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BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.
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Aterectomía Coronaria , Enfermedad de la Arteria Coronaria , Sistema de Registros , Calcificación Vascular , Humanos , Aterectomía Coronaria/efectos adversos , Aterectomía Coronaria/mortalidad , Masculino , Femenino , China , Anciano , Resultado del Tratamiento , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/mortalidad , Estudios Prospectivos , Persona de Mediana Edad , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/terapia , Calcificación Vascular/mortalidad , Factores de Tiempo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Medición de Riesgo , Pautas de la Práctica en Medicina/tendenciasRESUMEN
Fusion tag technology is an important tool for rapid separation, purification, and characterization of proteins. Combined with monoclonal antibodies, tag epitope systems can be rapidly adapted to many assay systems. A monoclonal antibody that reacts with the matrix protein of the rabies virus CVS-11 strain was reported. The epitope (termed M) targeted by this antibody contains only six amino acids. We examine whether this specific sequence epitope can be applied as a protein tag. We show ectopic expression of M-tagged proteins has little impact on cell viability or major signaling pathways. The M tag system can be used for western blotting, immunoprecipitation, immunofluorescence staining, and flow cytometry assays. The results indicate the specificity, sensitivity, and versatility of this novel epitope tag system are comparable to the widely used FLAG tag system, providing researchers with an additional tool for molecular analysis. KEY POINTS: ⢠A short peptide (Pro Pro Tyr Asp Asp Asp) can be applied as a new tag. ⢠The new epitope-tagging fusion system has no effect on the main cellular signaling pathway. ⢠The epitope-tagging fusion system can be widely used for western blotting, immunoprecipitation, immunofluorescence, flow cytometry, etc.
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Virus de la Rabia , Epítopos , Virus de la Rabia/genética , Péptidos/metabolismo , Anticuerpos Monoclonales , Western BlottingRESUMEN
BACKGROUND: Immune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration. METHODS: The particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments. RESULTS: Here, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1-6 cells. We found that the drug-treated Hepa1-6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer. CONCLUSION: Our results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition.
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Nanopartículas , Neoplasias , Humanos , Inmunoterapia/métodos , Proteínas de la Membrana/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Transducción de SeñalRESUMEN
The combination of ferroelectric-optical properties in halide perovskites has attracted tremendous interess because of its potential for optoelectronic and energy applications. However, very few reports focus on the ferroelectricity of all-inorganic halide perovskites quantum dots. Herein, we report a excellent ferroelectricity in CsPbBr3 quantum dots (QDs) with a saturation polarization of 0.25 µC/cm2. Differential scanning calorimetry, X-ray diffraction, and transmission electronic microscopy revealed that the mechanism of ferroelectric-paraelectric switching of CsPbBr3 QDs can be attributed to the phase transition from cubic phase (Pm3Ì m) to the orthorhombic phase (Pna21). In the orthorhombic CsPbBr3, the distortion of octahedral [PbBr6]4- structural units and the off-center Cs+ generated the slightly separated centers of positive charge and negative charge, resulting in the ferroelectric properties. The variable-temperature emission spectrum from 328 to 78 K exhibits green luminescence and a gradual red shift due to the phase transition. This finding opens up an avenue to explore the ferroelectric-optical properties of inorganolead halide perovskites for high-performance multifunctional materials.
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Human adenovirus (Adv) infection is responsible for most community-acquired pneumonia in infants and children, which results in significant morbidity and mortality in children every year. MicroRNAs (miRNAs) are associated with viral replication and host immune response. Knowing the miRNA expression profile will help understand the role of miRNAs in modulating the host response to adenovirus infection and possibly improve the diagnosis of adenovirus-infected pneumonia. In our study, total RNA extracted from whole blood of adenovirus-infected pneumonia children and healthy controls were analyzed by small RNA deep sequencing. Expression profiles of whole blood microRNAs were altered and distinctly different in adenovirus-infected children. The top 3 upregulated miRNA (hsa-miR-127-3p, hsa-miR-493-5p, and hsa-miR-409-3p) were identified in adenovirus-infected children and provided a clear distinction between infected and healthy individuals. Potential host target genes were predicated and validated by qRT-PCR to study the impact of microRNAs on the host genes. Most of the target genes were involved in the MAPK signaling pathway and innate immune response. These highly upregulated microRNAs may have crucial roles in Adv pathogenesis and are potential biomarkers for adenovirus-infected pneumonia.
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Adenoviridae/genética , MicroARNs/genética , Neumonía/genética , Neumonía/virología , Línea Celular , Preescolar , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Filogenia , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Developing new methods to synthesize intermetallics is one of the most critical issues for the discovery and application of multifunctional metal materials; however, the synthesis of Sn-containing intermetallics is challenging. In this work, we demonstrated for the first time that a self-disproportionation-induced in situ process produces cavernous Sn-Cu intermetallics (Cu3 Sn and Cu6 Sn5 ). The successful synthesis is realized by introducing inorganic metal salts (SnCl2 â 2 H2 O) to NaOH aqueous solution to form an intermediate product of reductant (Na2 SnO2 ) and by employing steam pressures that enhance the reduction ability. Distinct from the traditional in situ reduction, the current reduction process avoided the uncontrolled phase composition and excessive use of organic regents. An insight into the mechanism was revealed for the Sn-Cu case. Moreover, this method could be extended to other Sn-containing materials (Sn-Co, Sn-Ni). All these intermetallics were attempted in the catalytic effect on thermal decompositions of ammonium perchlorate. It is demonstrated that Cu3 Sn showed an outstanding catalytic performance. The superior property might be primarily originated from the intrinsic chemical compositions and cavernous morphology as well. We supposed that this smart solution reduction methodology reported here would provide a new recognition for the reduction reaction, and its modified strategy may be applied to the synthesis of other metals, intermetallics as well as some unknown materials.
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Transparent glass-ceramic containing rare-earth doped halide nanocrystals exhibits enhanced luminescence performance. In this study, a glass-ceramic with Tb doped gadolinium fluoride nanocrystals embedded in an aluminosilicate glass matrix is investigated for X-ray imaging applications. The nanocrystalline glass-ceramic scintillator was prepared by a melt-quench method followed by an anneal. The GdF3:Tb nanocrystals precipitated within the oxide glass matrix during the processing and their luminescence and scintillation properties were investigated. In this nanocomposite scintillator system, the incorporation of high atomic number Gd compound into the glass matrix increases the X-ray stopping power of the glass scintillator, and effective energy transfer between Gd3+ and Tb3+ ions in the nanocrystals enhances the scintillation efficiency.
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Aim of this comparative cross-sectional study was to evaluate the effect of anterior teeth retraction and related hard and soft tissue change under physiologic anchorage control in patients with chief complain of protrusive teeth. 68 Class I or II orthodontic patients undergoing four-premolar extraction and requiring maximum or medium anchorage were included. Patients were treated with physiologic anchorage control technique (PASS group, n = 34, 18.6 ± 7.7 years, 10 male and 24 female) and self-ligation technique (Damon group, n = 34, 17.5 ± 5.4 years, 13 male and 21 female), respectively. TADs were used for anchorage reinforcement in Damon group. Pre- and post-treatment cephalograms were collected. Twenty-six skeletal, dental and soft tissue items were measured and analyzed using a blinded method. T test and paired rank-sum test were used for statistical analysis. The baseline characteristics were similar between groups (P > 0.05). After treatment, inter-group comparison showed statistically significant differences in the decrease of skeletal measurements â ANB (- 0.73 ± 1.05° in PASS group and - 0.25 ± 0.84° in the Damon group), Wits value (- 2.56 ± 2.29 mm in PASS group and - 0.47 ± 2.15 mm in Damon group) and soft tissue measurement UL-E (- 2.75 ± 1.36 mm in PASS group and - 2.03 ± 1.30 mm in Damon group) and the increase of FCA and Z angle, which was 2.03 ± 2.12°and 9.52 ± 4.78°in PASS group and 0.97 ± 2.12°and 6.96 ± 4.43°in Damon group, respectively (P < 0.05). Our results indicated that significant anterior teeth retraction and profile improvement could be achieved with PASS technique without additional anchorage devices. Appropriate application of physiologic anchorage control could reduce the dependence of TADs for anterior teeth retraction.
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Métodos de Anclaje en Ortodoncia , Técnicas de Movimiento Dental , Humanos , Masculino , Femenino , Técnicas de Movimiento Dental/métodos , Estudios Transversales , Maxilar , CefalometríaRESUMEN
Rabies virus causes an estimated 59,000 annual fatalities worldwide and promising therapeutic treatments are necessary to develop. In this study, affinity tag-purification mass spectrometry was employed to delineate RABV glycoprotein and host protein interactions, and PDIA3/ERP57 was identified as a potential inhibitor of RABV infection. PDIA3 restricted RABV infection with follow mechanisms: PDIA3 mediated the degradation of RABV G protein by targeting lysine 332 via the selective macroautophagy/autophagy pathway; The PDIA3 interactor, AP3B1 (adaptor related protein complex 3 subunit beta 1) was indispensable in PDIA3-triggered selective degradation of the G protein; Furthermore, PDIA3 competitively bound with NCAM1/NCAM (neural cell adhesion molecule 1) to block RABV G, hindering viral entry into host cells. PDIA3 190-199 aa residues bound to the RABV G protein were necessary and sufficient to defend against RABV. These results demonstrated the therapeutic potential of biologics that target PDIA3 or utilize PDIA3 190-199 aa peptide to treat clinical rabies.Abbreviation: aa: amino acids; ANXA2: annexin A2; AP-MS: affinity tag purification-mass spectrometry; AP3B1: adaptor related protein complex 3 subunit beta 1; ATP6V1A: ATPase H+ transporting V1 subunit A; ATP6V1H: ATPase H+ transporting V1 subunit H; BafA1: bafilomycin A1; CHX: cycloheximide; co-IP: co-immunoprecipitation; DDX17: DEAD-box helicase 17; DmERp60: drosophila melanogaster endoplasmic reticulum p60; EBOV: Zaire ebolavirus virus; EV: empty vector; GANAB: glucosidase II alpha subunit; G protein: glycoprotein; GRM2/mGluR2: glutamate metabotropic receptor 2; HsPDIA3: homo sapiens protein disulfide isomerase family A member 3; IAV: influenza virus; ILF2: interleukin enhancer binding factor 2; KO: knockout; MAGT1: magnesium transporter 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MmPDIA3: mus musculus protein disulfide isomerase associated 3; NCAM1/NCAM: neural cell adhesion molecule 1; NGFR/p75NTR: nerve growth factor receptor; NGLY1: N-glycanase 1; OTUD4: OTU deubiquitinase 4; PDI: protein disulfide isomerase; PPIs: protein-protein interactions; RABV: rabies virus; RUVBL2: RuvB like AAA ATPase 2; SCAMP3: secretory carrier membrane protein 3; ScPdi1: Saccharomyces cerevisiae s288c protein disulfide isomerase 1; SLC25A6: solute carrier family 25 member 6; SQSTM1/p62: sequestosome 1; VSV: vesicular stomatitis virus.
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Influenza A virus (IAV) continuously poses a considerable threat to global health through seasonal epidemics and recurring pandemics. IAV RNA-dependent RNA polymerases (FluPol) mediate the transcription of RNA and replication of the viral genome. Searching for targets that inhibit viral polymerase activity helps us develop better antiviral drugs. Here, we identified heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) as an anti-influenza host factor. hnRNPAB interacts with NP of IAV to inhibit the interaction between PB1 and NP, which is dependent on the 5-amino-acid peptide of the hnRNPAB C-terminal domain (aa 318-322). We further found that the 5-amino-acid peptide blocks the interaction between PB1 and NP to destroy the FluPol activity. In vivo studies demonstrate that hnRNPAB-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. These data demonstrate that hnRNPAB perturbs FluPol complex conformation to inhibit IAV infection, providing insights into anti-influenza defense mechanisms.
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Virus de la Influenza A , Infecciones por Orthomyxoviridae , ARN Polimerasa Dependiente del ARN , Replicación Viral , Animales , Perros , Humanos , Ratones , Células A549 , Antivirales/farmacología , Células HEK293 , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/virología , Gripe Humana/tratamiento farmacológico , Células de Riñón Canino Madin Darby , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Nucleocápside , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , ARN Polimerasa Dependiente del ARN/metabolismo , ARN Polimerasa Dependiente del ARN/genética , Proteínas Virales/metabolismo , Proteínas Virales/genética , Replicación Viral/efectos de los fármacosRESUMEN
Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.
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Neoplasias Colorrectales , Hexoquinasa , Humanos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Fosforilación , Transducción de Señal , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , GlucólisisRESUMEN
BACKGROUND AND OBJECTIVE: Aortic pressure (Pa) is important for the diagnosis of cardiovascular disease. However, its direct measurement is invasive, not risk-free, and relatively costly. In this paper, a new simplified Kalman filter (SKF) algorithm is employed for the reconstruction of the Pa waveform using dual peripheral artery pressure waveforms. METHODS: Pa waveforms obtained in a previous study were collected from 25 patients. Simultaneously, radial and femoral pressure waveforms were generated from two simulation experiments, using transfer functions. In the first, the transfer function is a known finite impulse response; and in the second, it is derived from a tube-load model. To analyze the performance of the proposed SKF algorithm, variable amounts of noise were added to the observed output signal, to give a range of signal-to-noise ratios (SNRs). Additionally, central aortic, brachial and femoral pressure waveforms were simultaneously collected from 2 Sprague-Dawley rats and the measured and reconstructed Pa waveforms were compared. RESULTS: The proposed SKF algorithm outperforms canonical correlation analysis (CCA), which is the current state-of-the-art blind system identification method for the non-invasive estimation of central aortic blood pressure. It is also shown that the proposed SKF algorithm is more noise-tolerant than the CCA algorithm over a wide range of SNRs. CONCLUSION: The simulations and animal experiments illustrate that the proposed SKF algorithm is accurate and stable in the face of low SNRs. Improved methods for estimating central blood pressure as a measure of cardiac load adds to their value as a prognostic and diagnostic tool.
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Presión Arterial , Determinación de la Presión Sanguínea , Animales , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea/métodos , Humanos , Arteria Radial/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND OBJECTIVE: Arterial stiffness, commonly assessed by carotid-femoral pulse wave velocity (cfPWV), is an independent biomarker for cardiovascular disease. The measurement of cfPWV, however, has been considered impractical for routine clinical application. Pulse wave analysis using a single pulse wave measurement in the radial artery is a convenient alternative. This study aims to identify pulse wave features for a more accurate estimation of cfPWV from a single radial pulse wave measurement. METHODS: From a dataset of 140 subjects, cfPWV was measured and the radial pulse waveform was recorded for 30 s twice in succession. Features were extracted from the waveforms in the time and frequency domains, as well as by wave separation analysis. All-possible regressions with bootstrapping, McHenry's select algorithm, and support vector regression were applied to compute models for cfPWV estimation. RESULTS: The correlation coefficients between the measured and estimated cfPWV were r = 0.81, r = 0.81, and r = 0.8 for all-possible regressions, McHenry's select algorithm, and support vector regression, respectively. The features selected by all-possible regressions are physiologically interpretable. In particular, the amplitude ratio of the diastolic peak to the notch of the radial pulse waveform (Rn,dr,P) is shown to be correlated with cfPWV. This correlation was further evaluated and found to be independent of wave reflections using a dataset (n = 3,325) of simulated pulse waves. CONCLUSIONS: The proposed method may serve as a convenient surrogate for the measurement of cfPWV. Rn,dr,P is associated with aortic pulse wave velocity and this association may not be dependent on wave reflection.
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Análisis de la Onda del Pulso , Arteria Radial , Presión Sanguínea , Arterias Carótidas/fisiología , Velocidad de la Onda del Pulso Carotídeo-Femoral , Humanos , Análisis de la Onda del Pulso/métodosRESUMEN
Objective.Aortic stiffness is associated with risk of cardiovascular events. Carotid-femoral pulse wave velocity (cfPWV) is the current noninvasive gold standard for assessing aortic stiffness. However, the cfPWV measurement is challenging, requiring simultaneous signals at the carotid and femoral sites.Approach.In this study, the aortic PWV is estimated using a single radial pressure waveform and compared with cfPWV. 111 subjects' aortic PWVs are estimated from the decomposition of the derived central aortic pressure waveform based on three types of reconstructed flow waveform: the peak of triangular flow waveform based on 30% ejection time (Q30%tri), the peak of triangular flow waveform based on inflection point (Qtri), and averaged flow waveform (Qavg). The central aortic pressure waveform is derived from a radial pressure waveform via a validated transfer function.Main results.TheQavgis used for estimating aortic PWV without the determination of the peak point of the triangular flow waveforms. The estimated aortic PWV shows good agreement with cfPWV. The mean difference ± SD is 0.29 ± 1.50 m s-1(r2 = 0.29,p< 0.001) for theQ30%tri; 0.27 ± 1.40 m s-1(r2 = 0.38,p < 0.001) for theQtri; 0.23 ± 1.39 m s-1(r2 = 0.40,p < 0.001) for theQavg. The correlation between estimated aortic PWV based onQ30%triand measured cfPWV is weak. The results ofQtriandQavgshow no obvious difference.Significance.The proposed method can be used as a less complex way than conventional measurement of cfPWV to further assess arterial stiffness and predict cardiovascular risks or events.
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Análisis de la Onda del Pulso , Rigidez Vascular , Aorta , Presión Arterial , Presión Sanguínea , Arterias Carótidas , HumanosRESUMEN
For the first time, bulk-like g-C3N4 was achieved through initiating layer-by-layer assembly, which involves the important process of artificially manipulating protonated and oxygen doped g-C3N4 nanosheets. When acting as a photocatalyst under UV-visible light irradiation, bulk-like g-C3N4 exhibited an excellent photocatalytic H2 production rate of 1538 µmol h-1 g-1, about 8 times higher than that of the bulk g-C3N4 counterpart.
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Curcumin (CM) is a natural polyphenolic compound with multiple biomedical functions. However, clinical applications face more challenges due to its low dissolution rate and poor bioavailability. Micronization is an effective strategy to overcome these drawbacks. Herein, CM nanoparticles (CM NPs, â¼300 nm) were fabricated using solution enhanced dispersion by supercritical CO2 (SEDS). The solubility of CM NPs was remarkably enhanced. Aim to study the effects of micronization on the biological functions of CM, we investigated the antibacterial activity of original CM and CM NPs upon Pseudomonas aeruginosa. In vitro, the minimal inhibitory concentrations (MIC) assay, solid-medium spot assay, growth kinetics assay and morphologic observation using atomic force microscopy (AFM) confirmed that the anti-P. aeruginosa activity of CM NPs was enhanced compared to original CM. Moreover, CM NPs also showed stronger inhibition for adhesion and biofilm formation of P. aeruginosa compared to original CM. Experiments on mice infected with P. aeruginosa showed that CM NPs have a better therapeutic effect than the original CM in vivo. In summary, CM NPs may be a novel and promising therapeutic candidate for bacterial infection.
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Antibacterianos/química , Antibacterianos/farmacología , Dióxido de Carbono/química , Curcumina/química , Curcumina/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Adhesión Bacteriana/efectos de los fármacos , Biopelículas/efectos de los fármacos , Tamaño de la Partícula , Pseudomonas aeruginosa/fisiologíaRESUMEN
OBJECTIVES: This study aims to investigate the underlying mechanism of metformin in reducing myocardial apoptosis and improving mitochondrial function in rats and H9c2 cells subjected with myocardial ischemia-reperfusion injury (I/R). METHOD: Following pretreatment with metformin, male Sprague-Dawley (SD) rats were used to establish an ischemia-reperfusion (I/R) model in vivo. Serum creatinine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were examined by ELISA. Infarct size and apoptosis were measured by TTC staining and TUNEL assay. Pathological changes were evaluated by HE staining. H9c2 cells were used to establish a hypoxia-reoxygenation (H/R) model in vitro. Cell apoptosis and mitochondrial membrane potential (MMP) were examined by flow cytometry and Rhodamine 123. The expression levels of STEAP4, Bcl-2, Bax and GAPDH in both myocardial tissues and H9c2 cells were determined by western blotting. RESULTS: We found that metformin decreased infarct size, increased expression of STEAP4, mitigated myocardial apoptosis and increased mitochondrial membrane potential (MMP) when the models were subjected to H/R or I/R injuries. However, STEAP4 knockdown significantly abrogated the beneficial effect of metformin. CONCLUSIONS: We further demonstrated the protective effect of metformin on cardiomyocytes, which might be at least partly attributable to upregulation of STEAP4. Therefore, STEAP4 might be a new target to decrease apoptosis and rescue mitochondrial function in myocardial ischemia-reperfusion injury.
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Cardiotónicos/farmacología , Proteínas de la Membrana/efectos de los fármacos , Metformina/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Oxidorreductasas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Curcumin (CM) has multiple pharmacological activities including anti-fungal activity, but its clinical application is limited due to low solubility in aqueous media, poor bioavailability and extensive first pass metabolism. We aimed to resolve the limitation and enhance antifungal activity of CM using nanotechnology. Using silk fibroin (SF) as a carrier, we fabricated curcumin-silk fibroin nanoparticles (CM-SF NPs) by solution enhanced dispersion of supercritical CO2 (SEDS) technique. The characterization of CM-SF NPs was analyzed using scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC) and thermo gravimetric apparatus (TGA). Following characterization of the NPs, we evaluated the antifungal activity of CM-SF NPs against Candida albicans in vitro and in vivo. A SF-based drug delivery system (CM-SF NPs, 85 ± 15 nm) was established by SEDS. Compared to original CM, water solubility of CM-SF NPs was improved, and its antifungal activity was enhanced. The natural compound-loaded SF nanoparticles may be a promising therapeutic candidate for fungal infection.
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Nanopartículas , Candida albicans , Curcumina , Sistemas de Liberación de Medicamentos , Fibroínas , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Symbiotic hetero-nanocomposites prevail in many classes of minerals, functional substances and/or devices. However, design and development of a symbiotic hetero-nanocomposite that contains unachievable phases remain a significant challenge owing to the tedious formation conditions and the need for precise control over atomic nucleation in synthetic chemistry. Herein, we report a solution chemistry approach for a symbiotic hetero-nanocomposite that contains an unprecedented CaCl2-type titania phase inter-grown with rutile TiO2. CaCl2 structured TiO2, usually occurring when bulk rutile-TiO2 is compressed at an extreme pressure of several GPa, is identified to be a distorted structure with a tilt of adjacent ribbons of the c-axis of rutile. The structural specificity of the symbiotic CaCl2/rutile TiO2 hetero-nanocomposite was confirmed by Rietveld refinement, HRTEM, EXAFS, and Raman spectra, and the formation region (TiCl4 concentration vs. reaction temperature) was obtained by mapping the phase diagram. Due to the symbiotic relationship, this CaCl2-type TiO2 maintained a high stability via tight connection by edge dislocations with rutile TiO2, thus forming a CaCl2/rutile TiO2 heterojunction with a higher reduction capacity and enhanced charge separation efficiency. These merits endow symbiotic CaCl2/rutile TiO2 with a water splitting activity far superior to that of the commercial benchmark photocatalyst, P25 under simulated sunlight without the assistance of a cocatalyst. Our findings reported here may offer several useful understandings of the mechanical intergrowth process in functional symbiotic hetero-nanocomposites for super interfacial charge separation, where interfacial dislocation appears to be a universal cause.
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Diabetic patients are more sensitive to ischemic injury than non-diabetics. Endoplasmic reticulum (ER) stress has been reported to be closely associated with the pathophysiology of ischemic injury in diabetes. The aim of the present study was to investigate the mechanisms involved in the progression of diabetes complicated by myocardial infarction (MI) and further verify the role of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) using an in vitro model of diabetes/MI. The rats were exposed to 65 mg/kg streptozotocin (STZ) and left anterior descending (LAD) coronary artery ligation. ST-segment elevation, heart rate, left ventricular systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) were measured. Serum creatinine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were examined by ELISA. Infarct size and apoptosis were measured by triphenyltetrazolium chloride staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay. Pathological changes were evaluated by hematoxylin and eosin staining. H9c2 cells were used to establish an in vitro model of diabetes complicated by MI. Following CHOP knockdown, cell viability, cell cycle distribution and apoptosis were examined by Cell Counting Kit-8 assay, flow cytometry and Hoechst staining. Glucose-regulated protein 78 (GRP78), CHOP, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), endoplasmic reticulum oxidoreductase 1 (Ero1)-α, Ero1ß and protein disulfide isomerase (PDI) levels in both myocardial tissues and H9c2 cells were determined by western blotting. In the present study, diabetes complicated by MI promoted ST-segment elevation and myocardial apoptosis, increased infarct size, induced pathological changes and elevated LVEDP, CK-MB, cTnT, GRP78, CHOP, Bax, Ero1α, Ero1ß and PDI; however, it decreased heart rate, LVSP and Bcl-2. Additionally, high glucose combined with hypoxic treatment reduced cell viability, induced cell cycle arrest at G1 phase, promoted cell apoptosis, and activated the GRP78/CHOP and Ero1/PDI signaling pathways, which were reversed by CHOP knockdown. Thus, CHOP may be an effective therapeutic target for the treatment of diabetes complicated by MI.