formula (a Chinese medicineformula made by the China Academy of Chinese Medical Sciences to treat COVID-19, which is now in the clinical trial period) and Lopinavir-Ritonavir; and Group C, Huashi Baidu Formula. The use of antibiotics, antiviruses, and corticosteroids was permitted in Group A and B. Traditional Chinese medicine injections were permitted in Group C. The primary outcomes were clinical remission time (interval from admission to the first time the patient tested negatively for novel coronavirus or an obvious improvement was observed from chest CT) and clinical remission rate (number of patients whose clinical time was within 16 days/total number of patients). RESULTS: A total of 60 adult patients with COVID-19 were enrolled at sites in Wuhan, China, and the sample size of each group was 20. In Groups A, B and C, the clinical remission rates were 95.0%%(19/20), 100.0%%(20/20) and 100.0%%(20/20), respectively. Compared with Groups A and B, the clinical remission time of Group C was significantly shorter (5.9 days vs. 10.8 days, p < 0.05; 5.9 days vs. 9.7 days, p < 0.05). There was no significant difference among Groups A, B, and C in terms of the time taken to be released from quarantine. The clinical biochemical indicators and safety indexes showed no significant differences among the three groups. CONCLUSIONS: Our findings suggest that Lopinavir-Ritonavir has some efficacy in the treatment of COVID-19, and the Huashi Baidu Formula might enhance this effect to an extent. In addition, superiority was displayed in the treatment of COVID-19 through a combination of the Huashi Baidu Formula and traditional Chinese medicine injection. In future, well-designed prospective double-blinded randomised control trials are required to confirm our findings.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , COVID-19/diagnóstico por imagem , Combinação de Medicamentos , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Lopinavir/efeitos adversos , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Ritonavir/efeitos adversos , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
8.
Mater Sci Eng C Mater Biol Appl ; 119: 111613, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321656

RESUMO

Construction of biomimetic microenvironment is vital to understand the relationship between matrix mechanical cues and cell fate, as well as to explore potential tissue engineering scaffolds for clinical application. In this study, through the enzymatic mineralizable collagen hydrogel system, we established the biomimetic bone matrix which was capable of realizing mechanical regulation independent of mineralization by incorporation of phosphorylated molecules (vinylphosphonic acid, VAP). Then, based on the biomimetic mineralized matrix with same composition but significantly different mechanical stiffness, we further investigated the effect of matrix stiffness on osteogenic differentiation of bone marrow stromal cells (BMSCs). The results clearly demonstrated that biomimetic mineralized microenvironment with higher mechanical strength promoted osteogenic differentiation of BMSCs. Further mechanism analysis demonstrated that the mineralized hydrogel with higher stiffness promoted cytoskeletal assembly, which enhanced the expression and nuclear colocalization of YAP and RUNX2, thereby promoted the osteogenic differentiation of stem cells. This study supplies a promising material platform not only for bone tissue engineering but also for exploring the mechanism of biomimetic bone matrix mechanics on osteogenesis.


Assuntos
Células-Tronco Mesenquimais , Osteogênese , Biomimética , Diferenciação Celular , Células Cultivadas , Citoesqueleto , Tecidos Suporte
9.
Carbohydr Polym ; 247: 116686, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32829814

RESUMO

Conductive and self-healing hydrogel sensor is perspective in human-machine interaction applications. However, the design of ideal self-healing hydrogels are always challenging. Herein, by introducing disulfide modified Ag nanowires (AgNWs), we show a novel self-healing hydrogel strain sensor with superior mechanics, conductivity, antibacterial property, and firstly realizing of self-healing with both recovery of mechanics and sensing properties. We demonstrate that the covalent and reversible non-covalent hydrophobic blocks in hydrophobic modified polyacrylamide (HMPAM) achieves the basic self-healing network; dextran with plentiful hydroxyl groups synergistic helps the self-healing by hydrogen bonds; disulfide on the AgNWs surface forms a NIR-responsive and dynamic Ag-S coordination bridge between HMPAM and AgNWs. The resulted hydrogel sensor exhibits comprehensive electromechanical properties, and precisely monitors human motion and subtle electromyography (EMG) signals. Importantly, we firstly achieved the recovery of sensing properties on human motion detection and EMG signal detection after self-healing. This work provides a promising exploration to manufacture bionic strain sensors for potential applications in wearable electronics.


Assuntos
Resinas Acrílicas/química , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Dextranos/química , Nanogéis/química , Nanofios/química , Prata/química , Antibacterianos/farmacologia , Condutividade Elétrica , Escherichia coli/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Raios Infravermelhos , Sistemas Homem-Máquina , Fenômenos Mecânicos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Peso Molecular , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Movimento (Física) , Nanogéis/ultraestrutura , Dispositivos Eletrônicos Vestíveis
11.
Biomacromolecules ; 21(9): 3745-3755, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32786729

RESUMO

As a key mechanical signal of natural extracellular matrix (ECM), stress relaxation plays an essential role in cell fate decision. However, the biomimetic matrix with fast stress relaxation and its cellular response mechanism have received little attention. Meanwhile, the nanofibrillar architecture which is conductive to mechanical transduction has invariably been ignored in the previous viscoelastic matrix design. Herein, by introducing a dynamic covalent imine bond into a physically cross-linked collagen hydrogel, we prepared bionic fast-relaxing nanofibrillar hydrogels with relaxation time less than 10 s. Through a single control of imine bond content, we realized fine-tuning of the relaxation rate while maintaining a constant initial modulus and fiber density. Using MC3T3-E1 cells as a model, we then proved that the nanofibrillar matrix with fast relaxation mechanics can effectively promote cell spreading and differentiation. In particular, TRPV4 as a molecular sensor of matrix viscoelasticity was demonstrated to regulate cell fate on the nanofibrillar hydrogels by mediating calcium influx. It is expected that the material design principle combining both nanofibrillar structure and tunable fast-relaxation can provide a more broadly adaptable materials platform for simulating natural ECM mechanical cues, and the investigation of the TRPV4 ion channel mediated cellular response will facilitate discovery of more fundamental mechanisms in tissue growth and development.


Assuntos
Hidrogéis , Canais de Cátion TRPV , Diferenciação Celular , Matriz Extracelular , Iminas
12.
Adv Healthc Mater ; 9(14): e2000205, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32548979

RESUMO

Bioactive metal-organic frameworks (bio-MOFs) built from biofunctional metal ions and linkers show a new strategy to construct multifunctional theranostic platforms. Herein, a bio-MOF is synthetized via the self-assembling of Fe3+ ions and doxorubicin hydrochloride (DOX) molecules. Then, through a stepwise assembly strategy, another bio-MOFs structure consisting of Gd3+ ions and 1,3,5-benzenetricarboxylic acid (H3 BTC) is wrapped on the surfaces of Fe-DOX nanoparticles, followed by adsorbing photosensitizer indocyanine green (ICG). Specifically, the Gd-MOF shell structure can not only act as a contrast agent for magnetic resonance imaging (MRI), but also provides protection for Fe-DOX cores, controlling the release of DOX. The photoacoustic and photothermal imaging (PAI and PTI) methods are successfully introduced to the platform by loading ICG, providing potential applications for multimodal biological imaging. The in vitro and in vivo outcomes indicate that the Fe-DOX@Gd-MOF-ICG nanoplatform exhibits outstanding synergistic antitumor performance via MR/PA/PT imaging guided chemotherapy, photothermal and photodynamic combination therapy. The work may encourage further exploration of bio-MOFs based multifunctional theranostic platforms for multimodal imaging guided compound antitumor therapy, which will open an avenue of MOFs toward biological applications.


Assuntos
Hipertermia Induzida , Nanopartículas , Doxorrubicina/farmacologia , Imagem Multimodal , Fototerapia , Medicina de Precisão , Nanomedicina Teranóstica
13.
Chemosphere ; 255: 126889, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388256

RESUMO

Pyrimethanil is a broad-spectrum fungicide commonly used in the prevention and treatment of Botrytis cinerea. However, little information is available in the literature to show the toxicity of Pyrimethanil to cardiac development. In this study, we used an experimental animal model to explore the developmental and cardiac toxicity of Pyrimethanil in aquatic vertebrates; we exposed zebrafish embryos to Pyrimethanil at concentrations of 2, 4, and 6 mg/L from 5.5 to 72 h post fertilisation. We found that Pyrimethanil caused a decrease in the hatching rate, heart rate, and survival rate of zebrafish embryos. Pyrimethanil exposure also resulted in pericardial and yolk sac edema, spinal deformity, and heart loop failure. Moreover, Pyrimethanil increased reactive oxygen stress levels and heightened the activity of superoxide dismutase and catalase. Alterations were induced in the transcription of apoptosis-related genes (p53, Bax, Bcl2, Casp 9, and Casp6l1) and heart development-related genes (Tbx2b, Gata4, Myh6, Vmhc, Nppa, Bmp2b, Bpm 4, and Bpm 10). Our data showed that the activation of Wnt signalling by BML-284 could partially rescue the malformed phenotype caused by Pyrimethanil. Our results provide new evidence for Pyrimethanil's toxicity and the danger of its residues in the environment and agricultural products.


Assuntos
Fungicidas Industriais/toxicidade , Pirimidinas/toxicidade , Animais , Apoptose , Cardiotoxicidade , Caspase 9 , Embrião não Mamífero/metabolismo , Estresse Oxidativo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
14.
Biofabrication ; 12(3): 035013, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32240990

RESUMO

Nerve tissues contain hierarchically ordered nerve fibers, while each of the nerve fibers has nano-oriented fibrous extracellular matrix and a core-shell structure of tubular myelin sheath with elongated axons encapsulated. Here, we report, for the first time, a ready approach to fabricate biomimetic nerve fibers which are oriented and have a core-shell structure to spatially encapsulate two types of cells, neurons and Schwann cells. A microfluidic system was designed and assembled, which contained a coaxial triple-channel chip and a stretching loading device. Alginate was used first to assist the fabrication, which was washed away afterwards. The orientation of the biomimetic nerve fibers was optimized by the control of the compositions of methacrylate hyaluronan and fibrin, together with the parameters of microfluidic shearing and external stretching. Also, neurons and Schwann cells, which were respectively located in the core and shell of the fibers, displayed advanced biologic functions, including neurogenesis and myelinating maturation. We demonstrate that the neural performance is relatively good, compared to that resulted from individually encapsulated in single-layer microfibers. The present study brings insights to fabricate biomimetic nerve fibers for their potential in neuroscience research and nerve regeneration. Moreover, the present methodology on the fabrication of oriented fibers with different types of cells separately encapsulated should be applicable to biomimetic constructions of various tissues.


Assuntos
Materiais Biomiméticos/farmacologia , Bainha de Mielina/fisiologia , Fibras Nervosas/fisiologia , Engenharia Tecidual , Animais , Materiais Biocompatíveis/química , Fibrina/química , Humanos , Ácido Hialurônico/química , Metacrilatos/química , Microfluídica , Bainha de Mielina/efeitos dos fármacos , Nanopartículas/química , Fibras Nervosas/efeitos dos fármacos , Neurogênese , Células PC12 , Ratos
15.
J Mater Chem B ; 8(18): 4093-4105, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32249879

RESUMO

As a direct thin band gap n-type semiconductor, bismuth sulfide (Bi2S3) nanomaterials possess great near-infrared (NIR)-triggered photothermal effects, photoacoustic (PA) and computed tomography (CT) imaging properties. Hence, Bi2S3 nanomaterials have become a research focal point in multiple domains, such as the construction of NIR-triggered nanosystems for cancer therapy. In this study, through a simple one-pot synthesis with the assistance of EDTA-2Na, we first obtained monodispersed spherical Bi2S3 of uniform particle sizes with fascinating photothermal and PA/CT imaging properties. Based on this, we introduced the photosensitizer Ce6 with photodynamic property and CeO2 with the O2-evolving characteristic, and thus designed a core-shell structure of the Bi2S3@Ce6-CeO2 nanocomposites (Bi2S3@Ce6-CeO2 NCs). The as-received Bi2S3@Ce6-CeO2 NCs exhibited a remarkable synergetic photothermal and photodynamic therapeutic effect both in vitro and in vivo, demonstrating its promising potential for cancer treatments. In the long term, the multifunctional PA/CT properties of both Bi2S3 NPs and Bi2S3@Ce6-CeO2 NCs in this study also supply a novel Bi2S3-based platform for constructing integrated diagnosis and treatment platforms.


Assuntos
Antineoplásicos/uso terapêutico , Materiais Biocompatíveis/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Bismuto/química , Bismuto/uso terapêutico , Linhagem Celular Tumoral , Cério/química , Cério/uso terapêutico , Feminino , Raios Infravermelhos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanocompostos/química , Nanopartículas/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Sulfetos/síntese química , Sulfetos/química , Sulfetos/uso terapêutico , Propriedades de Superfície
16.
J Mater Chem B ; 8(15): 3064-3075, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32202266

RESUMO

The simulation of the native bone matrix formation process is crucial for the construction of the cellular microenvironment for bone regeneration. However, it is still challenging to design bioactive materials that simultaneously mimic the composition and dynamic mineralization process of the bone matrix, let alone realize osteoinduction by a biomimetic dynamic microenvironment. In this study, we prepared a biomimetic mineralizable collagen hydrogel (CAV) and explored the effects of a dynamic mineralized matrix on the osteogenesis of stem cells both in vitro and in vivo. We showed the feasibility of the biomimetic CAV hydrogel to induce mineralization in simulated media including simulated body fluid (SBF), glycerol phosphate calcium salt hydrate (CaGP) solution and cell co-cultured systems. The participation of cells in the mineralization process is more likely to induce matrix remodeling due to the synergistic effects of CAV mineralization and cellular secretion, resulting in higher matrix strength. We also demonstrated that the biomimetic mineralized hydrogel could up-regulate osteogenic genes and protein expression of bone marrow mesenchymal stem cells (BMSCs), thus enhancing osteogenesis in vivo. The interactions between the mineralizable hydrogel and cells play an important role in regulating dynamic matrix mineralization and osteogenesis. Our findings prove that the biomimetic mineralizable hydrogel is a promising candidate for implantable orthopedic applications and provides essential implications for the future design of materials for bone regeneration.


Assuntos
Materiais Biomiméticos/farmacologia , Matriz Óssea/efeitos dos fármacos , Colágeno/farmacologia , Hidrogéis/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Microambiente Celular/efeitos dos fármacos , Colágeno/síntese química , Colágeno/química , Feminino , Hidrogéis/síntese química , Hidrogéis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Estrutura Molecular , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície
17.
Nature ; 578(7796): 577-581, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32076270

RESUMO

Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues1-4. H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca2+ increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimologia , Peróxido de Hidrogênio/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Cisteína/química , Cisteína/metabolismo , Ativação Enzimática , Proteínas de Membrana/química , Proteínas de Membrana/genética , Mutação , Oxirredução , Células Vegetais/metabolismo , Domínios Proteicos , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética
18.
J Biol Chem ; 295(14): 4696-4708, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32041778

RESUMO

Cell senescence is one of the most important processes determining cell fate and is involved in many pathophysiological conditions, including cancer, neurodegenerative diseases, and other aging-associated diseases. It has recently been discovered that the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1 or CHIP) is up-regulated during the senescence of human fibroblasts and modulates cell senescence. However, the molecular mechanism underlying STUB1-controlled senescence is not clear. Here, using affinity purification and MS-based analysis, we discovered that STUB1 binds to brain and muscle ARNT-like 1 (BMAL1, also called aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL)). Through biochemical experiments, we confirmed the STUB1-BMAL1 interaction, identified their interaction domains, and revealed that STUB1 overexpression down-regulates BMAL1 protein levels through STUB1's enzymatic activity and that STUB1 knockdown increases BMAL1 levels. Further experiments disclosed that STUB1 enhances BMAL1 degradation, which is abolished upon proteasome inhibition. Moreover, we found that STUB1 promotes the formation of Lys-48-linked polyubiquitin chains on BMAL1, facilitating its proteasomal degradation. Interestingly, we also discovered that oxidative stress promotes STUB1 nuclear translocation and enhances its co-localization with BMAL1. STUB1 expression attenuates hydrogen peroxide-induced cell senescence, indicated by a reduced signal in senescence-associated ß-gal staining and decreased protein levels of two cell senescence markers, p53 and p21. BMAL1 knockdown diminishes this effect, and BMAL1 overexpression abolishes STUB1's effect on cell senescence. In summary, the results of our work reveal that the E3 ubiquitin ligase STUB1 ubiquitinates and degrades its substrate BMAL1 and thereby alleviates hydrogen peroxide-induced cell senescence.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Senescência Celular , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Transcrição ARNTL/antagonistas & inibidores , Fatores de Transcrição ARNTL/genética , Núcleo Celular/metabolismo , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Cicloeximida/farmacologia , Regulação para Baixo , Células HEK293 , Humanos , Peróxido de Hidrogênio/farmacologia , Mutagênese Sítio-Dirigida , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
19.
ACS Appl Mater Interfaces ; 12(1): 260-274, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31800206

RESUMO

Stem cells sense and respond to their local dynamic mechanical niches, which further regulate the cellular behaviors. While in naturally, instead of instantly responding to real-time mechanical changes of their surrounding niches, stem cells often present a delayed cellular response over a time scale, namely cellular mechanical memory, which may finally influence their lineage choice. Here, we aim to build a dynamic mechanical niche model with alginate-based hydrogel, therein the dynamic mechanical switching can be easily realized via the introduce or removal of Ca2+. The results show that stiffening hydrogel (from soft to stiff) suppresses osteogenic differentiation of human mesenchymal stem cells (hMSCs) early on, though it finally promoted osteogenic differentiation over a long time period. Instead, softening hydrogel (from stiff to soft) still retains the strong osteogenic differentiation in the early days, though it finally showed a lower level of osteogenic differentiation compared with stiff hydrogel. Further, microRNA miR-21 has been found as a long-term mechanical memory sensor of the osteogenic program in hMSCs, as its level remains to match early mechanics of substrate over a period of time. Regulation of miR-21 level is efficient to erase the past mechanical memory and resensitize hMSCs to subsequent substrate mechanics. Our findings highlight cellular mechanical memory effect as a key factor of cell and cellular microenvironment interactions, which has been largely neglected before, and as a crucial design element of biomaterials for cell culture.


Assuntos
Alginatos/química , Hidrogéis/química , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Nicho de Células-Tronco , Diferenciação Celular , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia
20.
ACS Appl Mater Interfaces ; 11(46): 43018-43030, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31660723

RESUMO

Traditional tumor treatments suffer from severe side effects on account of their invasive process and inefficient outcomes. Featuring a unique physical microenvironment, the tumor microenvironment (TME) provides a new research direction for designing more efficient and safer treatment paradigms. In this study, we fabricated a polydopamine (PDA)-based TME-responsive nanosystem, which successfully integrates glucose degradation, the Fenton reaction, and photothermal therapy for efficient cancer therapy. Through a convenient hydrothermal method, Fe2+-doped Fe(II)-PDA nanoparticles were successfully fabricated, which show an excellent photothermal effect and interesting reactivity for the Fenton reaction. Instead of introducing toxic anticancer agents, natural glucose oxidase (GOD) was grafted on Fe(II)-PDA, forming a cascade catalytic nanomedicine for a specific response to the glucose in TME. GOD grafted on Fe(II)-PDA-GOD is ought to catalyze abundant glucose in TME into gluconic acid and H2O2. The concomitant generation of H2O2 can enhance the efficiency of the sequential Fenton reaction, producing abundant hydroxyl radicals (•OH) for cancer therapy. Besides, the overconsumption of intratumoral glucose also could inhibit tumor growth by reducing the energy supply. Taken together, the in vitro and in vivo antitumor studies of such TME-based Fe(II)-PDA-GOD nanosystems displayed a favorable synergistic potency of glucose degradation, the Fenton reaction, and photothermal therapy against tumor growth. Our design expands the biological application of multifunctional PDA while providing novel strategies toward effective antitumor treatment with minimal side effects.


Assuntos
Compostos Ferrosos , Hipertermia Induzida , Indóis , Neoplasias Mamárias Experimentais , Nanopartículas , Fototerapia , Polímeros , Microambiente Tumoral/efeitos dos fármacos , Animais , Catálise , Linhagem Celular Tumoral , Feminino , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Indóis/química , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros/química , Polímeros/farmacologia
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