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The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor ß1 (TGF-ß1)-activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle-promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor-controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-ß/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Transformação Celular Neoplásica , Genes ras , Proteína Smad3 , Humanos , Transformação Celular Neoplásica/genética , Senescência Celular/genética , Genes Supressores de Tumor , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
BACKGROUND: The COVID-19 pandemic is bringing about substantial changes in health care systems, leading to a significant shift toward telemedicine for the delivery of health care services. OBJECTIVE: This study aims to examine the relationship between perceived usefulness and ease of use of telemedicine services and their association with the behavioral intention to use telemedicine. METHODS: An anonymous cross-sectional survey was conducted in China. Partial least squares structural equation modeling was used to determine significant predictors of intention to use telemedicine consultation. Types of illnesses that favored seeking telemedicine consultation, as well as the most preferred platform for conducting telemedicine consultations, were also investigated. RESULTS: In total, 1006 participants completed the survey. A total of 44.3% (n=446) reported being very likely and 49.3% (n=496) reported being likely to seek telemedicine consultation. Overall, the majority of participants expressed strong agreement or agreement regarding the perceived usefulness of telemedicine. Likewise, the majority indicated strong agreement or agreement when it came to their perception of the ease of using telemedicine. In the partial least squares structural equation modeling, perceived usefulness (ß=0.322; P<.001) and perceived ease of use (ß=0.118; P=.01) were significantly associated with a higher likelihood of seeking telemedicine consultation. A considerable number of participants expressed willingness to use telemedicine services for various medical conditions, particularly respiratory (n=340, 33.8%), skin (n=316, 31.4%), and musculoskeletal issues (n=316, 31.4%) while showing less interest in seeking telemedicine consultations for reproductive health (n=44, 4.4%) and cancer (n=64, 6.4%). The majority preferred video chat (n=443, 44%) and text chat (n=317, 31.5%) as their most preferred platforms for telemedicine consultation, while a smaller proportion preferred telephone (n=193, 19.2%) and email (n=53, 5.3%). CONCLUSIONS: Telemedicine has the potential to play a larger role in China's health care system. The preferences for certain platforms over others may influence service design and implementation.
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COVID-19 , Aceitação pelo Paciente de Cuidados de Saúde , Telemedicina , Humanos , Telemedicina/estatística & dados numéricos , Estudos Transversais , China , Masculino , Feminino , Adulto , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem , SARS-CoV-2 , Adolescente , PandemiasRESUMO
This paper presents a novel quasi-zero stiffness vibration sensing and energy harvesting integration system for absolute displacement measurements based on a buckled piezoelectric Euler beam (BPEB) with quasi-zero stiffness (QZS) characteristics. On one hand, BPEB provides negative stiffness to the system, thus creating a vibration-free point within the system and transforming the absolute displacement measurement problem into a relative motion sensing problem. On the other hand, during the measurement process, the BPEB collects the vibration energy from the system, which can provide electrical energy for low-power relative motion sensing devices and remarkably suppress the frequency range of the jump phenomenon, thereby further expanding the frequency domain measurement range of the sensing system. The research results have shown that this system can measure the absolute motion signal of the tested object in low-frequency vibration with small excitation. By adjusting parameters such as the force-electric coupling coefficient and damping ratio, the measurement accuracy of the sensing system can be improved. Furthermore, the system can convert the mechanical energy of vibrations into electrical energy to power the surrounding low-power sensors or provide partial power. This could potentially achieve self-powering integrated quasi-zero stiffness vibration sensing, offering another approach and possibility for the automation development in wireless sensing systems and the Internet of Things field.
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Depression is one of the most fatal mental diseases, and there is currently a lack of efficient drugs for the treatment of depression. Emerging evidence has indicated oxidative stress as a key pathological feature of depression. We targeted reactive oxygen species (ROS) and synthesized CeO2@BSA nanoclusters as a novel antidepression nanodrug via a convenient, green, and highly effective bovine serum albumin (BSA) incubation strategy. CeO2@BSA has ultrasmall size (2 nm) with outstanding ROS scavenging and blood-brain barrier crossing capacity, rapid metabolism, and negligible adverse effects in vitro and in vivo. CeO2@BSA administration alleviates depressive behaviors and depression-related pathological changes of the chronic restraint stress-induced depressive model, suggesting promising therapeutic effects of CeO2@BSA for the treatment of depression. Our study proved the validity by directly using nanodrugs as antidepression drugs instead of using them as a nanocarrier, which greatly expands the application of nanomaterials in depression treatment.
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Nanoestruturas , Soroalbumina Bovina , Depressão/tratamento farmacológico , Nanoestruturas/uso terapêutico , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND & AIMS: Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive. METHODS: A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed. RESULTS: A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P < .001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P < .001) and alcohol consumption (HR, 1.86; P < .001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea. CONCLUSIONS: Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).
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Insuficiência Pancreática Exócrina , Pancreatopatias , Pancreatite Crônica , Insuficiência Pancreática Exócrina/genética , Humanos , Masculino , Mutação , Pancreatopatias/complicações , Pancreatite Crônica/complicações , Pancreatite Crônica/epidemiologia , Pancreatite Crônica/genética , Estudos Prospectivos , Fatores de Risco , Inibidor da Tripsina Pancreática de Kazal/genéticaRESUMO
BACKGROUND: Glioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs' alteration remain unkown. METHODS: We collected EVs in the culture medium of three classic glioblastoma cell lines, U87 and A172 (male cell lines), and LN229 (female cell line). U87, A172, and LN229 were co-cultured with their corresponding EVs, respectively. Mouse NPCs (mNPCs) were co-cultured with glioblastoma-derived EVs. The proliferation and migration of tumor cells and mNPCs after EVs treatment were examined. Proteomic analysis and western blotting were utilized to identify the underlying mechanisms of glioblastoma-derived EVs-induced alterations in mNPCs. RESULTS: We first show that glioblastoma cell lines U87-, A172-, and LN229-derived EVs were essential for glioblastoma cell prolifeartion and migration. We then demonstrated that glioblastoma-derived EVs dramatically promoted NPC proliferation and migration. Mechanistic studies identify that glioblastoma-derived EVs achieve their functions via activating PI3K-Akt-mTOR pathway in mNPCs. Inhibiting PI3K-Akt pathway reversed the elevated prolfieration and migration of glioblastoma-derived EVs-treated mNPCs. CONCLUSION: Our findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy. Video Abstract.
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Vesículas Extracelulares , Glioblastoma , Células-Tronco Neurais , Animais , Linhagem Celular Tumoral , Proliferação de Células , Vesículas Extracelulares/metabolismo , Feminino , Glioblastoma/patologia , Masculino , Camundongos , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neurais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Traumatic brain injury (TBI) is a cause of disability and death worldwide, but there are currently no specific treatments for this condition. Release of excess reactive oxygen species (ROS) in the injured brain leads to a series of pathological changes; thus, eliminating ROS could be a potential therapeutic strategy. Herein, we synthesized insulin-incubated ultrasmall palladium (Pd@insulin) clusters via green biomimetic chemistry. The Pd@insulin clusters, which were 3.2 nm in diameter, exhibited marked multiple ROS-scavenging ability testified by the theoretical calculation. Pd@insulin could be rapidly excreted via kidney-urine metabolism and induce negligible adverse effects after a long-time treatment in vivo. In a TBI mouse model, intravenously injected Pd@insulin clusters aggregated in the injured cortex, effectively suppressed excessive ROS production, and significantly rescued motor function, cognition and spatial memory. We found that the positive therapeutic effects of the Pd@insulin clusters were mainly attributed to their ROS-scavenging ability, as they inhibited excessive neuroinflammation, reduced cell apoptosis, and prevented neuronal loss. Therefore, the ability of Pd@insulin clusters to effectively eliminate ROS, as well as their simple structure, easy synthesis, low toxicity, and rapid metabolism may facilitate their clinical translation for TBI treatment.
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Lesões Encefálicas Traumáticas , Lesões Encefálicas , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Insulina , Camundongos , Paládio/farmacologia , Paládio/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Neuroinflammation is the inflammatory responses that are involved in the pathogenesis of most neurological disorders. Glutaminase (GLS) is the enzyme that catalyzes the hydrolysis of glutamine to produce glutamate. Besides its well-known role in cellular metabolism and excitatory neurotransmission, GLS has recently been increasingly noticed to be up-regulated in activated microglia under pathological conditions. Furthermore, GLS overexpression induces microglial activation, extracellular vesicle secretion, and neuroinflammatory microenvironment formation, which, are compromised by GLS inhibitors in vitro and in vivo. These results indicate that GLS has more complicated implications in brain disease etiology than what are previously known. In this review, we introduce GLS isoforms, expression patterns in the body and the brain, and expression/activities regulation. Next, we discuss the metabolic and neurotransmission functions of GLS. Afterwards, we summarize recent findings of GLS-mediated microglial activation and pro-inflammatory extracellular vesicle secretion, which, in turns, induces neuroinflammation. Lastly, we provide a comprehensive discussion for the involvement of microglial GLS in the pathogenesis of various neurological disorders, indicating microglial GLS as a promising target to treat these diseases.
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Glutaminase , Microglia , Encéfalo/metabolismo , Ácido Glutâmico , Glutaminase/metabolismo , Glutamina , Humanos , Microglia/metabolismoRESUMO
OBJECTIVE: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). METHODS: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients' demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. RESULTS: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. CONCLUSIONS: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.
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Neoplasias Pancreáticas , Pancreatite Crônica , Inibidor da Tripsina Pancreática de Kazal/genética , Proteínas de Transporte/genética , China/epidemiologia , Humanos , Mutação , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Pancreatite Crônica/epidemiologia , Pancreatite Crônica/genética , Neoplasias PancreáticasRESUMO
It is well acknowledged that immune system is deeply involved in cancer initiation and progression, and can exert both pro-tumorigenic and anti-tumorigenic effects, depending on specific microenvironment. With the better understanding of cancer-associated immune cells, especially T cells, immunotherapy was developed and applied in multiple cancers and exhibits remarkable efficacy. However, currently only a subset of patients have responses to immunotherapy, suggesting that a boarder view of cancer immunity is required. Non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are identified as critical regulators in both cancer cells and immune cells, thus show great potential to serve as new therapeutic targets to improve the response of immunotherapy. In this review, we summarize the functions and regulatory mechanisms of ncRNAs in cancer immunity, and highlight the potential of ncRNAs as novel targets for immunotherapy.
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Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/imunologia , RNA Longo não Codificante/genética , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/farmacologia , Progressão da Doença , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/patologia , Transdução de SinaisRESUMO
Oral carcinoma (OC) is the major cancer type in the head and neck region; however, the molecular mechanisms of its pathogenesis and progression remain poorly understood. In recent years, the long noncoding RNAs (lncRNAs) have been uncovered as critical regulators in the development and progression of multiple human cancers, but most of the lncRNAs expression patterns, clinical relevance, and biological functions in OC are still unclear. To better understand the significance of lncRNAs in OC carcinogenesis, we analyzed the expression levels of lncRNAs between OC and healthy oral mucosa using The Cancer Genome Atlas Cancer Genome RNA sequencing data and another three independent microarray datasets from Gene Expression Omnibus. As a result, we found that thousands of lncRNAs expression are dysregulated in OC, and further somatic copy number variation analyses showed that some of these lncRNAs alterations are associated with copy number amplification or loss in OC. Moreover, lots of lncRNAs expression levels are associated with OC patients' overall survival and recurrence-free survival; for example, higher CASC9, LINC01232, and MIR4435-1HG expression levels are related to shorter overall survival and recurrence-free survival in OC patients. Finally, the potential function of two lncRNAs (CASC9 and LINC00152) that were upregulated in OC tissues and associated with patients' survival time was verified by loss-of-function assays in OC cells. Our findings indicate that these altered lncRNAs might play important roles in the development of OC, and our data can provide a valuable list of lncRNAs candidates for further investigation of their function and mechanisms in OC.
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Biomarcadores Tumorais/genética , Genoma Humano , Neoplasias Bucais/mortalidade , RNA Longo não Codificante/genética , Apoptose , Estudos de Casos e Controles , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
OBJECTIVES: The National Institute of Health Stroke Scale (NIHSS) is a predictor for the prognosis of acute ischaemic stroke (AIS) and its prediction is time-dependent. We examined the performance of NIHSS at different timepoints in predicting functional outcome of patients with thrombolysed AIS. METHODS: This prospective study included 269 patients with AIS treated with recombinant tissue plasminogen activator (rt-PA). Unfavourable functional outcome was defined as modified Rankin Scale score 4-6 at 3 months after rt-PA treatment. Receiver operating characteristic curves were used to examine the predictive power of NIHSS score at admission and 2 hours/24 hours/7 days/10 days after rt-PA treatment. Youden's index was used to select the threshold of NIHSS score. Logistic regression was used to estimate the ORs of unfavourable functional outcome for patients with NIHSS score higher than the selected thresholds. RESULTS: The threshold of NIHSS score at admission was 12 (sensitivity: 0.51, specificity: 0.84) with an acceptable predictive power (area under curve [AUC] 0.74) for unfavourable functional outcome. The threshold changed to 5 at 24 hours after rt-PA treatment (sensitivity: 0.83, specificity: 0.65) and remained unchanged afterwards. The predictive power and sensitivity sequentially increased over time and peaked at 10 days after rt-PA treatment (AUC 0.92, sensitivity: 0.85, specificity: 0.80). NIHSS scores higher than the thresholds were associated with elevated risk of unfavourable functional outcome at all timepoints (all p<0.001). CONCLUSIONS: NIHSS is time-dependent in predicting AIS prognosis with increasing predictive power over time. Since patients whose NIHSS score ≥ 12 are likely to have unfavourable functional outcome with rt-PA treatment only, mechanical thrombectomy should be largely taken into consideration for these patients.
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Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Fibrinolíticos/uso terapêutico , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Exosomes shed by tumor cells have been recognized as promising biomarkers for cancer diagnostics due to their unique composition and functions. Quantification of low concentrations of specific exosomes present in very small volumes of clinical samples may be used for noninvasive cancer diagnosis and prognosis. We developed an immunosorbent assay for digital qualification of target exosomes using droplet microfluidics. The exosomes were immobilized on magnetic microbeads through sandwich ELISA complexes tagged with an enzymatic reporter that produces a fluorescent signal. The constructed beads were further isolated and encapsulated into a sufficient number of droplets to ensure only a single bead was encapsulated in a droplet. Our droplet-based single-exosome-counting enzyme-linked immunoassay (droplet digital ExoELISA) approach enables absolute counting of cancer-specific exosomes to achieve unprecedented accuracy. We were able to achieve a limit of detection (LOD) down to 10 enzyme-labeled exosome complexes per microliter (â¼10-17 M). We demonstrated the application of the droplet digital ExoELISA platform in quantitative detection of exosomes in plasma samples directly from breast cancer patients. We believe our approach may have the potential for early diagnosis of cancer and accelerate the discovery of cancer exosomal biomarkers for clinical diagnosis.
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Biomarcadores Tumorais/imunologia , Neoplasias da Mama/sangue , Ensaio de Imunoadsorção Enzimática , Exossomos/imunologia , Biomarcadores Tumorais/isolamento & purificação , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Contagem de Células , Exossomos/patologia , Feminino , Humanos , Limite de Detecção , Microfluídica/métodosRESUMO
DNA linearization by nanoconfinement has offered a new avenue toward large-scale genome mapping. The ability to smoothly interface the widely different length scales from cell manipulation to DNA linearization is critical to the development of single-cell genomic mapping or sequencing technologies. Conventional nanochannel technologies for DNA analysis suffer from complex fabrication procedures, DNA stacking at the nanochannel entrance, and inefficient solution exchange. In this work, a dynamic and tunable confinement strategy is developed to manipulate and linearize genomic-length DNA molecules from a single cell. By leveraging pneumatic microvalve control and elastomeric collapse, an array of nanochannels with confining dimension down to 20 nm and length up to sub-millimeter is created and can be dynamically tuned in size. The curved edges of the microvalve form gradual transitions from microscale to nanoscale confinement, smoothly facilitating DNA entry into the nanochannels. A unified micro/nanofluidic device that integrates single-cell trapping and lysis, DNA extraction, purification, labeling, and linearization is developed based on dynamically controllable nanochannels. Mbp-long DNA molecules are extracted directly from a single cell and in situ linearized in the nanochannels. The device provides a facile and promising platform to achieve the ultimate goal of single-cell, single-genome analysis.
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DNA/química , Nanotecnologia/métodos , Nanoestruturas/química , Análise de Célula ÚnicaRESUMO
Preventing or minimizing ice formation in supercooled water is of prominent importance in many infrastructures, transportation, and cooling systems. The overall phase change heat transfer on icephobic surfaces, in general, is intentionally sacrificed to suppress the nucleation of water and ice. However, in a condensation frosting process, inhibiting freezing without compromising the water condensation has been an unsolved challenge. Here we show that this conflict between anti-icing and efficient condensation cooling can be resolved by utilizing biphilic topography with patterned high-contrast wettability. By creating a varying interfacial thermal barrier underneath the supercooled condensate, the biphilic structures tune the nucleation rates of water and ice in the sequential condensation-to-freezing process. Our experimental and theoretical investigation of condensate freezing dynamics further unravels the correlation between the onset of droplet freezing and its characteristic radius, offering a new insight for controlling the multiphase transitions among vapor, water, and ice in supercooled conditions.
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PURPOSE: To explain thermal stability enhancement of an organic compound, sucralose, with cyclodextrin based metal organic frameworks. METHODS: Micron and nanometer sized basic CD-MOFs were successfully synthesized by a modified vapor diffusion method and further neutralized with glacial acetic acid. Sucralose was loaded into CD-MOFs by incubating CD-MOFs with sucralose ethanol solutions. Thermal stabilities of sucralose-loaded basic CD-MOFs and neutralized CD-MOFs were investigated using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD). RESULTS: Scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) results showed that basic CD-MOFs were cubic crystals with smooth surface and uniform sizes. The basic CD-MOFs maintained their crystalline structure after neutralization. HPLC-ELSD analysis indicated that the CD-MOF crystal size had significant influence on sucralose loading (SL). The maximal SL of micron CD-MOFs (CD-MOF-Micro) was 17.5 ± 0.9% (w/w). In contrast, 27.9 ± 1.4% of sucralose could be loaded in nanometer-sized basic CD-MOFs (CD-MOF-Nano). Molecular docking modeling showed that sucralose molecules preferentially located inside the cavities of γ-CDs pairs in CD-MOFs. Raw sucralose decomposed fast at 90°C, with 86.2 ± 0.2% of the compound degraded within only 1 h. Remarkably, sucralose stability was dramatically improved after loading in neutralized CD-MOFs, with only 13.7 ± 0.7% degradation at 90°C within 24 h. CONCLUSIONS: CD-MOFs efficiently incorporated sucralose and maintained its integrity upon heating at elevated temperatures.
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Estruturas Metalorgânicas/química , Compostos Orgânicos/química , Sacarose/análogos & derivados , gama-Ciclodextrinas/química , Ácido Acético/química , Varredura Diferencial de Calorimetria/métodos , Microscopia Eletrônica de Varredura/métodos , Simulação de Acoplamento Molecular/métodos , Nanopartículas/química , Tamanho da Partícula , Pós/química , Sacarose/química , Termogravimetria , Difração de Raios X/métodosRESUMO
ß-artemether (ARM) is a widely used anti-malarial drug isolated from the Chinese antimalarial plant, Artemisia annua. The solvent effects on crystal habits and dissolution of ARM were thoroughly investigated and discussed herein. The ARM was recrystallized in nine different solvents of varied polarity, namely, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, acetone and hexane by solvent evaporation method. The obtained crystals were morphologically characterized using scanning electron microscope (SEM). The average sizes of crystals were 1.80-2.64 µm calculated from microscopic images using Image-Pro software. No significant change in chemical structure was noticed after recrystallization and the specific band at 875 cm-1 wavenumber (C-O-O-C) confirmed the presence of most sensitive functional group in the ARM chemical structure. The existence and production of two polymorphic forms, polymorph A and polymorph B, was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The data suggested that the fabrication of polymorph B can be simply obtained from the recrystallization of ARM in a specific solvent. Significant effects of solvent polarity, crystals shapes and sizes on drug dissolution were noticed during in vitro dissolution test. The release kinetics were calculated and well fitted by the Higuchi and Hixon-Crowell models. The ARM-methanol and ARM-hexane showed highest and slowest dissolution, respectively, due to the effects of solvent polarity and crystal morphologies. Overall, proper selection of the solvents for the final crystallization of ARM helps to optimize dissolution and bioavailability for a better delivery of anti-malarial drug.
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Antimaláricos/química , Artemisininas/química , Solventes/química , Antimaláricos/metabolismo , Artemeter , Artemisininas/metabolismo , Varredura Diferencial de Calorimetria , Cristalização , Solubilidade , Solventes/metabolismo , Difração de Raios XRESUMO
Objective To observe the effects of force signals and inflammatory cytokines on the expressions of functional proteins during the differentiation of periodontal ligament cells(PDLCs) into osteoclasts. Methods The caries-free premolars that needed to be removed for orthodontic treatment were collected,human periodontal ligament cells were cultured in vitro.Human PDLCs were exposed to inflammatory cytokines including interleukin(IL)-1ß,-6,-23,and tumor necrosis factor alpha(TNF-α). Cyclicmechanical tension with a maximum 5% elongation for different durations(0,2,4,8,12,and 24 hours) were applied. Then the expressions of signaling molecules related to osteoclastogenesis(OPG) and receptor activated nuclear factor κB ligand(RANKL) were determined at protein levels by Western blotting. Results Inflammatory cytokines improved the expressions of osteoclastgenesis regulators in hPDLCs,while cyclic-tension force reduced their expressions. However,the combined effect of inflammatory cytokines and cyclic-tension force resulted in high expressions of osteoclastgenesis regulators. Conclusion Inflammatory cytokines can promote the expressions of the osteoclastgenic factors,which can not be offset by cyclic-tension force.
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Interleucinas/farmacologia , Osteoclastos/citologia , Osteogênese , Ligamento Periodontal/citologia , Estresse Mecânico , Fator de Necrose Tumoral alfa/farmacologia , Diferenciação Celular , Células Cultivadas , Humanos , Osteoprotegerina/metabolismo , Ligante RANK/metabolismoRESUMO
The molecular mechanism underlying constitutive activation of AKT signaling, which plays essential roles in astrocytoma progression, is not fully characterized. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of astrocytoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we found that microRNA (miR)-542-3p expression was decreased in glioblastoma cell lines and astrocytoma tissues, and reduced levels of miR-542-3p expression correlated with high histopathological grades and poor prognosis of astrocytoma patients. Exogenous miR-542-3p suppressed glioblastoma cell invasion through not only targeting AKT1 itself but also directly down-regulating its two important upstream regulators, namely, integrin-linked kinase and PIK3R1. Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of ß-catenin to exert its anti-invasive effect. Furthermore, the miR-542-3p expression level negatively correlated with AKT activity as well as levels of integrin-linked kinase and PIK3R1 in human astrocytoma specimens. These findings suggest that miR-542-3p acts as a negative regulator in astrocytoma progression and that miR-542-3p down-regulation contributes to aberrant activation of AKT signaling, leaving open the possibility that miR-542-3p may be a potential therapeutic target for high grade astrocytoma.
Assuntos
Glioblastoma/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase , Progressão da Doença , Regulação para Baixo/genética , Glioblastoma/diagnóstico , Glioblastoma/genética , Humanos , Gradação de Tumores , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima/genética , beta Catenina/metabolismoRESUMO
Tuberculosis (TB) remains a major infectious disease partly due to the lack of an effective vaccine. Therefore, developing new and more effective TB vaccines is crucial for controlling TB. Mycobacterium tuberculosis (M. tuberculosis) usually parasitizes in macrophages; therefore, cell-mediated immunity plays an important role. The maintenance of memory T cells following M. tuberculosis infection or vaccination is a hallmark of immune protection. This review analyzes the development of memory T cells during M. tuberculosis infection and vaccine immunization, especially on immune memory induced by BCG and subunit vaccines. Furthermore, the factors affecting the development of memory T cells are discussed in detail. The understanding of the development of memory T cells should contribute to designing more effective TB vaccines and optimizing vaccination strategies.