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Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.
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Carcinoma de Pulmón de Células no Pequeñas , Receptor con Dominio Discoidina 1 , Resistencia a Antineoplásicos , Ferroptosis , Gefitinib , Neoplasias Pulmonares , Ferroptosis/efectos de los fármacos , Humanos , Gefitinib/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Línea Celular Tumoral , Receptor con Dominio Discoidina 1/metabolismo , Receptor con Dominio Discoidina 1/genética , Proliferación Celular/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratones , Proteínas Supresoras de la Señalización de CitocinasRESUMEN
Highly efficient recognition of cancer cells by immune cells is important for successful therapeutic-cell-based cancer immunotherapy. Herein, we present a facile NIR-II nanoadaptor [hyaluronic acid (HA)/dibenzocyclooctyne (DBCO)-Au:Ag2Te quantum dots (QDs)] for enhancing the tumor recognition and binding ability of natural killer (NK) cells via a bio-orthogonal click reaction in vivo. The Nanoadaptor possesses superior tumor-targeting capacity, facilitating the accumulation of the chemical receptor DBCO at the tumor sites. Subsequently, the enrichment of DBCO on tumor cell surfaces provides multivalent recognition sites for capturing pretreated azide engineered NK92 cells (NK92-N3) through an efficient click reaction, thereby significantly enhancing the therapeutical efficiency. The dynamic process of nanoadaptor-mediated recognition of NK cells to tumor cells could be vividly observed using multiplexed NIR-II fluorescence imaging in a mouse model of lung cancer. Such a nanoadaptor strategy can be extended to other therapeutic cellular systems and holds promise for future clinical applications.
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Química Clic , Células Asesinas Naturales , Células Asesinas Naturales/inmunología , Animales , Ratones , Humanos , Puntos Cuánticos/química , Ácido Hialurónico/química , Línea Celular Tumoral , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Oro/química , InmunoterapiaRESUMEN
Intravital fluorescence imaging in the second near-infrared window (NIR-II, 900-1700 nm) has emerged as a promising method for non-invasive diagnostics in complex biological systems due to its advantages of less background interference, high tissue penetration depth, high imaging contrast, and sensitivity. However, traditional NIR-II fluorescence imaging, which is characterized by the "always on" or "turn on" mode, lacks the ability of quantitative detection, leading to low reproducibility and reliability during bio-detection. In contrast, NIR-II ratiometric fluorescence imaging can realize quantitative and reliable analysis and detection in vivo by providing reference signals for fluorescence correction, generating new opportunities and prospects during in vivo bioimaging and biosensing. In this review, the current design strategies and sensing mechanisms of NIR-II ratiometric fluorescence probes for bioimaging and biosensing applications are systematically summarized. Further, current challenges, future perspectives and opportunities for designing NIR-II ratiometric fluorescence probes are also discussed. It is hoped that this review can provide effective guidance for the design of NIR-II ratiometric fluorescence probes and promote its adoption in reliable biological imaging and sensing in vivo.
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Natural killer (NK) cell-based adoptive immunotherapy has demonstrated encouraging therapeutic effects in clinical trials for hematological cancers. However, the effectiveness of treatment for solid tumors remains a challenge due to insufficient recruitment and infiltration of NK cells into tumor tissues. Herein, a programmed nanoremodeler (DAS@P/H/pp) is designed to remodel dense physical stromal barriers and for dysregulation of the chemokine of the tumor environment to enhance the recruitment and infiltration of NK cells in tumors. The DAS@P/H/pp is triggered by the acidic tumor environment, resulting in charge reversal and subsequent hyaluronidase (HAase) release. HAase effectively degrades the extracellular matrix, promoting the delivery of immunoregulatory molecules and chemotherapy drugs into deep tumor tissues. In mouse models of pancreatic cancer, this nanomediated strategy for the programmed remodeling of the tumor microenvironment significantly boosts the recruitment of NK92 cells and their tumor cell-killing capabilities under the supervision of multiplexed near-infrared-II fluorescence.
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Neoplasias , Neoplasias Pancreáticas , Animales , Ratones , Línea Celular Tumoral , Neoplasias/patología , Inmunoterapia/métodos , Inmunoterapia Adoptiva/métodos , Neoplasias Pancreáticas/patología , Células Asesinas Naturales , Microambiente TumoralRESUMEN
Stem cell-based cancer treatment has garnered significant attention, yet its safety and efficacy remain incompletely understood. The nuclear factor-kappa B (NF-κB) pathway, a critical signaling mechanism involved in tumor growth, angiogenesis, and invasion, serves as an essential metric for evaluating the behavior of stem cells in tumor models. Herein, we report the development of a triple-channel imaging system capable of simultaneously monitoring the tropism of stem cells towards tumors, assessing tumor proliferation, and quantifying tumor NF-κB activity. In this system, we generated a CRISPR-Cas9 gene-edited human glioblastoma cell line, GE-U87-MG, which provided a reliable readout of the proliferation and NF-κB activity of tumors by EF1α-RFLuc- and NF-κB-GLuc-based bioluminescent imaging, respectively. Additionally, near infrared-II emitting Tat-PEG-AgAuSe quantum dots were developed for tracking of stem cell tropism towards tumor. In a representative case involving human mesenchymal stem cells (hMSCs), multichannel imaging revealed no discernible effect of hMSCs on the proliferation and NF-κB activity of GE-U87-MG tumors. Moreover, hMSCs engineered to overexpress the necrosis factor-related apoptosis-inducing ligand were able to inhibit NF-κB activity and growth of GE-U87-MG in vivo. Taken together, our imaging system represents a powerful and feasible approach to evaluating the safety and therapeutic efficacy of stem cells in tumor models.
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Glioblastoma , FN-kappa B , Humanos , FN-kappa B/metabolismo , Línea Celular Tumoral , Células Madre/metabolismo , Apoptosis , Glioblastoma/diagnóstico por imagen , Glioblastoma/terapia , Glioblastoma/metabolismo , Proliferación Celular , Imagen Óptica , TropismoRESUMEN
This study aimed to investigate the cryoprotective properties of proline (1% and 3% (w/v)) on shrimp. The cryoprotective mechanism was studied using physico-chemical experiments and molecular simulations. Proline had a notable positive impact on the thawing loss and texture of shrimp in comparison to the control. The denaturation of myosin in frozen shrimp was delayed by proline. Microscopy analysis demonstrated that proline effectively lowered the harm caused by ice crystals to shrimp muscle. Molecular simulations indicated that proline potentially exerted a cryoprotective effect primarily through the "water substitution" and "glassy state" hypotheses. Proline formed hydrogen bonds with myosin to replace the water molecules around myosin. Additionally, proline interacted with water molecules to form a glassy state, impeding the growth of ice crystals. Consequently, the stability of shrimp myosin was enhanced during freezing. In conclusion, proline demonstrated promise as an efficacious cryoprotectant for aquatic products.
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Hielo , Penaeidae , Animales , Congelación , Hielo/análisis , Prolina , Crioprotectores/farmacología , Agua/farmacología , Miosinas , Penaeidae/químicaRESUMEN
Near-infrared (NIR) quantum dot (QD) light-emitting diodes (LEDs) (NIR-QLEDs) for recognition and tracking applications underpin the future of night-vision technology. However, the performance of environmentally benign materials and devices has lagged far behind that of their Pb-containing counterparts. In this study, we demonstrate the superior performance of NIR-QLEDs based on efficient AgAuSe QDs with contact interface mediation. Consequently, we reveal that using cysteamine-treated QD film contact heterointerfaces can effectively eliminate contact defects in devices and preserve their excellent emissive properties. Additionally, the dipole moment orientation of the coordinated additives is inverse of the heterojunction potential difference, simultaneously blocking electrons and enhancing hole injection in operando, optimizing the LED charge injection balance. These devices exhibit a high external quantum efficiency (EQE) and a power conversion efficiency (PCE) of 15.8 and 12.7% at 1046 nm, respectively, a sub-band gap turn-on voltage of 0.9 V, and a low current density (over 10% of the EQE from 0.0017 to 0.31 mA cm-2). These are the highest EQE and PCE values ever reported for environmentally benign NIR-QLEDs. The results of this study can provide a general strategy for the practical application of QDs in electroluminescent devices.
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Currently, mainstream lanthanide probes with fluorescence located in the second near-infrared subwindow of 1500-1700 nm (NIR-IIb) are predominantly Er(III)-based nanoparticles (NPs). Here we report a newly developed NIR-IIb fluorescent nanoprobe, α-Tm NP (cubic-phase NaYF4@NaYF4:Tm@NaYF4), with an emission at 1630 nm. We activate the 1630 nm emission of Tm(III) in α-Tm NP through the large spread of the Stark split sublevels induced by the crystal-field effect of the α-NaYF4 host. Further, we systematically investigated the effect of crystalline structure of the host NaYF4 NP (cubic phase (α) or hexagonal phase (ß)), the type and concentrations of dopants (Yb(III), Tm(III), and Ca(II) ions) in the α-phase host, and the thicknesses of the interlayer and inert shell on the NIR-IIb fluorescence of Tm(III). The ultimate nanostructure presents a significant enhancement factor of the NIR-IIb photoluminescence intensity of Tm(III) up to â¼315. With this bright NIR-IIb fluorescent nanoprobe, we demonstrate high-spatial-resolution time-coursing imaging of breast cancer bone metastasis.
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Carboxymethyl chitosan and resistant starch exhibit good performance in diabetes regulation. We prepared carboxymethyl chitosan - resistant starch complex. Test the properties of composite resistant starch by using X-ray diffraction, water contact angle, infrared spectroscopy, and scanning electron microscopy, interactions with intestinal microbiota and mouse experiments were also conducted. The results indicated that the composite resistant starch had a good effect on promoting the proliferation of probiotics on Bifidobacterium and a significant inhibitory effect on Escherichia coli than resistant starch (P < 0.05). After administration, the water intake and weight of diabetic mice were significantly reduced. The blood glucose of diabetic mice was also reduced, and oral glucose tolerance showed that the glucose degradation rates of composite resistant starch were significantly improved compared to model mice. Cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein were significantly lower than those in the diabetes group (P < 0.05). The diversity of the gut microbiota was also proven.
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Quitosano , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Animales , Ratones , Almidón Resistente/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Almidón/química , Quitosano/farmacología , Quitosano/química , Diabetes Mellitus Experimental/tratamiento farmacológicoRESUMEN
The present study aimed to investigate the effects of adding cinnamon bark oil (CBO) on the quality of ground lamb meat, considering different packaging conditions, including modified atmospheric packaging (MAP) using Hengxian HX-300H and overwrapped packaging. The CBO was incorporated into lamb meat samples at three different levels: 0% (control), 0.025% and 0.05% (v/w). The samples were then subjected to three packaging methods: MAP1 (80% O2 + 20% CO2), MAP2 (40% O2 + 30% CO2 + 30% N2) and overwrapped packaging and stored at 4 °C for 0, 4, 8, 12 and 16 days. The findings of the present study revealed that the addition of 0.025% and 0.05% CBO under MAP1 condition significantly improved the color of the meat samples after 12 days of storage at 4 °C (p < 0.05). The overwrapped samples exhibited higher levels of thiobarbituric acid reactive substances (TBARS) compared to all other treatments, starting from day 4 of storage (p < 0.05). Furthermore, microbial counts were notably higher in the overwrapped samples than in all other samples after day 8 of storage (p < 0.05). In conclusion, the combination of 0.05% CBO with MAP proved to be an effective strategy for enhancing the color stability and oxidative stability of ground lamb meat. These results suggest that CBO can be utilized as a beneficial protective agent in meat packaging processes.
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PURPOSE: Patients with the placement of a totally implantable venous access port (TIVAP) commonly suffer from pain caused by inserting a non-coring needle. At present, lidocaine cream and cold spray are extensively used for pain management, but they are complex to manage in busy medical environments and developing countries. The lidocaine spray combines the analgesic effect of lidocaine cream and the rapid onset of cold spray, which can effectively alleviate the pain related to non-coring needle puncture in patients with TIVAP. This randomized-controlled trial aimed to explore the effectiveness, acceptability, and safety of lidocaine spray in relieving the pain of non-coring needle puncture in patients with TIVAP. METHODS: A total of 84 patients who were hospitalized in the oncology department of a Grade III Level-A hospital in Shanghai from January 2023 to March 2023 and were implanted with TIVAP and required non-coring needle puncture were selected as the study subjects. The recruited patients were randomly assigned to the intervention group and the control group (n=42). Before routine maintenance, the intervention group received lidocaine spray 5 min before disinfection, while the control group received water spray 5 min before disinfection. The main clinical outcome was pain, and the degree of puncture pain in both groups was evaluated using the visual analogue scale. RESULTS: There were no significant differences between the two groups in age, gender, educational level, body mass index, port implantation time, and disease diagnosis (P>0.05). The pain score in the intervention and control groups was 15.12±6.61mm and 36.50±18.79mm, respectively (P<0.001). There were 2 (4.8%) patients with moderate pain in the intervention group and 18 (42.9%) patients with moderate pain in the control group (P<0.001). In the control group, 3 (7.1%) patients reported severe pain. The median comfortability score for the two groups of patients was 10, but there was a difference between the two groups (P<0.05) because the intervention group tilted to the right. The successful puncture rate of the first time puncture had no difference between the two groups, both being 100%. Moreover, 33 patients (78.6%) in the intervention group and 12 patients (28.6%) in the control group reported that they would choose the same spray for intervention in the future (P<0.001). During the 1 week of follow-up, 1 patient in the intervention group developed skin itching (P>0.05). CONCLUSIONS: The local use of lidocaine spray in patients with TIVAP is effective, acceptable, and safe to alleviate the pain caused by non-coring needle puncture. TRIAL REGISTRATION: Chinese Clinical Trial Registry (registration number: ChiCTR2300072976).
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Cateterismo Venoso Central , Lidocaína , Humanos , Lidocaína/uso terapéutico , Anestésicos Locales/uso terapéutico , Cateterismo Venoso Central/efectos adversos , China , Dolor/tratamiento farmacológico , Dolor/etiología , Punciones/efectos adversosRESUMEN
Hydrophilic semiconductor quantum dots (QDs) with emission in the second near-infrared window (NIR-II) have been widely studied in bioimaging applications. In such cases, QDs are usually dispersed in water. As is known, water has strong absorbance in the NIR-II region. However, investigations on the interaction between NIR-II emitters and water molecules are ignored in previous studies. Herein, we synthesized a series of mercaptoundecanoic acid-coated silver sulfide (Ag2S/MUA) QDs with various emissions that partially or completely overlapped with the absorbance of water at 1200 nm. By constructing a hydrophobic interface of cetyltrimethylammonium bromide (CTAB) with MUA on the Ag2S QDs surface via forming an ionic bond, significant enhancement of Ag2S QDs photoluminescence (PL) intensity was observed, as well as a prolonged lifetime. These findings suggest that there is an energy transfer between Ag2S QDs and water in addition to the classical resonance absorption. Transient absorption and fluorescence spectra results revealed that the increased PL intensities and lifetime of Ag2S QDs originated from the suppressed energy transfer from Ag2S QDs to the water due to the CTAB bridged hydrophobic interfaces. This discovery is important for a deeper understanding of the photophysical mechanisms of QDs and their applications.
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Puntos Cuánticos , Puntos Cuánticos/química , Agua/química , Cetrimonio , Fluorescencia , Transferencia de EnergíaRESUMEN
Effective drug delivery in the central nervous system (CNS) needs to have long blood-circulation half-lives, to pass through the blood-brain barrier (BBB), and subsequently to be taken up by target cells. Herein, a traceable CNS delivery nanoformulation (RVG-NV-NPs) is developed by encapsulating bexarotene (Bex) and AgAuSe quantum dots (QDs) within Lamp2b-RVG-overexpressed neural stem cell (NSC) membranes. The high-fidelity near-infrared-II imaging by AgAuSe QDs offers a possibility of in vivo monitoring the multiscale delivery process of the nanoformulation from the whole-body to the single-cell scale. It was revealed the synergy of acetylcholine receptor-targeting of RVG and the natural brain-homing and low immunogenicity of NSC membranes prolong the blood circulation, facilitate BBB crossing and nerve cell targeting of RVG-NV-NPs. Thus, in Alzheimer's disease (AD) mice, the intravenous delivery of as low as 0.5% of oral dose Bex showed highly effective up-regulation of the apolipoprotein E expression, resulting rapid alleviation of â¼40% ß-amyloid (Aß) level in the brain interstitial fluid after a single dose administration. The pathological progression of Aß in AD mice is completely suppressed during a 1 month treatment, thus effectively protecting neurons from Aß-induced apoptosis and maintaining the cognitive abilities of AD mice.
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Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Péptidos beta-Amiloides/metabolismo , Membrana Celular/metabolismoRESUMEN
Thymocyte antigen-1 (THY-1)is a potential target for rheumatoid arthritis (RA) treatment, and THY-1 positive fibroblast-like synoviocytes (FLS) are enriched in the synovium of RA patients and participate in angiogenesis to accelerate RA progression. In this study, we screened an antibody targeting THY-1 (THY-1 Ab) and explored its mechanism in alleviating RA progression. THY-1 Ab was screened from ScFv phage antibody library by phage display technology (PDT). THY-1 Ab-treated collagen induced arthritis (CIA) mice had lower degree of arthritis scores. We explore the mechanism of THY-1 Ab in alleviating RA progression. THY-1 Ab can remarkably inhibit the secretion of pro-inflammatory factors and promote the secretion of anti-inflammatory factors. Further experiments showed that THY1 Ab downregulated the expression of JUNB by the hsa_circ_0094342/miRNA-155-5P/SPI1 axis, inhibited RA angiogenesis and osteoclast differentiation, and relieved RA progression. These findings support that THY-1 Ab is a promising therapeutic antibody for RA treatment.
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Artritis Experimental , Artritis Reumatoide , MicroARNs , Animales , Humanos , Ratones , Artritis Experimental/terapia , Artritis Experimental/metabolismo , Artritis Reumatoide/terapia , Artritis Reumatoide/metabolismo , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Inmunoterapia , MicroARNs/genética , MicroARNs/metabolismo , Osteoclastos/metabolismo , Membrana Sinovial/metabolismo , Timocitos/metabolismo , Antígenos/inmunologíaRESUMEN
Drawing on the transactional theory of stress, the current study investigates whether employee job insecurity triggers employee behavioral strain reactions (i.e., alcohol use, marijuana use, and cigarette use) and psychological strain reactions (i.e., emotional exhaustion and depression) through stress during the COVID-19 pandemic. In addition, we integrate social support theory and expect the moderating role of pet attachment support in the above relationships. By collecting two-wave data from 187 employees with pets in the United States, we found that during the COVID-19 pandemic, stress mediated the relationships between job insecurity and predicted behavioral and psychological reactions. Moreover, pet attachment support buffered the relationships between stress and these behavioral and psychological strain reactions (all except cigarette use). Pet attachment support also alleviated the conditional indirect effects job insecurity had on the two types of strain reactions via stress. We discuss theoretical and practical implications of this study.
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COVID-19 , Empleo , Humanos , Empleo/psicología , Seguridad del Empleo , PandemiasRESUMEN
Starch nanoparticles (SNPs) was produced from type-A, B and C native starches (corn, potato and Trichosanthes kirilowii pulp starches respectively), via the nanoprecipitation method. The SNPs showed different amylose contents, water contact angles, surface morphologies and urea clearance performances. In this work, to examine the parameters of SNPs that may change the urea adsorption capacity, urea adsorption performance in adsorption environments with different pH values, urea concentrations, and adsorption times was examined. Thereafter, the characteristics of SNPs were tested by water contact angle measurements (WCA), transmission electron microscopy, specific surface area measurements, gel permeation chromatography, and zeta potential analysis. The results showed that the Trichosanthes kirilowii pulp (C) SNPs show better adsorption than the corn (A) and potato (B) SNPs. The hydrophobicity of SNPs promotes the urea adsorption of the SNPs. Using grey relational analysis, it was found that WCA and Mn are the critical parameter affecting the adsorption performance, with WCA and Mn within the ranges of 31-33° and 1900-2100 kDa, respectively, were found to be the conditions for optimal urea adsorption.
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Nanopartículas , Solanum tuberosum , Almidón/química , Adsorción , Urea , Soluciones para Diálisis/análisis , Amilosa/química , Solanum tuberosum/química , Zea mays/química , Nanopartículas/química , AguaRESUMEN
Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER-α36, a variant of the estrogen receptor (ER), mediated non-genomic estrogen signaling and is highly expressed in many ER-negative malignant tumors. ER-α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER-α36 and EGFR in estrogen-mediated GBM cell proliferation. Here, we showed that ER-α36 was highly expressed and confirmed that ER-α36 co-labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen-induced proliferation in ER-α-negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER-α36 expression, and knockdown of ER-α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC-Y-416 and inhibited SRC-Y-527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen-induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER-α36 promotes non-genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER-α-negative GBMs that retain high level of ER-α36, since estrogen may be a viable therapeutic target for these patients.
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Neoplasias de la Mama , Glioblastoma , Línea Celular Tumoral , Ciclinas , Receptores ErbB/metabolismo , Receptor alfa de Estrógeno/metabolismo , Estrógenos/metabolismo , Femenino , Humanos , Masculino , Receptores de EstrógenosRESUMEN
Axonal transport plays a significant role in the establishment of neuronal polarity, axon growth, and synapse formation during neuronal development. The axon of a naturally growing neuron is a highly complex and multifurcated structure with a large number of bends and branches. Nowadays, the study of dynamic axonal transport in morphologically complex neurons is greatly limited by the technological barrier. Here, a sparse gene transfection strategy was developed to locate fluorescent mCherry in the lysosome of primary neurons, thus enabling us to track the lysosome-based axonal transport with a single-particle resolution. Thereby, several axonal transport models were observed, including the forward or backward transport model, stop-and-go model, repeated back-and-forth transport model, and cross-branch transport model. Then, the accurate single-particle velocity quantification by TrackMate revealed a highly heterogeneous and discontinuous transportation process of lysosome-based axonal transport in freely orientated axons. And, multiple physical factors, such as the axonal structure and the size of particles, were disclosed to affect the velocity of particle transporting in freely orientated axons. The combined single-particle fluorescence tracking and TrackMate assay can be served as a facile tool for evaluating axonal transport in neuronal development and axonal transport-related diseases.
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Transporte Axonal , Axones , Transporte Axonal/fisiología , Axones/metabolismo , Fluorescencia , Lisosomas , NeuronasRESUMEN
Near-infrared (NIR) fluorescence imaging technology (NIR-I region, 650-950 nm and NIR-II region, 1000-1700 nm), with deeper tissue penetration and less disturbance from auto-fluorescence than that in visible region (400-650 nm), is playing a more and more extensive role in the field of biomedical imaging. With the development of precise medicine, intelligent NIR fluorescent probes have been meticulously designed to provide more sensitive, specific and accurate feedback on detection. Especially, recently developed ratiometric fluorescent probes have been devoted to quantify physiological and pathological parameters with a combination of responsive fluorescence changes and self-calibration. Herein, we systemically introduced the construction strategies of NIR ratiometric fluorescent probes and their applications in biological imagingin vivo, such as molecular detection, pH and temperature measurement, drug delivery monitoring and treatment evaluation. We further summarized possible optimization on the design of ratiometric probes for quantitative analysis with NIR fluorescence, and prospected the broader optical applications of ratiometric probes in life science and clinical translation.
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Colorantes Fluorescentes , Imagen Óptica , Colorantes Fluorescentes/química , Imagen Óptica/métodosRESUMEN
Previous research on the association between job characteristics and employee well-being has returned mixed results. In particular, the possible impact of individual appraisal of these job characteristics has not been well-acknowledged. To address this limitation, we drew on appraisal theory and examined: (a) how workers appraise particular job characteristics, and (b) how these appraisals affect the relationships between these job characteristics and well-being (i.e., work engagement and burnout). We tested our hypotheses across two studies. In a cross-occupation sample (Study 1, n = 514), we found that job demands and resources can be appraised as both challenges and hindrances. In addition, challenge appraisals can mitigate the detrimental impact of job demands on engagement and burnout; and hindrance appraisals can strengthen the detrimental effects of job demands on burnout. Further, hindrance appraisals of job resources reduce their beneficial effects on engagement and burnout. Study 2 (n = 316 nurses in a hospital) further showed that challenge appraisals of job demands can reduce their impact on burnout while challenge appraisals of job resources will strengthen their positive effect on employee engagement and burnout. We discuss study implications as well as future research directions.