RESUMO
Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.
Assuntos
Proliferação de Células , Ácido Hialurônico , Melanoma , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias Uveais , Verteporfina , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Animais , Fotoquimioterapia/métodos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologia , Camundongos , Melanoma/tratamento farmacológico , Melanoma/patologia , Humanos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Linhagem Celular Tumoral , Nanopartículas/química , Proliferação de Células/efeitos dos fármacos , Ácido Hialurônico/química , Receptores de Hialuronatos/metabolismo , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Camundongos Nus , Terapia de Alvo Molecular/métodos , Camundongos Endogâmicos BALB C , FemininoRESUMO
The fabrication of amphiphobic materials requires a precise and complicated design, especially for 3D porous materials, and amphiphobic sponges have rarely been investigated. This paper describes the synthesis of a superhydrophobic and oleophobic silicone sponge (SS-F) by simply building hierarchical structures, that is, introducing a secondary structure on the pore walls of a hydrophobic and oleophilic silicone sponge. This simple and efficient synthesis method is based on the thiol-ene click reaction. The uniform structure, composition, and hierarchical structures of SS-F are confirmed. The results of the analyses show that the secondary microstructure improves liquid repellency, while the rough and porous surface design ensures durability. Thus, SS-F exhibits good stability, and the amphiphobicity of the surface could withstand scalpel cutting, cyclic compression, extreme temperatures of 250 and -196 °C for 5 h, and long-term storage in an ambient environment. Both its outer and inner surfaces show superhydrophobicity and oleophobicity, which restrict the ability of the adsorption of liquids, enabling its use in oil and water. The introduction of hierarchical structures paves a way for preparing other 3D porous materials.
Assuntos
Silicones , Água , Adsorção , Bandagens , Interações Hidrofóbicas e HidrofílicasRESUMO
Silicone sponge, which is nontoxic, highly flexible, insulated, and chemically inert, has great promise in the aerospace, electronics, and health care industries. However, the inherent surface properties and the harsh synthesis method limit its application. A super-amphiphilic 3D silicone sponge is designed by a thiol-ene click reaction for the first time. The sponge possesses high porosity, low density, excellent adsorption ability, and reusability for water, oil, emulsions, and Hg2+ or dyes or suspended solids in them. The sponge can selectively adsorb a very high amount (941.3 mg g-1 ) of Hg2+ from solutions (water, oil, emulsions) containing various ions at a nearly 100% removal efficiency. Cation dyes can also be selectively captured by the sponge. Furthermore, the sponge is designed as a filter element for a filtration system, and the content of the pollutants in the filtrate reaches drinkable levels after the Hg2+ and dye solutions are processed. The filter can be reused with almost unchanged filtration efficiency after a simple washing process. The successful treatment of actual/artificial polluted water proves its practical value.
Assuntos
Poluentes Ambientais , Purificação da Água , Adsorção , Porosidade , SiliconesRESUMO
The preparation of a series of luminescent perovskite-silicone elastomer (PSE) composites by embedding inorganic lead halide perovskite nanocrystals (CsPbBr3 NCs) into networks constructed by trimethylolpropane tris(2-mercaptoacetate) and sulfone-containing silicone copolymers with vinyl side groups (PSMVS) is reported herein. The networks are obtained by an environmentally friendly thiol-ene cross-linking reaction under 30 W household LED light. The conducted analysis shows that the prepared PSEs display strong green fluorescence due to encapsulation of CsPbBr3 NCs, which constitute a luminescent center in sulfone-containing silicone networks. Using PSMVS as basic polymers instead of commercial polysiloxanes endows PSEs with enhanced mechanical strength and excellent luminescent stability at high temperatures. The PSEs show robust tensile stress and >650% elongation. Additionally, the construction of colorful ultraviolet light-emitting diodes (UV-LEDs) by an in situ cross-linking process is described.
Assuntos
Elastômeros de Silicone , Compostos de Sulfidrila , Compostos de Cálcio , Luminescência , Óxidos , TitânioRESUMO
CE is a promising technique for the analysis of glycosylated proteins, especially at the intact level. In the present study, the utility of CE for the separation of protein glycoforms is developed by using methyl chitosan as capillary coating. Methyl chitosan, in contrast to the polymers commonly used for coating, bears different types of amine groups, allowing for tunable charge states for various applications. The addition of methyl chitosan in background electrolyte can modulate the EOF and improve the separation performance. The methyl chitosan-coated capillary provided good separation of acidic or basic glycosylated proteins. Five ribonuclease B glycoforms were resolved by CE in less than 18 min, and the profile was essentially in agreement with that obtained by MALDI-TOF MS. The recombinant human erythropoietin glycoforms were well separated within 9 min. The developed method shows a great potential in protein glycoform analysis.
Assuntos
Quitosana/química , Eletroforese Capilar/métodos , Glicoproteínas/análise , Glicosilação , Humanos , Concentração de Íons de Hidrogênio , Proteínas Recombinantes/análiseRESUMO
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Microbioma Gastrointestinal/fisiologia , Animais , Disbiose/imunologia , Disbiose/microbiologia , Humanos , Imunomodulação/fisiologiaRESUMO
BACKGROUND: The development of a noninvasive, objective, and accurate method to assess peripheral nerve disorders in Guillain-Barre syndrome (GBS) is of clinical significance. Diffusion tensor imaging (DTI) has been used to evaluate some peripheral nerve disorders. PURPOSE: To investigate the feasibility of DTI in evaluating the peripheral nerve disorders in patients with GBS. STUDY TYPE: Case control. SUBJECTS: Twenty GBS patients and 16 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T, T1 WI-SE, T2 WI-SPAIR, DTI; electrophysiology. ASSESSMENT: MRI data were analyzed by two radiologists blindly and independently. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusion coefficient (AD), and radial diffusion coefficient (RD) values of tibial nerve (TN) and common peroneal nerve (CPN) were recorded. Motor nerve conduction velocity (MCV) and motor nerve conduction amplitude of TN and CPN were recorded. STATISTICAL TESTS: Intraclass correlation coefficient (ICC), t-test, receiver-operating characteristic (ROC), and area under the curve (AUC) analysis, Pearson correlation coefficient. RESULTS: The FA and AD values of TN and CPN in the GBS group were significantly lower and the ADC and RD values were higher than those in the controls (P <0.05). The AUC of the FA values (0.970 for TN and 0.927 for CPN) were higher than that of the ADC, AD, and RD values. FA and AD values were positively correlated and ADC, RD values were negatively correlated with MCV and motor nerve conduction amplitude, respectively (P <0.05). The correlations between FA value and electrophysiology parameters were the highest. DATA CONCLUSION: DTI quantitative parameters could evaluate the disorders of peripheral nerves in patients with GBS. A moderate correlation was observed between DTI and electrophysiology parameters. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1356-1364.
Assuntos
Imagem de Tensor de Difusão , Síndrome de Guillain-Barré/diagnóstico por imagem , Nervo Fibular/diagnóstico por imagem , Nervo Tibial/diagnóstico por imagem , Adolescente , Adulto , Idoso , Anisotropia , Estudos de Casos e Controles , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução NervosaRESUMO
Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy. Immunohistochemical analysis showed that EZH2 protein expression was absent in normal conjunctival melanocytes and primary acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and seven (88%) of eight lymph node metastases. Increased expression was positively associated with tumour thickness (p =0.03). Next, we targeted EZH2 with specific inhibitors (GSK503 and UNC1999) or depleted EZH2 by stable shRNA knockdown in three primary CM cell lines. Both pharmacological and genetic inactivation of EZH2 inhibited cell growth and colony formation and influenced EZH2-mediated gene transcription and cell cycle profile in vitro. The tumour suppressor gene p21/CDKN1A was especially upregulated in CM cells after EZH2 knockdown in CM cells. Additionally, the potency of GSK503 against CM cells was monitored in zebrafish xenografts. GSK503 profoundly attenuated tumour growth in CM xenografts at a well-tolerated concentration. Our results indicate that elevated levels of EZH2 are relevant to CM tumourigenesis and progression, and that EZH2 may become a potential therapeutic target for patients with CM. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Túnica Conjuntiva/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Melanoma/tratamento farmacológico , Piridonas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias da Túnica Conjuntiva/genética , Neoplasias da Túnica Conjuntiva/metabolismo , Neoplasias da Túnica Conjuntiva/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/secundário , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Peixe-ZebraRESUMO
BACKGROUND Diabetic retinopathy is a primary contributor of visual impairment in adult diabetes mellitus patients. Diabetic retinopathy causes breakdown of blood retinal barrier (BRB), and leads to diabetic macular edema. Previous studies have demonstrated angiopoietin-like protein 4 (ANGPTL4) as an effective diabetic retinopathy therapeutic target, however, its role in maintaining the outer BRB in diabetic retinopathy has yet not elucidated. MATERIAL AND METHODS We established an in vivo diabetic rat model with the use of streptozotocin injections and cultured ARPE-19 cells under (hypoxia, 1%) condition. We first investigated the expression of hypoxia induced factor-1alpha (HIF-1alpha) and ANGPTL4 in vivo and subsequently studied the transcriptional regulation and underlying molecular mechanisms in ARPE-19 cells under oxygen-deprived situations. RESULTS The expression of HIF-1alpha and ANGPTL4 was increased with diabetic retinopathy progression both in vivo and in vitro. Depletion of HIF-1alpha by siRNA inhibited hypoxia-induced ANGPTL4 expression. Repressing the HIF-1alpha/ANGPTL4 signaling effectively alleviated the migration and cellular permeability induced by hypoxia in ARPE-19 cells. Depletion of ANGPTL4 by siRNA significantly alleviated signal transducer and activator of transcription 3 (STAT3) activity in vitro, thereby attenuating the decrease of tight junction proteins occludin and zona occludens-1 (ZO-1) under hypoxia in ARPE-19 cells. CONCLUSIONS Our results suggest that ANGPTL4 partially modulates STAT3 and could serve as an effective diabetic retinopathy treatment strategy.
Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fator de Transcrição STAT3/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Animais , Glicemia/metabolismo , Peso Corporal , Hipóxia Celular , Linhagem Celular , Permeabilidade da Membrana Celular , Movimento Celular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Progressão da Doença , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Modelos Biológicos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Estreptozocina , Proteínas de Junções Íntimas/metabolismo , Regulação para Cima/genéticaRESUMO
Conjunctival melanoma (CM) is associated with metastases formation, can be fatal, and occurs in all different races. While cell lines are essential for experimental research, all available CM cell lines are derived from Caucasian patients. Furthermore, they are not derived from metastases. We aimed to establish a new CM cell line from a parotid metastasis in a Han Chinese patient and to depict its characteristics. The novel cell line, CM-AS16, was obtained from a surgical parotid sample and determined as a unique one with short tandem repeat (STR) analysis. It has been successively sub-cultured in vitro for more than 100 passages and exhibits rapid proliferation and migration. Chromosome analysis shows abundant chromosome aberrations, while whole exome sequencing (WES) reveals a typical NRAS mutation (Q61R). In vivo tumor growth was successfully established in a NOD/SCID mice model, and the immunophenotypes, such as HMB45, Melan A, S100, SOX10 and Ki67, manifested similar between the original tumor and the xenograft by immunohistochemistry. A MEK inhibitor binimetinib prominently suppressed in vitro cell growth by inhibiting ERK1/2 phosphorylation. In addition, monoclonal cells were used to demonstrate the drug sensitivity of different cells. In conclusion, the first cell line, CM-AS16, that is derived from a CM in a Han Chinese patient has highly malignant characteristics and a typical NRAS mutation. It may be used as a tool for further exploration of the molecular mechanisms of CM.
Assuntos
Neoplasias da Túnica Conjuntiva/patologia , Melanoma/patologia , Animais , Povo Asiático/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , China/epidemiologia , Neoplasias da Túnica Conjuntiva/genética , Neoplasias da Túnica Conjuntiva/metabolismo , DNA de Neoplasias/genética , Citometria de Fluxo , Genes ras , Humanos , Metástase Linfática , Masculino , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Glândula Parótida , Reação em Cadeia da Polimerase em Tempo Real , Sequenciamento do ExomaRESUMO
OBJECTIVE: The aim of the study was to investigate the molecular subtypes of breast cancer based on the texture features derived from magnetic resonance images (MRIs). METHODS: One hundred seven patients with preoperative confirmed breast cancer were recruited. One hundred eight breast lesions were divided into 4 subtypes according to the status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor type 2, and Ki67. Fisher discriminant analysis was performed on the texture features that extracted from the enhanced high-resolution T1-weighted images and diffusion weighted images to establish the classification model of molecular subtypes. RESULTS: The differentiation accuracies of Fisher discriminant analysis on the enhanced high-resolution T1-weighted images were 82.8% and 86.4% for 1.5T and 3.0T imaging. Fisher discriminant analysis on diffusion weighted imaging texture features were achieved with a classification ability of 73.4% and 88.6%. The combined discriminant results for 2 kinds magnetic resonance images were 95.0%, 97.7% in 1.5T and 3.0T imaging, respectively. CONCLUSIONS: The fine results indicated a promising approach to predict the molecular subtypes of breast cancer.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Inhibitory synchronization is commonly observed and may play some important functional roles in excitatory/inhibitory (E/I) neuronal networks. The firing rate contrast enhancement is a general feature of information processing in sensory pathways, and a new mechanism of contrast enhancement by inhibitory synchronization in E/I neuronal networks is investigated in this paper. Inspired by the firing rate contrast enhancement phenomenon by the lateral feed-forward inhibition, we reveal that the firing rate contrast enhancement could also occur by recurrent inhibition in E/I networks. It is further found that the synchronized inhibitory neurons act as a global inhibition which can enhance the firing rate contrast of excitatory neurons globally in synchronized E/I networks, even in partially synchronous states. Therefore, the firing rate contrast enhancement might be an important function of inhibitory synchronization and might facilitate information transmission in neural systems.
Assuntos
Potenciais de Ação/fisiologia , Inibição Neural/fisiologia , Redes Neurais de Computação , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Processamento Eletrônico de Dados , Humanos , Modelos Neurológicos , Células Receptoras Sensoriais , Transmissão SinápticaRESUMO
OBJECTIVES: To determine the diagnostic accuracy and interobserver performance of diffusion tensor imaging (DTI) in diabetic peripheral neuropathy (DPN) and detect correlations with electrophysiology. METHODS: Twelve healthy volunteers (controls) and ten DPN patients were enrolled to undergo MR examinations. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of tibial nerve (TN) and common peroneal nerve (CPN) were measured. Unpaired t test and Levene tests were performed to assess differences between the two groups. Receiver operating characteristic (ROC) analysis was performed for FA and ADC values. Pearson correlation coefficient was used to assess the correlation between DTI and electrophysiology parameters in the patient group. RESULTS: The FA values of TN and CPN in the DPN group were significantly lower and ADC were higher than the control group (p < 0.05). Interobserver agreement was excellent. FA positively correlated and ADC negatively correlated with motor nerve conduction velocity (MCV) (p < 0.05). There were no significant differences between motor nerve conduction amplitude and DTI parameters (p > 0.05). Moderate diagnostic accuracy of DTI was seen in the diagnosis of DPN. CONCLUSIONS: DTI demonstrates moderate diagnostic accuracy and excellent interobserver performance in the detection of DPN involving the TN and CPN. There is moderate correlation with MCV. KEY POINTS: ⢠FA values of TN and CPN are significantly lower in DPN. ⢠ADC values of TN and CPN are significantly higher in DPN. ⢠DTI demonstrates moderate diagnostic accuracy in detection of DPN. ⢠There is excellent interobserver performance in DTI measurements. ⢠Moderate correlation is seen between DTI parameters and MCV.
Assuntos
Neuropatias Diabéticas/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Nervo Fibular/diagnóstico por imagem , Nervo Tibial/diagnóstico por imagem , Adulto , Idoso , Anisotropia , Estudos de Casos e Controles , Neuropatias Diabéticas/fisiopatologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Variações Dependentes do Observador , Doenças do Sistema Nervoso Periférico/fisiopatologia , Curva ROCRESUMO
MicroRNAs (miRs) play a key role in the control of gene expression in a wide array of tissue systems, where their functions include the regulation of self-renewal, cellular differentiation, proliferation and apoptosis. However, the function and mechanisms of individual miRs in regulating spermatogonial stem cell (SSC) homeostasis remain unclear. In the present study, we report for the first time that miR-224 is highly expressed in mouse SSCs. Functional assays using miRNA mimics and inhibitors reveal that miR-224 is essential for differentiation of SSCs. Mechanistically, miR-224 promotes differentiation of SSCs via targeting doublesex and Mab-3-related transcription factor 1 (DMRT1). Moreover, WNT/ß-catenin signalling pathway is involved in miR-224-mediated regulation of SSCs self-renewal. We further demonstrate that miR-224 overexpression increases the expression of GFRα1 and PLZF, accompanied by the down-regulation of DMRT1 in mouse testes. Our findings provide novel insights into molecular mechanisms regulating differentiation of SSCs and may have important implications for regulating male reproduction.
Assuntos
Autorrenovação Celular/genética , MicroRNAs/metabolismo , Espermatogônias/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Biomarcadores/metabolismo , Diferenciação Celular/genética , Regulação da Expressão Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica , Frações Subcelulares/metabolismo , Testículo/citologia , Transfecção , Via de Sinalização Wnt/genéticaRESUMO
Ethambutol (EMB) is an essential first-line drug for tuberculosis (TB) treatment. Nucleotide substitutions at embB codon 306 (embB306) have been proposed to be a potential marker for EMB resistance and a predictor of broad drug resistance in clinical Mycobacterium tuberculosis isolates. However, discordant findings about the association between embB306 mutations and EMB resistance were reported. Hebei Province is located in the Beijing-Tianjin-Hebei integration region in China; however, little information about the genetic diversity of the embB locus in this area is available. In this study, we sequenced the region surrounding embB306 (codons 207 to 445) in 62 ethambutol-resistant (EMBr) isolates, 214 ethambutol-susceptible isolates resistant to other first-line drugs (EMBs isolates), and 100 pan-sensitive isolates. Our data indicated that none of the pan-sensitive isolates showed mutations at embB306 and 63 drug-resistant isolates harbored embB306 substitutions, with these substitutions being found in 56.5% (35/62) of EMBr isolates and 13.1% (28/214) of EMBs isolates. A significant association between the embB306 mutation and resistance to isoniazid, rifampin, EMB, and multiple drugs was observed, and the rate of mutation of embB306 increased with increasing numbers of first-line drugs to which the isolates were resistant. The embB306 mutation is not the sole causative factor for EMB resistance, and the poor sensitivity limits its utility as a marker for drug-resistant TB. However, it may be a potential marker for broad drug resistance, especially for multidrug resistance. The mycobacterial interspersed repetitive unit-variable-number tandem-repeat profiles may serve as markers for predicting the embB306 substitutions that may occur in drug-resistant M. tuberculosis isolates under antimicrobial selection pressure.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Etambutol/uso terapêutico , Mycobacterium tuberculosis/genética , Pentosiltransferases/genética , Tuberculose Pulmonar/tratamento farmacológico , Sequência de Bases , China , DNA Bacteriano/genética , Humanos , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/uso terapêutico , Análise de Sequência de DNA , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/microbiologiaRESUMO
Polysaccharide-based injectable hydrogels have several advantages in the context of biomedical use. However, the main obstruction associated with the utilization of these hydrogels in clinical application is their poor mechanical properties. Herein, we describe in situ gelling of nanocomposite hydrogels based on quaternized cellulose (QC) and rigid rod-like cationic cellulose nanocrystals (CCNCs), which can overcome this challenge. In all cases, gelation immediately occurred with an increase of temperature, and the CCNCs were evenly distributed throughout the hydrogels. The nanocomposite hydrogels exhibited increasing orders-of-magnitude in the mechanical strength, high extension in degradation and the sustained release time, because of the strong interaction between CCNCs and QC chains mediated by the cross-linking agent (ß-glycerophosphate, ß-GP). The results of the in vitro toxicity and in vivo biocompatibility tests revealed that the hydrogels did not show obvious cytotoxicity and inflammatory reaction to cells and tissue. Moreover, DOX-encapsulated hydrogels were injected beside the tumors of mice bearing liver cancer xenografts to assess the potential utility as localized and sustained drug delivery depot systems for anticancer therapy. The results suggested that the QC/CCNC/ß-GP nanocomposite hydrogels had great potential for application in subcutaneous and sustained delivery of anticancer drug to increase therapeutic efficacy and improve patient compliance.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cátions/química , Celulose/química , Hidrogéis/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Feminino , Glicerofosfatos/química , Humanos , Hidrogéis/química , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Engenharia Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Polymerization reactions are very common in the chemical industry, however, the reaction in which monomers are obtained from polymers is rarely invesitgated. This work reveals for the first time that oxone can break the Si-O-Si bond and induce further rearrangement to yield an ordered cyclic structure. The oxidation of P1, which is obtained by reaction of 2,2'-1,2-ethanediylbis(oxy)bis(ethanethiol) (DBOET) with 1,3-divinyl-1,1,3,3-tetramethyldisiloxane (MM(Vi)), with oxone yielded cyclic crystallized sulfone-siloxane dimer (P1-ox) after unexpected cleavage and rearrangement of the Si-O-Si bond.
Assuntos
Polímeros/química , Siloxanas/química , Sulfonas/química , Cristalização , Ciclização , Dimerização , Modelos Moleculares , Oxirredução , Ácidos Sulfúricos/químicaRESUMO
Although human echovirus 25 (E-25), a type of the enterovirus B species, is implicated in aseptic meningitis, information on its gene structure, evolution, and virulence are limited. We report here the complete genome sequence of a novel recombinant E-25 strain (E25/2010/CHN/BJ) isolated from a neonate with hand, foot, and mouth disease complicated by encephalitis in Beijing, China in 2010. The complete viral genome consists of 7429 nucleotides (nts), including a 6585-nt open reading frame. Phylogenetic dendrogram based on VP1 gene regions revealed that this strain belonged to subgroup D4, which contains the other E-25 strains isolated from China in recent years. The difference in the amino acid sites (P130S, K/T135I) of the VP1 region may affect its immunogenicity. SimPlot and Bootscan analyses suggested that E25/2010/CHN/BJ is a recombination result of E-25 and Coxsackievirus B3 (CVB-3) strains. Our results would facilitate the study of the origin, evolution, and molecular epidemiology of E-25.
Assuntos
Encefalite Viral/virologia , Enterovirus Humano B/genética , Genoma Viral , Doença de Mão, Pé e Boca/virologia , RNA Viral/genética , Recombinação Genética , Análise de Sequência de DNA , Pequim , Análise por Conglomerados , Enterovirus Humano B/classificação , Enterovirus Humano B/isolamento & purificação , Doença de Mão, Pé e Boca/complicações , Humanos , Dados de Sequência Molecular , Fases de Leitura Aberta , Filogenia , Homologia de SequênciaRESUMO
Background: Pre-eclampsia is a pregnancy-related disorder characterized by hypertension and proteinuria, severely affecting the health and quality of life of patients. However, the molecular mechanism of macrophages in pre-eclampsia is not well understood. Methods: In this study, the key biomarkers during the development of pre-eclampsia were identified using bioinformatics analysis. The GSE75010 and GSE74341 datasets from the GEO database were obtained and merged for differential analysis. A weighted gene co-expression network analysis (WGCNA) was constructed based on macrophage content, and machine learning methods were employed to identify key genes. Immunoinfiltration analysis completed by the CIBERSORT method, R package "ClusterProfiler" to explore functional enrichment of these intersection genes, and potential drug predictions were conducted using the CMap database. Lastly, independent analysis of protein levels, localization, and quantitative analysis was performed on placental tissues collected from both preeclampsia patients and healthy control groups. Results: We identified 70 differentially expressed NETs genes and found 367 macrophage-related genes through WGCNA analysis. Machine learning identified three key genes: FNBP1L, NMUR1, and PP14571. These three key genes were significantly associated with immune cell content and enriched in multiple signaling pathways. Specifically, these genes were upregulated in PE patients. These findings establish the expression patterns of three key genes associated with M2 macrophage infiltration, providing potential targets for understanding the pathogenesis and treatment of PE. Additionally, CMap results suggested four potential drugs, including Ttnpb, Doxorubicin, Tyrphostin AG 825, and Tanespimycin, which may have the potential to reverse pre-eclampsia. Conclusion: Studying the expression levels of three key genes in pre-eclampsia provides valuable insights into the prevention and treatment of this condition. We propose that these genes play a crucial role in regulating the maternal-fetal immune microenvironment in PE patients, and the pathways associated with these genes offer potential avenues for exploring the molecular mechanisms underlying preeclampsia and identifying therapeutic targets. Additionally, by utilizing the Connectivity Map database, we identified drug targets like Ttnpb, Doxorubicin, Tyrphostin AG 825, and Tanespimycin as potential clinical treatments for preeclampsia.
RESUMO
Plant-derived biomaterials have great application prospects in solving environmental pollution and sustainable resource utilization, but the insufficient mechanical strength and lack of functional responsiveness often limit their further development. Inspired by natural small molecules functionalization, a vacuum-assisted filtration nanofibrillated cellulose (NFC)-based film with excellent antibacterial properties, mechanical strength, and electrothermal/photothermal dual-responsiveness was fabricated. As a natural bioactive molecule, antibacterial cinnamaldehyde (CA) is grafted onto tannic acid (TA) rich in pyrogallols via a small molecule self-assembly strategy, and then co-assembled with zinc acetate (ZA) through ion crosslinking to synthesize the functional TACA@ZA nanospheres. After incorporating the MXene and TACA@ZA, an inorganic-organic 3D network system was established in the NFC matrix through dynamic intermolecular hydrogen bonding and strong ionic cross-linking. The mechanical strength and toughness of hybrid composites are remarkably improved by 83.6 % and 418.9 %, respectively. Due to the synergistic effects of MXene and TACA@ZA, the designed NFC-based film also shows significantly enhanced antibacterial activity, UV-blocking ability, as well as photothermal and electrothermal performance. This bioinspired small molecule functionalization strategy opens an innovative design concept for the fabrication of multirole NFC-based biomaterials, which has great application prospects in the commercial fields of multifunctional adhesives, electronic devices, UV shielding coatings, and antibacterial materials.