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Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
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Células Madre Hematopoyéticas , Esfingosina , Glucólisis/genética , Células Madre Hematopoyéticas/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol) , Prolil Hidroxilasas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450âmg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Antineoplásicos Inmunológicos , Carcinoma Hepatocelular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Hepáticas , Neoplasias del Cuello Uterino , Humanos , Masculino , Femenino , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Empatía , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Artificial bionic nanochannels have attracted wide attention and successfully used in various fields. In this work, a novel nanochannel with asymmetric surface charge is proposed to investigate the ion enrichment effect. The results show that the proposed nanochannel has excellent ion enrichment performance and the obtained ion enrichment ratio is up to 1500 when the ion concentration is 0.01 mM, which is much higher than precedent researches typically ranging from tens to hundreds. Besides, we found that the forward voltage bias will produce ions enrichment and the reverse voltage bias will produce ions depletion. The ion enrichment ratio is higher at the larger voltage bias, absolute surface charge density and smaller nanochannel height. In addition, the ion enrichment performance is more sensitive to the change of charged wall length and not sensitive to the change of uncharged wall length. The research report offers important information and instructions for the design and optimum on ion enrichment performance.
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Micro/nano electronic devices heat dissipation depends heavily on the thermal interface materials (TIMs). Despite notable progress, it is hard to efficaciously enhance the thermal properties of the hybrid TIMs with high-load additives due to an absence of effective heat transfer routes. Herein, the low content of three-dimensional (3D) graphene with interconnected networks is adopted as the additive to improve the thermal properties of epoxy composite TIMs. The thermal diffusivity and thermal conductivity of the as-prepared hybrids were dramatically improved by constructing thermal conduction networks after adding 3D graphene as fillers. The 3D graphene/epoxy hybrid's optimal thermal characteristics were observed at 1.5 wt% of 3D graphene content, corresponding to a maximum enhancement of 683%. Besides, heat transfer experiments were further performed to determine the superb heat dissipation potential of the 3D graphene/epoxy hybrids. Moreover, the 3D graphene/epoxy composite TIM was also applied to high-power LED to improve heat dissipation. It effectively reduced the maximum temperature from 79.8 °C to 74.3 °C. These results are beneficial for the better cooling performance of electronic devices and provide useful guidelines for advancing the next-generation TIMs.
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LCN2 (Lipocalins) was first identified as iron transporter through associating with its siderophores and also involved in many cancer metastases, but its function is still paradoxical. We questioned that whether LCN2 might also associate exogenous iron chelator as does in inherent way and the association may influence their respective function. To address this issue, we investigated the effect of LCN2 on action of DpdtC (2,2'-dipyridine ketone hydrazone dithiocarbamte), an iron chelator in proliferation and metastasis-related gene expression. The results showed that exogenous LCN2 and DpdtC could inhibit growth of HepG2 cells, while the combination treatment enhanced their inhibitory effect both in proliferation and colony formation. This encouraged us to investigate the effect of the interaction on metastasis-related gene expression. The results revealed that both LCN2 and DpdtC impaired the wound healing of HepG2, but the inhibitory effect of DpdtC was significantly enhanced upon association with LCN2. Undergoing epithelium-mesenchymal transition (EMT) is a crucial step for cancer metastasis, LCN2 and DpdtC had opposite effects on EMT markers, the binding of DpdtC to LCN2 significantly weakened the regulation of it (or its iron chelate) on EMT markers. To insight into the interaction between LCN2 and DpdtC-iron, fluorescence titration and molecular docking were performed to obtain the association constant (~ 104 M-1) and thermodynamic parameters (ΔG = - 26.10 kJ/mol). Importantly this study provided evidence that siderophores-loading state of LCN2 may influence its function, which be helpful for understanding the contradictory role of LCN2 in the metastasis of cancer.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Ditiocarba/análogos & derivados , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quelantes del Hierro/farmacología , Lipocalina 2/metabolismo , Autofagia/efectos de los fármacos , Ditiocarba/farmacología , Ferritinas/metabolismo , Células Hep G2 , Humanos , Hidrazonas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Tiocarbamatos/farmacología , Canales de Potencial de Receptor TransitorioRESUMEN
Herein, we demonstrate a distinctive energy harvesting method that electricity can be generated from the ionic solution flowing through the interstices between packed three-dimensional graphene powders. A constructed electrokinetic nanogenerator with an effective flow area of â¼0.34 cm2can generate a large current of 91.33 nA under 10-6M NaCl solution with a flow rate of 0.4 ml min-1, corresponding to a maximum power density of 0.45µW m-2. Besides, it shows a good linear relationship between the streaming current and the flow rate, suggesting that it could be used as a self-powered micro-flowmeter. These results provide a convenient way for clean energy harvesting and show a bright future for self-powered systems.
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Abnormal changes in hippocampal function and neuroplasticity are involved in neuropathic pain, which induces hyperalgesia and learning and memory deficits. Previous studies from our group have shown that electroacupuncture at Huantiao (GB30) and Yanglingquan (GB34) has an obvious analgesic effect on neuropathic pain. However, the central regulatory mechanism occurring in the hippocampus remains to be investigated. In this study, behavioral and proteomic analyses were performed to identify differentially expressed hippocampal proteins involved in electroacupuncture-induced analgesia. Our results showed both upregulated (TMEM126A, RDH13, and Luc7L) and downregulated proteins (Mettl7A, GGA1 RTKN, RSBN1, and CDKN1B). Further protein verification revealed for the first time that hippocampal TMEM126A plays an important anti-inflammatory role in the treatment of neuralgia by electroacupuncture.
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Disfunción Cognitiva/terapia , Electroacupuntura , Hipocampo/metabolismo , Hiperalgesia/terapia , Neuralgia/terapia , Animales , Disfunción Cognitiva/metabolismo , Hiperalgesia/metabolismo , Masculino , Neuralgia/metabolismo , Manejo del Dolor , Proteómica , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis. Our findings revealed that the serum levels and hepatic expression of Slit2 were significantly increased in patients with primary biliary cirrhosis (PBC). Additionally, Slit2-Tg mice were much more vulnerable to BDL-induced liver injury and fibrosis compared to WT control. Slit2 up-regulation by Slit2 recombinant protein induced proliferation, and inhibited apoptosis of human HSCs cell line LX-2 via p38 and ERK signaling pathway, resulting in the activation of HSCs. In contrast, Slit2 down-regulation by siRNA silencing inhibit the activation of HSCs. In conclusion, Slit2 is involved in the activation of HSCs and liver fibrogenesis, highlighting Slit2 as a potential therapeutic target for liver fibrosis.
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Colestasis/metabolismo , Células Estrelladas Hepáticas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Apoptosis/fisiología , Línea Celular , Proliferación Celular/fisiología , Células Cultivadas , Regulación hacia Abajo/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1-dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human. SphK1 was coexpressed with a range of HSC/KC markers including desmin, α-smooth muscle actin (α-SMA) and F4/80 in fibrotic liver. Deficiency of SphK1 (SphK1-/- ) resulted in a marked amelioration of hepatic injury, including transaminase activities, histology, collagen deposition, α-SMA and inflammation, in CCl4 or bile duct ligation (BDL)-induced mice. Likewise, treatment with a specific inhibitor of SphK1, 5C, also significantly prevented liver injury and fibrosis in mice induced by CCl4 or BDL. In cellular levels, inhibition of SphK1 significantly blocked the activation and migration of HSCs and KCs. Moreover, SphK1 knockout in KCs reduced the secretion of CCL2, and SphK1 knockout in HSCs reduced C-C motif chemokine receptor 2 ([CCR2] CCL2 receptor) expression in HSCs. CCL2 in SphK1-/- mice was lower whereas microRNA-19b-3p in SphK1-/- mice was higher compared with wild-type (WT) mice. Furthermore, microRNA-19b-3p downregulated CCR2 in HSCs. The functional effect of SphK1 in HSCs on liver fibrosis was further strengthened by the results of animal experiments using a bone marrow transplantation (BMT) method. CONCLUSION: SphK1 has distinct roles in the activation of KCs and HSCs in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR-19b-3p. (Hepatology 2018).
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Cirrosis Hepática/etiología , MicroARNs/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptores CCR2/metabolismo , Animales , Trasplante de Médula Ósea , Quimiocina CCL2/metabolismo , Células Estrelladas Hepáticas/enzimología , Humanos , Macrófagos del Hígado/metabolismo , Cirrosis Hepática/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Excessive degradation of the cartilage articular extracellular matrix (ECM) in chondrocytes has been considered as an important pathological characteristics of OA. In the present study, we demonstrate that the G protein-coupled receptor GPR39 is expressed on SW1353 chondrocytes and is significantly downregulated in response to advanced glycation end products (AGEs). Our findings show that agonism of GPR39 exerts significant protective effects against AGE-induced degradation of articular extracellular matrix. Agonism of GPR39 rescued degradation of type II collagen by decreasing expression of the collagen-degrading enzymes matrix metalloproteinase (MMP)-3 and MMP-13. Additionally, agonism of GPR39 rescued AGE-induced suppression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Agonism of GPR39 prevented degradation of aggrecan by downregulating AGE-induced expression of a disintegrin and metalloproteinase with type I thrombospondin motif (ADAMTS)-4 and ADAMTS-5. Finally, we demonstrate that the effects of GPR39 are mediated through the p38 mitogen activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) cellular signaling pathway. Taken together, our findings show for the first time that targeted therapies involving GPR39 may provide a novel approach for the prevention and treatment of osteoarthritis.
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Matriz Extracelular/efectos de los fármacos , Productos Finales de Glicación Avanzada/farmacología , Sustancias Protectoras/farmacología , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacología , Agrecanos/química , Agrecanos/metabolismo , Línea Celular Tumoral , Colágeno Tipo II/química , Colágeno Tipo II/metabolismo , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloendopeptidasas/metabolismo , Osteoartritis/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Receptores Acoplados a Proteínas G/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Zinc/metabolismoRESUMEN
Graphene has been highlighted as a great potential material in wearable devices, owing to its extraordinary properties such as mechanical softness, high electrical conductivity and ultra-thin thickness. However, there are remaining challenges in thermal dissipation of graphene under such complicated conditions, which significantly affect the performance of portable electronics. Using molecular dynamics simulations, we have performed systematic analysis of thermal performance for the application in wearable devices in terms of graphene with defects, under uniaxial tensile strain, and vertical stress. Three kinds morphology of defects (horizontal line defect, circular defect, and vertical line defect) are constructed by deleting atoms on the pristine graphene plane. The thermal conductivity is related to the projected defected area perpendicular to the direction of the heat current. The relative thermal conductivity displays a cubic decreasing trend with the increase of uniaxial tensile strain. Besides, the thermal conductivity of graphene is not only related to the deformation quantity, but also related to the type of compression region. Our results show that the thermal conductivity decreases a lot under local stress with larger vertical deformation, while no obvious decline is observed under the global stress. This study aims to provide guidelines and ballpark estimates for experimentalists fabricating flexible devices from graphene.
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Allylic sulfones were synthesized with excellent selectivity and good yield via Pd-catalyzed cross-coupling of vinyl iodide with N-tosylhydrazone. This process involves palladium carbene migratory insertion/trapping with sulfinic acid salts. For the previous Pd-catalyzed N-tosylhydrazone cross-coupling, sulfinic acid salt is generated as a byproduct. In this transformation, the diazo compound and the sulfinic acid salt, which are all generated from N-tosylhydrazone, were used as cross-coupling partner.
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Oxymatrine (OXY) has antioxidative and antiinflammatory activities. In the present work, we investigate the effects of OXY on gastric ulcer models and elucidate the underlying mechanisms of action. Ethanol, indometacin, and restraint water immersion stress-induced ulcerated models were used. The ulcer area was measured, and samples of gastric tissue were taken for pathological, histochemical, and biochemical analyses. OXY effectively reduced the area of gastric ulcers and improved the pathological changes of ulcerated tissue. OXY enhanced expression of Bcl-2, reduced Bax protein expression, and inhibited alcohol-induced apoptotic death in both ulcerated tissue and human gastric epithelial cells. OXY increased the prostaglandin E2 level and improved oxidative stress (malondialdehyde, superoxide dismutase, catalase, and nitric oxide) and inflammatory parameters (TNF-a, IL-6, and IL-1) of ulcer tissue. OXY prevented an inflammatory response via decreasing expression of p38, p-ERK, p-JNK, and inhibiting NF-κB p65 translocation from the cytoplasm to the nucleus. Our results reveal that OXY has remarkable protective effects on gastric ulcers. The action of OXY may be mediated via suppression of gastric inflammatory reactions, oxidative stress, and pro-apoptotic actions, which were the results of blockades of MAPKs and NF-κB signaling pathways. Our results provide evidence for the beneficial effects of OXY for treating peptic ulcers.
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Alcaloides/farmacología , Antiinflamatorios/farmacología , Antiulcerosos/farmacología , Antioxidantes/farmacología , Quinolizinas/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Línea Celular , Dinoprostona/metabolismo , Etanol , Mucosa Gástrica/efectos de los fármacos , Humanos , Indometacina , Inflamación/tratamiento farmacológico , Interleucinas/metabolismo , Masculino , Malondialdehído/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND/AIMS: The generation of reactive oxygen species (ROS) caused by amyloid-ß (Aß) is considered to be one of mechanisms underlying the development of Alzheimer's disease. Curcumin can attenuate Aß-induced neurotoxicity through ROS scavenging, but the protective effect of intracellular curcumin on neurocyte membranes against extracellular Aß may be compromised. To address this issue, we synthesized a palmitic acid curcumin ester (P-curcumin) which can be cultivated on the cell membrane and investigated the neuroprotective effect of P-curcumin and its interaction with Aß. METHODS: P-curcumin was prepared through chemical synthesis. Its structure was determined via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). An MTT assay was used to assess Aß cytotoxicity and the protective effect of P-curcumin on SH-SY5Y cells. The effect of P-curcumin on Aß-induced ROS production in vitro and in vivo were assessed based on changes in dichlorofluorescein (DCF) fluorescence. A spectrophotometric method was employed to detect lipid peroxidation. To mimic the interaction of P-curcumin on cell membranes with Aß, liposomes were prepared by thin film method. Finally, the interactions between free P-curcumin and P-curcumin cultivated on liposomes and Aß were determined via spectrophotometry. RESULTS: A novel derivative, palmitic acid curcumin ester was prepared and characterized. This curcumin, cultivated on the membranes of neurocytes, may prevent Aß-mediated ROS production and may inhibit the direct interaction between Aß and the cellular membrane. Furthermore, P-curcumin could scavenge Aß-mediated ROS as curcumin in vitro and in vivo, and had the potential to prevent lipid peroxidation. Morphological analyses showed that P-curcumin was better than curcumin at protecting cell shape. To examine P-curcumin's ability to attenuate direct interaction between Aß and cell membranes, the binding affinity of Aß to curcumin and P-curcumin was determined. The association constants for free P-curcumin and curcumin were 7.66 × 104 M-1 and 7.61 × 105 M-1, respectively. In the liposome-trapped state, the association constants were 3.71 × 105 M-1 for P-curcumin and 1.44× 106 M-1 for curcumin. With this data, the thermodynamic constants of P-curcumin association with soluble Aß (ΔH, ΔS, and ΔG) were also determined. CONCLUSION: Cultivated curcumin weakened the direct interaction between Aß and cell membranes and showed greater neuroprotective effects against Aß insult than free curcumin.
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Péptidos beta-Amiloides/toxicidad , Proliferación Celular/efectos de los fármacos , Curcumina/farmacología , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Forma de la Célula/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/síntesis química , Humanos , Peroxidación de Lípido/efectos de los fármacos , Liposomas/química , Neuroblastoma/metabolismo , Neuroblastoma/patología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ácido Palmítico/química , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , TermodinámicaRESUMEN
Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer.
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Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/farmacología , Animales , Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Receptor ErbB-2/metabolismo , Relación Estructura-Actividad , Trastuzumab/químicaRESUMEN
OBJECTIVES: Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA. METHODS: The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions. RESULTS: MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1ß, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells. CONCLUSIONS: Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.
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Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Células Mieloides/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Técnicas de Cocultivo , Progresión de la Enfermedad , Humanos , Tolerancia Inmunológica/inmunología , Masculino , Ratones Endogámicos C57BL , Osteoartritis/inmunología , Índice de Severidad de la Enfermedad , Líquido Sinovial/inmunología , Células Th17/inmunologíaRESUMEN
A fluorescence signal has been demonstrated as an effective implement for micro/nanoscale temperature measurement which can be realized by either direct fluorescence excitation from materials or by employing nanoparticles as sensors. In this work, a steady-state electrical-heating fluorescence-sensing (SEF) technique is developed for the thermal characterization of one-dimensional (1D) materials. In this method, the sample is suspended between two electrodes and applied with steady-state Joule heating. The temperature response of the sample is monitored by collecting a simultaneous fluorescence signal from the sample itself or nanoparticles uniformly attached on it. According to the 1D heat conduction model, a linear temperature dependence of heating powers is obtained, thus the thermal conductivity of the sample can be readily determined. In this work, a standard platinum wire is selected to measure its thermal conductivity to validate this technique. Graphene quantum dots (GQDs) are employed as the fluorescence agent for temperature sensing. Parallel measurement by using the transient electro-thermal (TET) technique demonstrates that a small dose of GQDs has negligible influence on the intrinsic thermal property of platinum wire. This SEF technique can be applied in two ways: for samples with a fluorescence excitation capability, this method can be implemented directly; for others with weak or no fluorescence excitation, a very small portion of nanoparticles with excellent fluorescence excitation can be used for temperature probing and thermophysical property measurement.