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Exosomes are nanovesicles secreted by cells, which play a crucial role in various pathological processes. Exosomes have shown great promise as tumor biomarkers because of the abundant secretion during tumor formation. The development of a convenient, efficient, and cost-effective method for simultaneously enriching and detecting exosomes is of utmost importance for both basic research and clinical applications. In this study, an aptamer-functionalized magnetic Ti3C2 composite material (Fe3O4@Ti3C2@PEI@DSP@aptamer@FAM-ssDNA) is prepared for the simultaneous enrichment and detection of exosomes. CD63 aptamers are utilized to recognize and capture the exosomes, followed by magnetic separation. The exosomes are then released by cleaving the disulfide bonds of DSP. Compared to traditional methods, Fe3O4@Ti3C2@PEI@DSP@aptamer@FAM-ssDNA exhibited superior efficiency in enriching exosomes while preserving their structural and functional integrity. Detection of exosome concentration is achieved through the fluorescence quenching of Ti3C2 and the competitive binding between the exosomes and a fluorescently labeled probe. This method exhibited a low detection limit of 4.21 × 104 particles mL-1, a number that is comparable to the state-of-the-art method in the detection of exosomes. The present study demonstrates a method of simultaneous enrichment and detection of exosomes with a high sensitivity, accuracy, specificity, and cost-effectiveness providing significant potential for clinical research and diagnosis.
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Vitamin B12 is a group of biologically active cobalamin compounds. In this study, we investigated the inhibitory effects of methylcobalamin (MeCbl) and hydroxocobalamin acetate (OHCbl Acetate) on protein tyrosine phosphatase 1B (PTP1B). MeCbl and OHCbl Acetate exhibited an IC50 of approximately 58.390 ± 2.811 µM and 8.998 ± 0.587 µM, respectively. The Ki values of MeCbl and OHCbl Acetate were 25.01 µM and 4.04 µM respectively. To elucidate the inhibition mechanism, we conducted a 500 ns Gaussian accelerated molecular dynamics (GaMD) simulation. Utilizing PCA and tICA, we constructed Markov state models (MSM) to examine secondary structure changes during motion. Our findings revealed that the α-helix at residues 37-42 remained the most stable in the PTP1B-OHCbl Acetate system. Furthermore, upon binding of OHCbl Acetate or MeCbl, the WPD loop of PTP1B moved inward to the active pocket, forming a closed conformation and potentially obstructs substrate entry. Protein-ligand interaction analysis and MM-PBSA showed that OHCbl Acetate exhibited lower binding free energy and engaged in more residue interactions with PTP1B. In summary, our study confirmed the substantial inhibitory activity of OHCbl Acetate against PTP1B, with its inhibitory potency notably surpassing that of MeCbl. We demonstrated potential molecular mechanisms of OHCbl Acetate inhibiting PTP1B.
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Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Vitamina B 12 , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Vitamina B 12/química , Vitamina B 12/análogos & derivados , Vitamina B 12/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Cinética , Relación Estructura-ActividadRESUMEN
Phosphorylation of tyrosine is the basic mode of protein function and signal transduction in organisms. This process is regulated by protein tyrosine kinases (PTKs) and protein tyrosinases (PTPs). Immunoreceptor tyrosine-based inhibition motif (ITIM) has been considered as regulating the PTP activity through the interaction with the partner proteins in the cell signal pathway. The ITIM sequences need to be phosphorylated first to active the downstream signaling proteins. To explore potential regulatory mechanisms, the ITIM sequences of two transmembrane immunoglobulin proteins, myelin P0 protein-related protein (PZR) and programmed death 1 (PD-1), were analyzed to investigate their interaction with proteins involved in regulatory pathways. We discovered that phosphorylated ITIM sequences can selectively interact with the tyrosine phosphatase SHP2. Specifically, PZR-N-ITIM (pY) may be critical in the interaction between the ITIM and SH2 domains of SHP2, while PD1-C-ITSM (pY) may play a key role in the interaction between the ITIM and SH2 domains of SHP2. Quite a few proteins were identified containing the SH2 domain, exhibiting phosphorylation-mediated interaction with PZR-ITIM. In this study, 14 proteins with SH2 structural domains were identified by GO analysis on 339 proteins associated to the affinity pull-down of PZR-N-ITIM (pY). Through the SH2 domains, these proteins may interact with PZR-ITIM in a phosphorylation-dependent manner.
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Motivo de Inhibición del Inmunorreceptor Basado en Tirosina , Unión Proteica , Proteómica , Fosforilación , Humanos , Proteómica/métodos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Dominios Homologos src , Secuencia de Aminoácidos , Transducción de Señal , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/químicaRESUMEN
Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.
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Manosa , Farmacología en Red , Enfermedad del Hígado Graso no Alcohólico , Serina-Treonina Quinasas TOR , Animales , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Manosa/farmacología , Manosa/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic ß-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography-mass spectrometry (LC-MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.
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Diabetes Mellitus Tipo 2 , Flavanonas , Resistencia a la Insulina , Scutellaria baicalensis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cromatografía Líquida con Espectrometría de Masas , Cromatografía Liquida , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Flavonoides/farmacología , Inflamación , Antiinflamatorios/farmacologíaRESUMEN
In this study, we report a new carbazole-malononitrile fluorescent probe CBC with an interesting aggregation-induced emission (AIE) characteristic. Probe CBC could rapidly and selectively detect hydrazine (N2H4) in ï½100% aqueous media, and also exhibit an exceedingly low detection limit of 6.3 nM for sensitively detecting N2H4. The sensing mechanism of CBC towards N2H4 has been well demonstrated through the spectra of 1H NMR, HRMS and FTIR. Interestingly, probe CBC was applied to visualize and detect gaseous and aqueous N2H4 with sensitive color changes. Importantly, probe CBC was applied to effectively detect N2H4 in practical samples such as soil, human serum, human urine, plants, foods and beverages, as well as sensitively sense and image N2H4 in biological systems including living mungbean sprouts, Arabidopsis thaliana, and HeLa cells.
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Arabidopsis , Colorantes Fluorescentes , Humanos , Colorantes Fluorescentes/química , Células HeLa , Imagen Molecular/métodos , Agua/química , Carbazoles , Hidrazinas , Espectrometría de Fluorescencia/métodosRESUMEN
Gelatin-based hydrogels have gained considerable attention due to their resemblance to the extracellular matrix and hydrophilic three-dimensional network structure. Apart from providing an air-permeable and moist environment, these hydrogels optimize the inflammatory microenvironment of the wounds. These properties make gelatin-based hydrogels highly competitive in the field of wound dressings. In this study, a series of composite hydrogels were prepared using gelatin (Gel) and carboxymethyl chitosan (CMCh) as primary materials, glutaraldehyde as a crosslinker, and aloe vera juice as an anti-inflammatory component. The properties of the hydrogel, including its rheological properties, microscopic structures, mechanical properties, swelling ratios, thermal stability, antibacterial properties, and biocompatibility, were investigated. The results demonstrate that the gelatin-based hydrogels exhibit good elasticity and rapid self-healing ability. The hydrogels exhibited slight shear behavior, which is advantageous for skin care applications. Furthermore, the inclusion of aloe vera juice into the hydrogel resulted in a dense structure, improved mechanical properties and enhanced swelling ratio. The Gel/CMCh/Aloe hydrogels tolerate a compressive strength similar to that of human skin. Moreover, the hydrogels displayed excellent cytocompatibility with HFF-1 cells, and exhibited antibacterial activity against E. coli and S. aureus. Lomefloxacin was used as a model drug to study the releasing behavior of the Gel/CMCh/aloe hydrogels. The results showed that the drug was released rapidly at the initial stage, and could continue to be released for 12 h, the maximum releasing rate exceeded 20 %. These findings suggest that the gelatin-based hydrogels hold great promise as effective wound dressings.
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Aloe , Quitosano , Humanos , Hidrogeles/farmacología , Hidrogeles/química , Quitosano/farmacología , Quitosano/química , Aloe/química , Gelatina/química , Escherichia coli , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
Dipeptidyl peptidase 4 (DPP4) inhibitors can effectively inhibit the activity of DPP4, increasing the concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which allows for them to effectively contribute to the reduction of blood sugar levels. Leu-Pro-Ala-Val-Thr-Ile-Arg (LPAVTIR) and Leu-Pro-Pro-Glu-His-Asp-Trp-Arg (LPPEHDWR) were the two peptides with the strongest inhibitory activity against DPP4 selected from silkworm pupa proteins. In this study, four systems were established: Apo (ligand-free DPP4), IPI (IPI-bound DPP4), LPAVTIR (LPAVTIR-bound DPP4), LPPEHDWR (LPPEHDWR-bound DPP4), and Gaussian accelerated molecular dynamic (GaMD) simulation was conducted to investigate the mechanism of action of two inhibitory peptides binding to DPP4. Our study revealed that the LPAVTIR peptide possessed a more stable structure and exhibited a tighter binding to the Ser630 active site in DPP4, thus exhibiting a favorable competitive inhibition effect. In contrast, the LPPEHDWR peptide caused the horizontal α-helix (residues 201-215) composed of Glu205 and Glu206 residues in DPP4 to disappear. The spatial arrangement of active sites Ser630 relative to Glu205 and Glu206 was disrupted, resulting in enzyme inactivation. Moreover, the size of the substrate channel and cavity volume was significantly reduced after the binding of the inhibitory peptide to the protein, which was an important factor in the inhibition of the enzyme activity. A similar effect was also found from IPI (our positive control). By stabilizing the active site of DPP4, the IPI peptide induced the disappearance of the horizontal α-helix and a notable reduction in the active cavity volume. In conclusion, our study provided a solid theoretical foundation for the inhibitory mechanisms of IPI, LPAVTIR, and LPPEHDWR on DPP4, offering valuable insights for advancing the development of drug targets for type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Dipeptidil Peptidasa 4 , Simulación de Dinámica Molecular , Péptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacologíaRESUMEN
A pH-responsive amphiphilic chitosan derivative, N-lauric-O-carboxymethyl chitosan (LA-CMCh), is synthesized. Its molecular structures are characterized by FTIR, 1H NMR, and XRD methods. The influencing factors are investigated, including the amount of lauric acid (LA), carboxymethyl chitosan (CMCh), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and N-hydroxysuccinimide (NHS), and their molar ratio, reaction time, and reaction temperature on the substitution. The degrees of substitution (DS) of the lauric groups on the -NH2 groups are calculated based on the integrated data of 1H NMR spectra. The optimum reaction condition is obtained as a reaction time of 6 h, a reaction temperature of 80 °C, and a molar ratio of lauric acid to O-carboxymethyl chitosan to N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride to N-hydroxysuccinimide of 1:3:4.5:4.5, respectively. The crystallinity and initial decomposition temperature of LA-CMCh decrease, but the maximum decomposition temperature increases. The crystallinity is reduced due to the introduction of LA and the degree of hydrogen bonding among LA-CMCh molecules. LA-CMCh could self-aggregate into particles, which size and critical aggregation concentration depend on the degree of substitution and medium pH. LA-CMCh aggregates could load curcumin up to 21.70 %, and continuously release curcumin for >200 min. LA-CMCh shows nontoxicity to fibroblast HFF-1 cells and good antibacterial activity against S. aureus and E. coli, indicating that it could be used as an oil-soluble-drug carrier.
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Carbodiimidas , Quitosano , Curcumina , Metilaminas , Succinimidas , Quitosano/química , Curcumina/farmacología , Escherichia coli , Staphylococcus aureus , Concentración de Iones de HidrógenoRESUMEN
A sophisticated high-order framework nucleic acid (FNA) was engineered for the targeted delivery and responsive release of environment tolerant antisense peptide nucleic acids (asPNAs). The dendritic FNA-asPNAs system was constructed via simple one-pot modular assembly and demonstrated a good synergistic effect with chemotherapy on drug resistant cancer cells.
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Ácidos Nucleicos , Ácidos Nucleicos de Péptidos , Ácidos Nucleicos de Péptidos/farmacología , Oligonucleótidos Antisentido/farmacología , Péptidos , Resistencia a MedicamentosRESUMEN
Type H vessels couple angiogenesis with osteogenesis, while sympathetic cues regulate vascular and skeletal function. The crosstalk between sympathetic nerves and type H vessels in bone remains unclear. Here, we first identify close spatial connections between sympathetic nerves and type H vessels in bone, particularly in metaphysis. Sympathoexcitation, mimicked by isoproterenol (ISO) injection, reduces type H vessels and bone mass. Conversely, beta-2-adrenergic receptor (ADRB2) deficiency maintains type H vessels and bone mass in the physiological condition. In vitro experiments reveal indirect sympathetic modulation of angiogenesis via paracrine effects of mesenchymal stem cells (MSCs), which alter the transcription of multiple angiogenic genes in endothelial cells (ECs). Furthermore, Notch signaling in ECs underlies sympathoexcitation-regulated type H vessel formation, impacting osteogenesis and bone mass. Finally, propranolol (PRO) inhibits beta-adrenergic activity and protects type H vessels and bone mass against estrogen deficiency. These findings unravel the specialized neurovascular coupling in bone homeostasis and regeneration.
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BACKGROUND: Fibrobronchoscopy is a common adjunct tool that requires anesthesia and is widely used in the diagnosis and treatment of various respiratory diseases. However, current anesthesia methods, such as spray, nebulized inhalation, and cricothyroid membrane puncture, have their own advantages and disadvantages. Recently, studies have shown that bronchoscopic direct-view glottis anesthesia is a simple and inexpensive method that shortens the examination time and provides excellent anesthetic results. AIM: To evaluate the effectiveness of bronchoscopic direct vision glottis anesthesia for bronchoscopy. METHODS: The study included 100 patients who underwent bronchoscopy during thoracic surgery. A random number table method was used to divide the patients into control and observation groups (50 patients each). The control and observation groups were anesthetized using the nebulized inhalation and bronchoscopic direct vision glottis method, respectively. Hemodynamic indices [systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and oxygen saturation (SpO2) before (T1), 5 min after anesthesia (T2), and at the end of the operation (T3)] serum stress hormone indices [norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), and cortisol (Cor) before and after treatment] were compared between the 2 groups. Adverse effects were also compared between the two groups. RESULTS: At T2 and T3, SBP, DBP, and HR were lower in the observation group than the control group, whereas SpO2 was higher than the control group [(119.05 ± 8.01) mmHg vs (127.05 ± 7.83) mmHg, (119.35 ± 6.66) mmHg vs (128.39 ± 6.56) mmHg, (84.68 ± 6.04) mmHg vs (92.42 ± 5.57) mmHg, (84.53 ± 4.97) mmHg compared to (92.57 ± 6.02) mmHg, (74.25 ± 5.18) beats/min compared to (88.32 ± 5.72) beats/min, (74.38 ± 5.31) beats/min compared to (88.42 ± 5.69) beats/min, (97.36 ± 2.21)% vs (94.35 ± 2.16)%, (97.42 ± 2.36)% vs (94.38 ± 2.69%], with statistically significant differences (all P < 0.05). After treatment, NE, E, ACTH, and Cor were significantly higher in both groups than before treatment, but were lower in the observation group than in the control group [(68.25 ± 8.87) ng/mL vs (93.35 ± 14.00) ng/mL, (53.59 ± 5.89) ng/mL vs (82.32 ± 10.70) ng/mL, (14.32 ± 1.58) pg/mL vs (20.35 ± 3.05) pg/mL, (227.35 ± 25.01) nmol/L vs (322.28 ± 45.12) nmol/L], with statistically significant differences (all P < 0.05). The incidence of adverse reactions was higher in the control group than in the observation group [12.00% (12/50) vs 6.00% (3/50)] (P < 0.05). CONCLUSION: The use of bronchoscopic direct vision glottis anesthesia method for bronchoscopy patients is beneficial for stabilizing hemodynamic indices during bronchoscopy and reducing the level of patient stress, with good safety and practicality.
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Protein zero related (PZR) serves as a substrate and anchor protein for SHP-2, the product of the proto-oncogene PTPN11 that is frequently mutated in cancers. The expression level of PZR is elevated in various cancers, which is correlated with an unfavorable prognosis. The role of PZR in lung cancer is not fully studied. To investigate how PZR affects signaling pathways involved in LUAD development, we utilized the CRISPR technology to knock out PZR expression in SPC-A1 lung adenocarcinoma cells and then conducted RNA sequencing to profile the transcriptome. Our results showed that 226 genes exhibited differential expressions in PZR-knockout SPC-A1 cells vs wild-type cells. Many of the genes encode proteins involved in cell adhesion, migration, actin cytoskeleton organization, and regulation of cell shape. Furthermore, our experimental data showed that PZR-knockout SPC-A1 cells displayed faster attachment to tissue culture dishes and slower detachment from the dishes upon EDTA treatment. The data suggest an important role of PZR in cell-matrix interaction and may provide new insights into the signaling events that regulate cancer development.
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Excessive levels of cyanide (CN-) and hypochlorite (ClO-) anions are the significant threats to the human health and the environment. Thus, great efforts have been to design and synthesize molecular sensors for the simple, instantaneous and efficient detecting environmentally and biologically important anions. Currently, developing a single molecular sensor for multi-analyte sensing is still a challenging task. In our present work, we developed a new molecular sensor (3TM) based on oligothiophene and Meldrum's acid units for detecting cyanide and hypochlorite anions in biological, environmental and food samples. The detecting ability of 3TM has been examined to various testing substances containing amino acids, reactive oxygen species, cations and anions, showing its high selectivity, excellent sensitivity, short response time (ClO-: 30 s, CN-: 100 s), and broad pH working range (4-10). The detection limits were calculated as 4.2 nM for ClO- in DMSO/H2O (1/8, v/v) solution and 6.5 nM for CN- in DMSO/H2O (1/99, v/v) solution. Sensor 3TM displayed sharp turn-on fluorescence increasement (555 nm, 435 nm) and sensitive fluorescence color changes caused by CN-/ClO-, which is ascribed to the nucleophilic addition and oxidation of ethylenic linkage by cyanide and hypochlorite, respectively. Moreover, sensor 3TM was applied for hypochlorite and cyanide detecting in real-world water, food samples and bio-imaging in live cells and zebrafish. To our knowledge, the developed 3TM sensor is the seventh single-molecular sensor for simultaneous and discriminative detecting hypochlorite and cyanide in food, biological and aqueous environments using two distinct sensing modes.
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Cianuros , Pez Cebra , Animales , Humanos , Cianuros/química , Ácido Hipocloroso , Dimetilsulfóxido , Colorantes Fluorescentes/química , Aniones , Agua/químicaRESUMEN
Uncontrolled bleeding in emergency situations is a great threat to both military and civilian lives, and an ideal hemostat for effectively controlling prehospital hemorrhage is urgently needed but still lacking. Although hemostatic hydrogels are promising for emergency hemostasis, they are currently challenged by either the mutual exclusion between a short gelation time and strong adhesive network or the insufficient functionality of ingredients and complicated operations for in situ curing. Herein, an extracellular matrix biopolymer-based and multifunctional hemostatic hydrogel that simultaneously integrates rapid thermoresponsive gelation, robust wet adhesion, and ease of use in emergencies is rationally engineered. This hydrogel can be conveniently used via simple injection and achieves instant sol-gel phase transition at body temperature. Its comprehensive performance could be facilely regulated by tuning the proportions of components, and the optimal performance (gelation time 6-8 s, adhesion strength 125 ± 3.6 kPa, burst pressure 282 ± 4.1 mmHg) is established due to the coordinated enhancement of the photo-cross-linking pretreatment and the hydrophilic-hydrophobic balance among various interactions in the hydrogel system. Additionally, it exhibits significant coagulation effect in vitro and enables effective hemostasis and wound healing in vivo. This work provides a promising platform for versatile applications of hydrogel-based materials, including emergency hemostasis.
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Hemostáticos , Hidrogeles , Hidrogeles/farmacología , Hidrogeles/química , Hemostáticos/farmacología , Biomimética , Hemostasis , Coagulación SanguíneaRESUMEN
Objective: This study aimed to evaluate the results and complications related to revision total hip arthroplasty within a short-to-medium follow up period. Methods: From January 2016 to January 2020, we reviewed 31 prosthetic hip arthroplasty stem revisions using a fluted, tapered modular stem with distal fixation. The median age of the patients was 74.55-79 years. The survival rate was 100%, and there were no re-revisions. The Harris hip score improved from an average of 36.5 ± 7.8 before surgery to 81.8 ± 6.2 at the final follow-up. Results: The average final follow-up was 36 (24-60) months. During this time, there was no periprosthetic infection, no prosthesis loosening or breakage, and no sciatic nerve injury. Complications included four (12.9%) intraoperative fractures and eight (25.8%) dislocations that had no stem fractures. The postoperative limb was lengthened by 17.8 ± 9.8 mm. In most cases, bone regeneration was an early and important finding. Three cases underwent extended trochanteric osteotomy, and bone healing was achieved by the final follow-up. Conclusion: The modular tapered stem reviewed in this study was very versatile, could be used in most femoral revision cases, and allowed for rapid bone reconstruction. However, a long-term follow-up study is needed to confirm these results.
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PZR is a transmembrane glycoprotein encoded by the MPZL1 gene. It serves as a specific binding protein and substrate of tyrosine phosphatase SHP-2 whose mutations cause developmental diseases and cancers. Bioinformatic analyses of cancer gene databases revealed that PZR is overexpressed in lung cancer and correlated with unfavorable prognosis. To investigate the role of PZR in lung cancer, we employed the CRISPR technique to knockout its expression and recombinant lentiviruses to overexpress it in lung adenocarcinoma SPC-A1 cells. While knockout of PZR reduced colony formation, migration, and invasion, overexpression of PZR had the opposite effects. Furthermore, when implanted in immunodeficient mice, PZR-knockout SPC-A1 cells showed suppressed tumor-forming ability. Finally, the underlying molecular mechanism for these functions of PZR is its positive role in activating tyrosine kinases FAK and c-Src and in maintaining the intracellular level of reactive oxygen species (ROS). In conclusion, our data indicated that PZR plays an important role in lung cancer development, and it may serve as a therapeutic target for anti-cancer development and as a biomarker for cancer prognosis.
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Neoplasias Pulmonares , Animales , Ratones , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias Pulmonares/genética , Estrés Oxidativo , Fosforilación , Tirosina/metabolismoRESUMEN
Recently, single-wavelength synergetic photothermal/photodynamic (PTT/PDT) therapy is beginning to make its mark in cancer treatment, and the key to it is a photosensitizer. In this work, an iron-doped metal-zinc-centered organic framework mesoporous carbon derivative (denoted as Fex-Zn-NCT) with a similar porphyrin property was successfully synthesized by a mild, simple, and green aqueous reaction. The effects of different Fe contents and pyrolysis temperatures on the morphology, structure, and PTT/PDT of Fex-Zn-NCT were investigated. Most importantly, we found that Fe50-Zn-NC900 exhibited excellent PTT/PDT performance under single-wavelength near-infrared (808 nm) light irradiation in a hydrophilic environment. The photothermal conversion efficiency (η) was counted as â¼81.3%, and the singlet oxygen (1O2) quantum yield (Φ) was compared with indocyanine green (ICG) as â¼0.0041. Furthermore, Fe50-Zn-NC900 is provided with a clear ability for generating 1O2 in living tumor cells and inducted massive necrosis/apoptosis of tumor cells with single-wavelength near-infrared laser irradiation. All of these are clear to consider that Fe50-Zn-NC900 displays great potential as an excellent photosensitizer for single-wavelength dual-mode PTT/PDT therapy.
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Carbono/química , Zinc/farmacología , Rayos Infrarrojos , Línea Celular Tumoral , Verde de Indocianina/química , Neoplasias/tratamiento farmacológicoRESUMEN
Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer's disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound R-9-(4fluorophenyl)-3-methyl-10,10,-Hydrogen-6-hydrogen-benzopyran named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. 6 months old APP/PS1 transgenic mice were intragastrical administered with FMDB (1.25, 2.5 and 5 mg/kg) every other day for 8 weeks. LV-ERß-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown estrogen receptor ß (ERß). We found that FMDB ameliorated cognitive impairment in the Morris water maze and novel object recognition tests, increased hippocampal neurogenesis and prevented hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERß mediated CBP/p300, CREB and brain-derived neurotrophic factor (BDNF) signaling, and membrane ERß mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Our study demonstrated the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.
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Enfermedad de Alzheimer , Fármacos Neuroprotectores , Ratones , Animales , Femenino , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Ratones Transgénicos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fosfatidilinositol 3-Quinasas , Receptor beta de Estrógeno , Cognición , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Neurogénesis , Apoptosis , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genéticaRESUMEN
An insightful understanding of the interaction between the electrolyte and reaction intermediate and how promotion reaction occurs of electrolyte is challenging in the electrocatalysis reaction. Herein, theoretical calculations are used to investigate the reaction mechanism of CO2 reduction reaction to CO with different electrolytes at the Cu(111) surface. By analyzing the charge distribution of the chemisorbed CO2 (CO2 δ-) formation process, we find that the charge transfer is from metal electrode transfer to CO2 and the hydrogen bond interaction between electrolytes and CO2 δ- not only plays a key role in the stabilization of CO2 δ- structure but also reduces the formation energy of *COOH. In addition, the characteristic vibration frequency of intermediates in different electrolyte solutions shows that H2O is a component of HCO3 -, promoting CO2 adsorption and reduction. Our results provide essential insights into the role of electrolyte solutions in interface electrochemistry reactions and help understand the catalysis process at the molecular level.