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The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
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Proteínas Quinasas Activadas por AMP , Complejo I de Transporte de Electrón , Ferroptosis , Animales , Femenino , Humanos , Ratones , Quinasas de la Proteína-Quinasa Activada por el AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Línea Celular Tumoral , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/genética , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/genética , Mitocondrias/efectos de los fármacos , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Menstrual blood-derived endometrial stem cells (MenSCs) have attracted increasing interest due to their excellent safety, and lack of ethical dilemma as well as their ability to be periodically obtained in a noninvasive manner. However, although preclinical research as shown the therapeutic potential of MenSCs in several diseases, their poor cell survival and low engraftment at disease sites reduce their clinical efficacy. Flotillins (including Flot1 and Flot2) are implicated in various cellular processes, such as vesicular trafficking, signal transduction, cell proliferation, migration and apoptosis. In this study, we aimed to determine the effects of Flotillins on MenSCs survival, proliferation and migration. Our experimental results show that MenSCs were modified to overexpress Flot1 and/or Flot2 without altering their intrinsic characteristics. Flot1 and Flot2 co-overexpression promoted MenSC viability and proliferation capacity. Moreover, Flot1 or Flot2 overexpression significantly promoted the migration and inhibited the apoptosis of MenSCs compared with the negative control group, and these effects were stronger in the Flot1 and Flot2 gene co-overexpression group. However, these effects were significantly reversed after Flot1 and/or Flot2 knockdown. In conclusion, our results indicate that Flot1 and Flot2 overexpression in MenSCs improved their proliferation and migration and inhibited their apoptosis, and this might be an effective approach to improve the efficiency of cell-based therapies.
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Apoptosis , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Proteínas de la Membrana , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Femenino , Endometrio/citología , Endometrio/metabolismo , Células Madre/metabolismo , Células Madre/citología , Células Cultivadas , Transducción de SeñalRESUMEN
BACKGROUND: Exosomes derived from breast cancer have been reported to play a role in promoting cell proliferation, migration, and angiogenesis, which has the potential to accelerate the healing process of diabetic wounds. The aim of this investigation was to examine the function of exosomes originating from 4T1 mouse breast carcinoma cells (TEXs) in the process of diabetic wound healing. METHODS: The assessment of primary mouse skin fibroblasts cell proliferation and migration was conducted through the utilization of CCK-8 and wound healing assays, while the tube formation of HUVECs was evaluated by tube formation assay. High-throughput sequencing, RT-qPCR and cell experiments were used to detect the roles of miR-126a-3p in HUVECs functions in vitro. The in vivo study employed a model of full-thickness excisional wounds in diabetic subjects to explore the potential therapeutic benefits of TEXs. Immunohistochemical and immunofluorescent techniques were utilized to evaluate histological changes in skin tissues. RESULTS: The findings suggested that TEXs facilitate diabetic wound healing through the activation of cell migration, proliferation, and angiogenesis. An upregulation of miR-126a-3p has been observed in TEXs, and it has demonstrated efficient transferability from 4T1 cells to HUVEC cells. The activation of the PI3K/Akt pathway has been attributed to miR-126a-3p derived from TEXs. CONCLUSIONS: The promotion of chronic wound healing can be facilitated by TEXs through the activation of cellular migration, proliferation, and angiogenesis. The activation of the PI3K/Akt pathway by miR-126a-3p originating from TEXs has been discovered, indicating a potential avenue for enhancing the regenerative capabilities of wounds treated with TEXs.
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Movimiento Celular , Proliferación Celular , Exosomas , Células Endoteliales de la Vena Umbilical Humana , Cicatrización de Heridas , Animales , Exosomas/metabolismo , Humanos , Ratones , Femenino , MicroARNs/metabolismo , MicroARNs/genética , Línea Celular Tumoral , Ratones Endogámicos BALB C , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Diabetes Mellitus Experimental , Fibroblastos/metabolismo , Neovascularización Fisiológica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from patients with BRCA1-mutant breast cancer with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers. Significance: BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers. See related commentary by Alborzinia and Friedmann Angeli, p. 1372.
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Proteína BRCA1 , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Ferroptosis/efectos de los fármacos , Humanos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteína BRCA1/genética , Femenino , Animales , Ratones , Línea Celular Tumoral , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Coactivadores de Receptor NuclearRESUMEN
Soil solution pH and dissolved organic carbon (DOC) influence cadmium (Cd) uptake by hyperaccumulators but their tradeoff in calcareous soils is unclear. This study investigated the mechanisms of Solanum nigrum L. and Solanum alatum Moench in calcareous soil using a combination of concentration gradient experiments (0.6-100 mg Cd kg-1) and soil solution composition analysis. The results showed that the soil solution pH of S. nigrum remained stable despite Cd stress. On average, the soil solution pH of S. alatum was 0.23 units higher than that of S. nigrum, although pH decreased significantly under high Cd stress. In addition, the concentrations of potassium (K) and calcium (Ca) in the soil solution of S. nigrum increased and decreased under low and high levels of Cd stress, respectively. In S. alatum, the K and Ca concentrations in the soil solution generally increased with increasing Cd stress levels. Moreover, the level of DOC in the soil solution of both plants was higher under Cd stress compared to the control, and a gradually increasing trend with Cd stress level was observed in S. alatum. Consequently, the bioconcentration factors of the roots (2.62-19.35) and shoots (1.20-9.59) of both plants were >1, while the translocation factors were <1, showing an obstacle of Solanum hyperaccumulators in transferring Cd into their aboveground parts. Redundancy analysis revealed that the Cd concentration in S. nigrum roots was significantly negatively correlated with the soil solutions of K and Ca. In contrast, Cd concentrations in S. alatum roots and shoots were significantly positively correlated with soil solution DOC, K, and Ca but negatively correlated with pH. Our results suggest that calcareous soil neutralizes the acidity of released protons but does not affect cation exchange, inhibiting DOC in assisting the translocation of Cd within plants.
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Contaminantes del Suelo , Solanum nigrum , Solanum , Cadmio/análisis , Materia Orgánica Disuelta , Suelo/química , Biodegradación Ambiental , Contaminantes del Suelo/análisis , Minerales/análisis , Iones/análisis , Raíces de Plantas/química , Calcio/análisis , Concentración de Iones de HidrógenoRESUMEN
N6-methyladenosine (m6 A) is one of the main epitranscriptomic modifications that accelerates the progression of malignant tumors by modifying RNA. Methyltransferase-like 16 (METTL16) is a newly identified methyltransferase that has been found to play an important oncogenic role in a few malignancies; however, its function in osteosarcoma (OS) remains unclear. In this study, METTL16 was found to be upregulated in OS tissues, and associated with poor prognosis in OS patients. Functionally, METTL16 substantially promoted OS cell proliferation, migration, and invasion in vitro and OS growth in vivo. Mechanistically, vacuolar protein sorting protein 33b (VPS33B) was identified as the downstream target of METTL16, which induced m6 A modification of VPS33B and impaired the stability of the VPS33B transcript, thereby degrading VPS33B. In addition, VPS33B was found to be downregulated in OS tissues, VPS33B knockdown markedly attenuated shMETTL16-mediated inhibition on OS progression. Finally, METTL16/VPS33B might facilitate OS progression through PI3K/AKT pathway. In summary, this study revealed an important role for the METTL16-mediated m6 A modification in OS progression, implying it as a promising target for OS treatment.
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Adenosina , Neoplasias Óseas , Metiltransferasas , Osteosarcoma , Fosfatidilinositol 3-Quinasas , Proteínas de Transporte Vesicular , Humanos , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Osteosarcoma/genética , Osteosarcoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Transporte de Proteínas , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Línea Celular TumoralRESUMEN
Irregularly shaped microplastics (MPs) released from infant feeding bottles (PP-IFBs) may exhibit increased cytotoxicity, in contrast to the commonly studied spherical MPs. This study presents an initial analysis of the thermal-oxidative aging process of plastic shedding from feeding bottles, and investigates the inflammatory response induced by these atypical MPs in human intestinal cells (Caco-2). The PP-IFBs' surface displayed non-uniform white patches and increased roughness, revealing substantial structural alteration and shedding, especially during actions such as shaking, boiling water disinfection, and microwave heating. FT-IR and 2D-COS analyses revealed that oxygen targeted the C-H and C-C bonds of polypropylene molecular chain, producing RO· and ·OH, thereby hastening polypropylene degradation. When human intestinal cells were exposed to MPs from PP-IFBs, oxidative stress was triggered, resulting in lowered glutathione levels, augmented reactive oxygen species (ROS), and heightened lipid peroxidation. Elevated levels of pro-inflammatory cytokines (IL-6 and TNFα) signified an active inflammatory process. The inflammatory response was notably more intense when exposed to MPs released through boiling water disinfection and microwave heating treatments, primarily due to the larger quantity of MPs released and their higher proportion of smaller particles. Furthermore, the NLRP3 inflammasome was identified as critical in initiating this inflammatory chain reaction due to the mitochondrial ROS surge caused by MPs exposure. This was further validated by inhibitor studies, emphasizing the role of the ROS/NLRP3/Caspase-1/IL-1ß signaling pathway in in promoting intestinal inflammation. Therefore, swift actions are recommended to protect infants against the potential health effects of MPs exposure.
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Proteína con Dominio Pirina 3 de la Familia NLR , Plásticos , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Caspasa 1/metabolismo , Microplásticos , Células CACO-2 , Polipropilenos , Espectroscopía Infrarroja por Transformada de Fourier , Inflamación/metabolismo , Transducción de Señal , AguaRESUMEN
Background: Glioma is the most frequent malignant primary brain tumor, and mitochondria may influence the progression of glioma. The aim of this study was to analyze the role of nuclear mitochondria related genes (MTRGs) in glioma, identify subtypes and construct a prognostic model based on nuclear MTRGs and machine learning algorithms. Methods: Samples containing both gene expression profiles and clinical information were retrieved from the TCGA database, CGGA database, and GEO database. We selected 16 nuclear MTRGs and identified two clusters of glioma. Prognostic features, microenvironment, mutation landscape, and drug sensitivity were compared between the clusters. A prognostic model based on multiple machine learning algorithms was then constructed and validated by multiple datasets. Results: We observed significant discrepancies between the two clusters. Cluster One had higher nuclear MTRG expression, a lower survival rate, and higher immune infiltration than Cluster Two. For the two clusters, we found distinct predictive drug sensitivities and responses to immune therapy, and the infiltration of immune cells was significantly different. Among the 22 combinations of machine learning algorithms we tested, LASSO was the most effective in constructing the prognostic model. The model's accuracy was further verified in three independent glioma datasets. We identified MGME1 as a vital gene associated with infiltrating immune cells in multiple types of tumors. Conclusion: In short, our research identified two clusters of glioma and developed a dependable prognostic model based on machine learning methods. MGME1 was identified as a potential biomarker for multiple tumors. Our results will contribute to precise medicine and glioma management.
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Treating chronic wounds requires transition from proinflammatory M1 to anti-inflammatory M2 dominant macrophages. Based on the role of tumor extracellular vesicles (tEVs) in regulating the phenotypic switching from M1 to M2 macrophages, we propose that tEVs may have a beneficial impact on alleviating the overactive inflammatory microenvironment associated with refractory wounds. On the other hand, as a nitric oxide donor, S-nitrosoglutathione (GSNO) can regulate inflammation, promote angiogenesis, enhance matrix deposition, and facilitate wound healing. In this study, a guar gum-based hydrogel with tEVs and GSNO was designed for the treatment of diabetic refractory wounds. This hybrid hydrogel was formed through the phenyl borate bonds, which can automatically disintegrate in response to the high reactive oxygen species (ROS) level at the site of refractory diabetic wounds, releasing tEVs and GSNO. We conducted a comprehensive evaluation of this hydrogel in vitro, which demonstrated excellent performance. Meanwhile, using a full-thickness excision model in diabetic mice, the wounds exposed to the therapeutic hydrogel healed completely within 21 days. The increased closure rate was associated with macrophage polarization and collagen deposition, accelerated fibroblast proliferation, and increased angiogenesis in the regenerating tissues. Therefore, this multifunctional hybrid hydrogel appears to be promising for clinical applications.
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Diabetes Mellitus Experimental , Hidrogeles , Ratones , Animales , Hidrogeles/farmacología , Hidrogeles/química , S-Nitrosoglutatión/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Cicatrización de Heridas , RegeneraciónRESUMEN
The flow behavior of oil in nanochannels has attracted extensive attention for oil transport applications. In most, if not all, of the prior theoretical simulations, oil molecules were observed to flow steadily in nanochannels under pressure gradients. In this study, non-equilibrium molecular dynamics simulations are conducted to simulate the Poiseuille flow of oil with three different hydrocarbon chain lengths in graphene nanochannels. Contrary to the conventional perception of steady flows of oil in nanochannels, we find that oil molecules with the longest hydrocarbon chain (i.e., n-dodecane) exhibit notable stick-slip flow behavior. An alternation between the high average velocity of n-dodecane in the slip motion and the low average velocity in the stick motion is observed, with a drastic, abrupt velocity jolt of up to 40 times occurring at the transition in a stick-slip motion. Further statistical analyses show that the stick-slip flow behavior of n-dodecane molecules originates from the molecular alignment change of oil near the graphene wall. The molecular alignment of n-dodecane shows different statistical distributions under stick and slip motion states, leading to significant changes of friction forces and thus notable velocity fluctuations. This work provides new insights into the Poiseuille flow behavior of oil in graphene nanochannels and may offer useful guidelines for other mass transport applications.
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Formaldehyde oxidation at room temperature with low-cost catalysts is one of the main development directions of environmental governance. Herein, we developed a low-cost and superior performance highly dispersed Ce on Na-ZSM-5 (Ce/Na-ZSM-5) catalyst, which is close to atomic dispersion for indoor formaldehyde (HCHO) oxidation at low temperature. The highly dispersed catalyst that was similar to atomic dispersion was characterized by EXAFS and AC HAADF-STEM. The optimal Ce/Na-ZSM-5 displays high HCHO removal performance (95%, at room temperature), as well as 100 h stable testing (â¼90% HCHO removal). In addition, a reasonable reaction mechanism of the HCHO catalytic oxidation is proposed based on the in situ DRIFT spectra and DFT calculation. This work provides a new way to design an efficient catalyst for the complete oxidation of formaldehyde.
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In this work, novel potential anthraquinone-temozolomide (TMZ) antitumor hybrids N-(2-((9,10-dioxo-9,10-dihydroanthracen-1-yl)amino)ethyl)-3-methyl-4-oxo-3,4-dihydroimidazo [5, 1-d][1,2,3,5]tetrazine-8-carboxamide (C-1) and 2-(9,10-dioxo-9,10-dihydroanthracen-1-yl)amino) ethyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (C-9) were designed and synthesized successfully. The electrochemical behaviors of C-1 (C-9) involved the reversible processes of 9,10-anthraquinone ring, the irreversible reduction and oxidation processes of TMZ ring. Electrochemical biosensors were constructed with ctDNA, poly (dG) and poly (dA) modifying the surface of glassy carbon electrode (GCE) to evaluate the DNA oxidative damage caused by the interaction of C-1 (C-9) with DNA. Anthracycline skeleton and TMZ ring in C-1 (C-9) could exhibit bifunctional effects with both intercalating and alkylation modes toward DNA strands. The DNA biosensor had good practicability in mouse serum. The results of gel electrophoresis further demonstrated that C-1 (C-9) could effectively intercalated into ctDNA and disrupt plasmid conformation. Finally, anthraquinone-TMZ hybrid C-1 possessed high cytotoxicity toward A549 and GL261 cells, which could be a novel and optimal candidate for the clinic antitumor treatment.
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Antraquinonas , Técnicas Biosensibles , Animales , Ratones , Temozolomida , Carbono , ADN/química , Electrodos , Técnicas Electroquímicas/métodosRESUMEN
In this work, we design and synthesize 2,2'-(7,9-dimethyl-2,4,6,8-tetraoxo-6,7,8,9-tetrahydropyrimido[5,4-g]pteridine-1,3(2H,4H)-diyl)bis(N,N-bis(2-chloroethyl)acetamide) (PT-MCA) as a novel DNA intercalator and potential antitumor agent. Electrochemical analysis reveals the redox process of PT-MCA on the electrode surface. The bioelectrochemical sensors are obtained by modifying the surface of GCE with calf thymus DNA (ctDNA), poly (dG), poly (dA), and G-quadruplex, respectively. The DNA oxidative damage induced by PT-MCA is investigated by comparing the peak intensity change of dGuo and dAdo and monitoring the peaks of the oxidation products of guanine and/or adenine (8-oxoGua and/or 2,8-oxoAde). UV-vis absorption and fluorescence spectra and gel electrophoresis are further employed to understand the intercalation of PT-MCA into DNA base pairs. Moreover, PT-MCA is proved to exhibit stronger anti-proliferation activity than mitoxantrone against both 4T1 and B16-F10 cancer cells. At last, the oxidative damage of PT-MCA toward ctDNA is not interfered by the coexistence of ions and also can be detected in real serums.
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Antineoplásicos , Pteridinas , ADN/genética , Antineoplásicos/farmacología , Adenina , Estrés Oxidativo , Daño del ADNRESUMEN
Neuroinflammation is a common response in various neurological disorders. Mesenchymal stem cell-based treatment has become a promising therapy for neuroinflammation-associated diseases. However, the effects of mesenchymal stem cells are controversial, and the underlying mechanism is incompletely understood. In the present study, menstrual blood-derived endometrial stem cells were intravenously transplanted into a mouse model of neuroinflammation established by peripheral injection of lipopolysaccharide. Microglial cells challenged with lipopolysaccharide were cultured with conditioned medium from endometrial stem cells. The levels of cytokines were detected by enzyme-linked immunosorbent assay. Cell proliferation and death were detected by Cell Counting Kit 8 and flow cytometry, respectively. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (Casp1) were evaluated by western blotting. The results showed that intravenous transplantation of endometrial stem cells downregulated proinflammatory factors and upregulated anti-inflammatory factors in the brain of mice with neuroinflammation. Conditioned medium suppressed the inflammatory reaction and hyperactivation of microglial cells and protected microglial cells from cell death induced by lipopolysaccharide in vitro. The expression of TLR4, MyD88, NLRP3 and Casp1 in the brain of mice with neuroinflammation and in lipopolysaccharide-stimulated microglial cells was downregulated by endometrial stem cells and conditioned medium, respectively. These data suggested that menstrual blood-derived endometrial stem cells may suppress neuroinflammatory reactions partially by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 signalling pathway. Our findings may be very useful for the development of an alternative stem cell-based therapy for neuroinflammation-associated disorders.
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Microglía , Proteína con Dominio Pirina 3 de la Familia NLR , Ratones , Animales , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 4/genética , Caspasa 1/metabolismo , Enfermedades Neuroinflamatorias , Lipopolisacáridos/toxicidad , Medios de Cultivo Condicionados/farmacología , Medios de Cultivo Condicionados/metabolismo , FN-kappa B/metabolismoRESUMEN
Cervical squamous cell carcinoma (CSCC) is one of the leading causes of cancer death in women worldwide. Patients with advanced cervical carcinoma always have a poor prognosis once resistant to cisplatin due to the lack of effective treatment. It is urgent to investigate the molecular mechanisms of cisplatin resistance. Circular RNAs (circRNAs) are known to exert their regulatory functions in a series of malignancies. However, their effects on CSCC remain to be elucidated. Here, we found that cytoplasmic circARHGAP5, derived from second and third exons of the ARHGAP5 gene, was downregulated in cisplatin-resistant tissues compared with normal cervix tissues and untreated cervical cancer tissues. In addition, experiments from overexpression/knockdown cell lines revealed that circARHGAP5 could inhibit cisplatin-mediated cell apoptosis in CSCC cells both in vitro and in vivo. Mechanistically, circARHGAP5 interacted with AU-rich element RNA-binding protein (AUF1) directly. Overexpression of AUF1 could also inhibit cell apoptosis mediated by cisplatin. Furthermore, we detected the potential targets of AUF1 related to the apoptotic pathway and found that bcl-2-like protein 11 (BIM) was not only negatively regulated by AUF1 but positively regulated by circARHGAP5, which indicated that BIM mRNA might be degraded by AUF1 and thereby inhibited tumor cell apoptosis. Collectively, our data indicated that circARHGAP5 directly bound to AUF1 and prevented AUF1 from interacting with BIM mRNA, thereby playing a pivotal role in cisplatin resistance in CSCC. Our study provides insights into overcoming cancer resistance to cisplatin treatment.
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Carcinoma de Células Escamosas , Ribonucleoproteína Nuclear Heterogénea D0 , ARN Circular , Neoplasias del Cuello Uterino , Femenino , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Proteínas Activadoras de GTPasa/genética , Ribonucleoproteína Nuclear Heterogénea D0/metabolismo , ARN Circular/genética , ARN Mensajero/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
The diagnosis of peripheral pulmonary lesions (PPLs) remains a challenge for physicians. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been applied in the diagnosis of PPLs, but its diagnostic rate varies widely. The systematic review and meta-analysis was conducted to figure out the accuracy and safety of EBUS-TBNA in the diagnosis of PPLs. We searched the PubMed and Embase databases for relevant studies published from January 1, 2000 to December 30, 2021 and used PICO (Participants, Intervention, Comparison, and Outcome) to worked out the diagnostic rate of EBUS-TBNA in PPLs. Two reviewers independently performed the data extraction and assessed study quality. Statistical analysis was carried out via R software. In 7 studies of totally 510 patients of PPLs, the overall EBUS-TBNA diagnosis yield is 0.75 (95% CI 0.67-0.84) by the random effect model. EBUS-TBNA showed a higher accuracy of 0.64 (95% CI 0.53-0.74) compared to 0.46 (95% CI 0.19-0.72) of endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) when EBUS probe is adjacent to lesions. In the case of malignant lesions, the diagnostic rate of EBUS-TBNA is 0.79 (95% CI 0.72-0.88). Combined EBUS-TBNA with conventional bronchoscopy procedures showed the highest diagnostic yield (0.83 (95% CI 0.79-0.87)). Collectively, EBUS-TBNA should be performed firstly in patients with PPLs suspected to lung cancer especially when the EBUS probe was adjacent to the lesions. No serious procedure-related complications were observed.
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Broncoscopía , Neoplasias Pulmonares , Humanos , Broncoscopía/efectos adversos , Broncoscopía/métodos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/efectos adversos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Biopsia Guiada por Imagen/efectos adversos , Biopsia Guiada por Imagen/métodos , Ultrasonografía , Estudios RetrospectivosRESUMEN
Tumor-targeted near-infrared (NIR) fluorescence imaging by using NIR fluorescent probes has attracted extensive attentions in the field of tumor imaging and is becoming an attractive strategy for early cancer diagnosis and surgical guidance for the past few decades. Especially, due to the high affinity and low toxicity, the peptide-based NIR fluorescent probes play an important role in the field of tumor-targeted imaging and therapy. Extensive attempts have been made to develop a set of nontoxic and efficacious "always-on" peptide-based NIR fluorescent probes. In this review, we give a comprehensive analysis of the "always-on" peptide-based NIR fluorescent probes for tumor-targeting for the past 5 years, highlighting the design strategy, chemical synthesis, therapeutical applications, spectroscopic and pharmacological characterization, as well as the multifaceted roles of peptides. A comprehensive understanding of the tumor-targeted, "always-on" peptide-based NIR fluorescent probes will increase our knowledge of cancer diagnosis and benefit clinical cancer therapeutics.
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Colorantes Fluorescentes , Neoplasias , Humanos , Colorantes Fluorescentes/química , Espectroscopía Infrarroja Corta/métodos , Imagen Óptica/métodos , Neoplasias/diagnóstico por imagen , Péptidos/químicaRESUMEN
Ga2O3 has emerged as a promising ultrawide bandgap semiconductor for numerous device applications owing to its excellent material properties. In this paper, we present a comprehensive review on major advances achieved over the past thirty years in the field of Ga2O3-based gas sensors. We begin with a brief introduction of the polymorphs and basic electric properties of Ga2O3. Next, we provide an overview of the typical preparation methods for the fabrication of Ga2O3-sensing material developed so far. Then, we will concentrate our discussion on the state-of-the-art Ga2O3-based gas sensor devices and put an emphasis on seven sophisticated strategies to improve their gas-sensing performance in terms of material engineering and device optimization. Finally, we give some concluding remarks and put forward some suggestions, including (i) construction of hybrid structures with two-dimensional materials and organic polymers, (ii) combination with density functional theoretical calculations and machine learning, and (iii) development of optical sensors using the characteristic optical spectra for the future development of novel Ga2O3-based gas sensors.
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Circulating tumor cells (CTCs) acquire enhanced anti-anoikis abilities after experiencing flow shear stress in the circulatory system. Our previous study demonstrated that low shear stress (LSS) promotes anoikis resistance of human breast carcinoma cells via caveolin-1 (Cav-1)-dependent extrinsic and intrinsic apoptotic pathways. However, the underlying mechanism how LSS enhanced Cav-1 expression in suspended cancer cells remains unclear. Herein, we found that LSS induced redox signaling was involved in the regulation of Cav-1 level and anoikis resistance in suspension cultured cancer cells. Exposure of human breast carcinoma MDA-MB-231 cells to LSS (2 dyn/cm2) markedly induced ROS and â¢NO generation, which promoted the cell viability and reduced the cancer cell apoptosis. Furthermore, ROS and â¢NO scavenging inhibited the upregulation of Cav-1 by interfering ubiquitination, and suppressed the anoikis resistance of suspended tumor cells. These findings provide new insight into the mechanism by which LSS-stimulated ROS and â¢NO generation increases Cav-1 stabilization in suspended cancer cells through inhibition of ubiquitination and proteasomal degradation, which could be a potential target for therapy of metastatic tumors.
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Neoplasias de la Mama , Caveolina 1 , Femenino , Humanos , Anoicis/fisiología , Neoplasias de la Mama/genética , Caveolina 1/genética , Caveolina 1/metabolismo , Células MDA-MB-231 , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Encequidar, a gut-specific P-glycoprotein (P-gp) inhibitor, makes oral paclitaxel possible, and has been used in clinical treatment of metastatic breast cancer, however, its pharmacological effect and mechanism of reversal of drug resistance in drug-resistant colon cancer cells SW620/AD300 are still unknown. Herein, we first synthesized encequidar and demonstrated that it could inhibit the transport activity of P-gp, reduced doxorubicin (DOX) efflux, enhanced DOX cytotoxicity and promoted tumor-apoptosis in SW620/AD300 cells. Metabolomic analysis of cell samples was performedusing liquid chromatography Q-Exactive mass spectrometer, the results of metabolite enrichment analysis and pathway analysis showed that the combination of encequidar and DOX could: i) significantly affect the citric acid cycle (TCA cycle) and reduce the energy supply required for P-gp to exert its transport activity; ii) affect the metabolism of glutathione, which is the main component of the anti-oxidative stress system, and reduce the ability of cells to resist oxidative stress; iii) increase the intracellular reactive oxygen species (ROS) production and enhance ROS-induced cell damage and lipid peroxidation, which in turn restore the sensitivity of drug-resistant cells to DOX. In conclusion, these results provide sufficient data support for the therapeutical application of the P-gp inhibitor encequidar to reverse MDR, and are of great significance to further understand the therapeutic advantages of encequidar in anti-tumor therapy and guide clinical rational drug use.