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The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum protein signatures of IPF currently remains unclear. The present study analyzed the specific proteins and patterns associated with the clinical parameters of IPF based on a serum proteomic dataset by data-independent acquisition using MS. Differentiated proteins in sera distinguished patients with IPF into three subgroups in signal pathways and overall survival. Aging-associated signatures by weighted gene correlation network analysis coincidently provided clear and direct evidence that aging is a critical risk factor for IPF rather than a single biomarker. Expression of LDHA and CCT6A, which was associated with glucose metabolic reprogramming, was correlated with high serum lactic acid content in patients with IPF. Cross-model analysis and machine learning showed that a combinatorial biomarker accurately distinguished patients with IPF from healthy individuals with an area under the curve of 0.848 (95% CI = 0.684-0.941) and validated from another cohort and ELISA assay. This serum proteomic profile provides rigorous evidence that enables an understanding of the heterogeneity of IPF and protein alterations that could help in its diagnosis and treatment decisions.
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Fibrosis Pulmonar Idiopática , Proteómica , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Proteínas Sanguíneas , Biomarcadores , Chaperonina con TCP-1RESUMEN
Lung cancer is a major cause of morbidity and mortality. The specific pulmonary structure to directly connect with ambient air makes it more susceptible to damage from airborne toxins. External oxidative stimuli and endogenous reactive oxygen species (ROS) play a crucial role in promoting lung carcinogenesis and development. The biological properties of higher ROS levels in tumor cells than in normal cells make them more sensitive and vulnerable to ROS injury. Therefore, the strategy of targeting ROS has been proposed for cancer therapy for decades. However, it is embarrassing that countless attempts at ROS-based therapies have had very limited success, and no FDA approval in the anticancer list was mechanistically based on ROS manipulation. Even compared with the untargetable proteins, such as transcription factors, ROS are more difficult to be targeted due to their chemical properties. Thus, the pleiotropic roles of ROS provide therapeutic potential for anticancer drug discovery, while a better dissection of the mechanistic action and signaling pathways is a prerequisite for future breakthroughs. This review discusses the critical roles of ROS in cancer carcinogenesis, ROS-inspired signaling pathways, and ROS-based treatment, exemplified by lung cancer. In particular, an eight considerations rule is proposed for ROS-targeting strategies and drug design and development.
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Carcinogénesis , Neoplasias Pulmonares , Especies Reactivas de Oxígeno , Humanos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Carcinogénesis/metabolismo , Animales , Transducción de Señal , Antineoplásicos/farmacologíaRESUMEN
Considering the potential threats posed by oily wastewater to the ecosystem, it is urgently in demand to develop efficient, eco-friendly, and intelligent oil/water separation materials to enhance the safety of the water environment. Herein, an intelligent hydrogel-coated wood (PPT/PPy@DW) membrane with self-healing, self-cleaning, and oil pollution detection performances is fabricated for the controllable separation of oil-in-water (O/W) emulsions and water-in-oil (W/O) emulsions. The PPT/PPy@DW is prepared by loading polypyrrole (PPy) particles on the delignified wood (DW) membranes, further modifying the hydrogel layer as an oil-repellent barrier. The layered porous structure and selective wettability endow PPT/PPy@DW with great separation performance for various O/W emulsions (≥98.69% for separation efficiency and ≈1000 L m-2 h-1 bar-1 for permeance). Notably, the oil pollution degree of PPT/PPy@DW can be monitored in real-time based on the changed voltage generated during O/W emulsion separation, and the oil-polluted PPT/PPy@DW can be self-cleaned by soaking in water to recover its separation performance. The high affinity of PPT/PPy@DW for water makes it effective in trapping water from the mixed surfactant-stabilized W/O emulsions. The prepared eco-friendly and low-cost multifunctional hydrogel wood membrane shows promising potential in on-demand oil/water separation and provides new ideas for the functional improvement of new biomass oil/water separation membrane materials.
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Marine oil spills pose a serious threat to the marine ecological environment. Phase-selective organogelators (PSOGs) are ideal candidates for oil spill gelation when used in combination with a mechanical recovery method. However, the toxicity of an organic solvent carrier has become a key problem when it is applied in the remediation of marine oil pollution. In this study, through an inexpensive and nontoxic ionic cross-linking and freeze-drying method, we successfully developed composite oil gelling agents that used a biomass sodium alginate aerogel as the carrier of 12-hydroxystearic acid (12-HSA). Simultaneously, carboxylated cellulose nanofibers (CNF-C) with large specific surface area and graphene oxide (GO) with excellent mechanical properties as reinforcing fillers were combined with an alginate matrix. 12-HSA, as a green and inexpensive organic gelator, was uniformly loaded on the aerogels by vacuum impregnation. The sodium alginate aerogel was capable of absorbing and storing oil due to its three-dimensional network skeleton and high porosity. Rheological studies have demonstrated that the organic gelator 12-HSA can be released from the aerogel substrate and self-assemble to form an oleogel with the absorbed oil quickly. The synergistic effect between absorption and congelation endows the composite oil gelling agent with efficient oil spill recovery capability. Based on eco-friendly, biodegradable, and simple synthesis methods, this composite oil gelling agent shows great potential for application in marine oil spill recovery.
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Drug resistance is a major challenge in cancer treatment. The substrates of NAD(P)H:quinone oxidoreductase 1 (NQO1) show a promising anticancer effect in clinical trials. We previously identified a natural NQO1 substrate 2-methoxy-6-acetyl-7-methyljuglone (MAM) with a potent anticancer effect. The present study was designed to explore the efficacy of MAM in fighting against drug-resistant non-small cell lung cancer (NSCLC). The anticancer effect of MAM was evaluated in cisplatin-resistant A549 and AZD9291-resistant H1975 cells. The interaction of MAM with NQO1 was measured by cellular thermal shift assay and drug affinity responsive target stability assay. The NQO1 activity and expression were measured using NQO1 recombinant protein, Western blotting, and immunofluorescence staining assay. The roles of NQO1 were examined by NQO1 inhibitor, small interfering RNA (siRNA), and short hairpin RNA (shRNA). The roles of reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation were determined. MAM induced significant cell death in drug-resistant cells with similar potency to that of parental cells, which were completely abolished by NQO1 inhibitor, NQO1 siRNA, and iron chelators. MAM activates and binds to NQO1, which triggers ROS generation, LIP increase, and lipid peroxidation. MAM significantly suppressed tumor growth in the tumor xenograft zebrafish model. These results showed that MAM induced ferroptosis by targeting NQO1 in drug-resistant NSCLC cells. Our findings provided a novel therapeutic strategy for fighting against drug resistance by induction of NQO1-mediated ferroptosis.
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Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Neoplasias Pulmonares , NAD(P)H Deshidrogenasa (Quinona) , Animales , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , NAD/uso terapéutico , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ARN Interferente Pequeño/genética , Pez Cebra/genética , Pez Cebra/metabolismo , Resistencia a AntineoplásicosRESUMEN
AIMS: This study explored the relationships between family resilience, dyadic coping and psychological adjustment among adolescents with chronic illnesses and their parents. The actor-partner interdependence mediation model was used to validate the mediating role of dyadic coping in the relationship between family resilience and psychological adjustment. DESIGN: This is a cross-sectional study. METHODS: A total of 318 parent-adolescents dyads were recruited from three paediatric hospitals in Wenzhou, Hangzhou, Shanghai city, China, between June 2022 and August 2023. The parents had a mean age of 41.62 years, and the adolescents had a mean age of 12.66 years. Participants independently completed a self-report questionnaire assessed family resilience, dyadic coping and psychological adjustment. Data analysis was conducted using the actor-partner interdependence mediation model. RESULTS: The findings suggest that in the actor effects, family resilience directly influenced psychological adjustment, and family resilience is related to psychological adjustment through positive dyadic coping. In the partner effect, parents' family resilience influenced adolescents' psychological adjustment through the parents' positive dyadic coping. Similarly, adolescents' family resilience influenced parents' psychological adjustment through both parents' positive dyadic coping and adolescents' negative dyadic coping. Additionally, there was a partner effect between parents' family resilience and adolescents' psychological adjustment. CONCLUSION: This study demonstrated the importance of developing effective dyadic interventions based on family resilience or positive dyadic coping strategies to improve the mental health of adolescents with chronic illnesses and their parents. IMPACT: The mediating role of dyadic coping in the relationship between family resilience and psychological adjustment among adolescents with chronic illnesses and their parents was demonstrated. Future psychosocial interventions should focus on increasing parents' positive dyadic coping strategies and improving adolescents' negative dyadic coping strategies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.
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The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches.
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Antineoplásicos , Autofagia , Neoplasias , Humanos , Autofagia/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cloroquina/farmacología , Cloroquina/uso terapéutico , Hidroxicloroquina/uso terapéutico , Hidroxicloroquina/farmacologíaRESUMEN
The study investigates the therapeutic effects and mechanisms of ginsenoside Rg_1(GRg_1) on sepsis-induced acute lung injury(SALI). A murine model of SALI was created using cecal ligation and puncture(CLP) surgery, and mice were randomly assigned to groups for GRg_1 intervention. Survival and body weight changes were recorded, lung function was assessed with a non-invasive lung function test system, and lung tissue damage was evaluated through HE staining. The content and expression of inflammatory factors were measured by ELISA and qRT-PCR. Apoptosis was examined using flow cytometry and TUNEL staining. The activation and expression of apoptosis-related molecules cysteinyl aspartate specific proteinase 3(caspase-3), B-cell lymphoma-2(Bcl-2), Bcl-2 associated X protein(Bax), and endoplasmic reticulum stress-related molecules protein kinase R-like endoplasmic reticulum kinase(PERK), eukaryotic initiation factor 2α(eIF2α), activating transcription factor 4(ATF4), and C/EBP homologous protein(CHOP) were studied using Western blot and qRT-PCR. In addition, an in vitro model of lipopolysaccharide(LPS)-induced lung alveolar epithelial cell injury was used, with the application of the endoplasmic reticulum stress inducer tunicamycin to validate the action mechanism of GRg_1. RESULTS:: indicated that, when compared to the model group, GRg_1 intervention significantly enhanced the survival time of CLP mice, mitigated body weight loss, and improved impaired lung function indices. The GRg_1-treated mice also displayed reduced lung tissue pathological scores, a reduced lung tissue wet-to-dry weight ratio, and lower protein content in the bronchoalveolar lavage fluid. Serum levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α), as well as the mRNA expressions of these cytokines in lung tissues, were decreased. There was a notable decrease in the proportion of apopto-tic alveolar epithelial cells, and down-regulated expressions of caspase-3, Bax, PERK, eIF2α, ATF4, and CHOP and up-regulated expression of Bcl-2 were observed. In vitro findings showed that the apoptosis-lowering and apoptosis-related protein down-regulating effects of GRg_1 were significantly inhibited with the co-application of tunicamycin. Altogether, GRg_1 reduces apoptosis of alveolar epithelial cells, inhibits inflammation in the lungs, alleviates lung injury, and enhances lung function, possibly through the PERK/eIF2α/ATF4/CHOP pathway.
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Factor de Transcripción Activador 4 , Lesión Pulmonar Aguda , Células Epiteliales Alveolares , Apoptosis , Factor 2 Eucariótico de Iniciación , Ginsenósidos , Sepsis , Factor de Transcripción CHOP , eIF-2 Quinasa , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/genética , Ginsenósidos/farmacología , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Ratones , Apoptosis/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Masculino , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Humanos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Profiting from the sustained clinical improvement and prolonged patient survival, immune checkpoint blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has emerged as a revolutionary cancer therapy approach. However, the anti-PD-1/PD-L1 antibodies only achieve a clinical response rate of approximately 20%. Herein, we identified a novel combination strategy that Chinese medicine ginseng-derived ginsenoside Rh2 (Rh2) markedly improved the anti-cancer efficacy of anti-PD-L1 antibody in mice bearing MC38 tumor. Rh2 combined with anti-PD-L1 antibody (combo treatment) further triggered the infiltration, proliferation and activation of CD8+ T cells in the tumor microenvironment (TME). Depletion of CD8+ T cells by mouse CD8 blocking antibody abolished the anti-cancer effect of combo treatment totally. Mechanistically, combo treatment further increased the expression of CXCL10 through activating TBK1-IRF3 signaling pathway, explaining the increased infiltration of T cells. Employing anti- CXC chemokine receptor 3 (CXCR3) blocking antibody prevented the T cells infiltration and abolished the anti-cancer effect of combo treatment. Meanwhile, combo treatment increased the percentage of M1-like macrophages and raised the ratio of M1/M2 macrophages in TME. By comparing the anti-cancer effect of combo treatment among MC38, CT26 and 4T1 tumors, resident T cells were considered as a prerequisite for the effectiveness of combo treatment. These findings demonstrated that Rh2 potentiated the anti-cancer effect of PD-L1 blockade via promoting the T cells infiltration and activation, which shed a new light on the combination strategy to enhance anti-PD-L1 immunotherapy by using natural product Rh2.
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Antígeno B7-H1 , Linfocitos T CD8-positivos , Humanos , Animales , Ratones , Línea Celular Tumoral , Inmunoterapia , Microambiente Tumoral , Quimiocina CXCL10/farmacologíaRESUMEN
Dichloroacetonitrile (DCAN) is a common biotoxic disinfection by-product (DBP) of chlorine. The current methods used for detecting DCAN are tedious and heavily instrument-dependent, and are not suitable for on-site detection. In the present study, we developed a colorimetric assay for rapid detection of DCAN. DCAN in water acted as a complexing agent that formed a complex with cuprous species. The cuprous species was then extracted by chloroform and visualized using dithizone. The visual detection limit for DCAN was 20 ng mL-1, while fluorescence quantification could detect DCAN at a concentration as low as 8.75 ng mL-1. Moreover, haloacetonitriles (HANs) derived from chlorine disinfection and structurally similar to DCAN, including TCAN, BCAN, and DBAN, could also be detected using this method. Other DBPs at concentrations as high as 200 ng mL-1 did not affect the detection process. The low cost and instrument-independence characteristic of the present method enables its routine determination of the concentration of DCAN in water.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia and insulin resistance. Mung bean sprouts are traditionally considered a "folk" hypoglycemic food and their pharmacological effects and underlying mechanisms warrant further investigation. PURPOSE: This study aimed to investigate the anti-diabetic effects of the exosomes-like nanoparticles in mung bean sprouts (MELNs) and explore the related molecular mechanisms. RESULTS: MELNs were isolated using a differential centrifugation-polyethylene glycol (PEG) method, and the identification of MELNs were confirmed by PAGE gel electrophoresis, agarose gel electrophoresis, thin-layer chromatography (TLC), and transmission electron microscopy (TEM). In the high-fat diet/streptozotocin (HFD/STZ) mouse model, MELNs ameliorated the progression of T2DM by increasing oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) results, decreasing the fasting blood glucose level, and reducing the serum triglycerides (TG) and total cholesterol (TC). Histopathological examinations indicated MELNs diminished inflammatory infiltration of hepatocytes and amplified the area of islet B cells. In addition, MELNs decreased the oxidative stress levels in liver tissue and had good biocompatibility. In vitro experiments verified that MELNs improved the viability of glucosamine (GlcN) induced insulin-resistant hepatocytes. Furthermore, this study also revealed that MELNs upregulated GLUT4 & Nrf2 and down-regulated GSK-3ß via activating the PI3K/Akt signaling pathway, promoting the production of antioxidant enzymes, such as HO-1 and SOD, to reduce oxidative stress. CONCLUSION: MELNs mitigated the progression of type 2 diabetes in HFD/STZ mouse model. The underlying molecular mechanism is related to PI3K/Akt/GLUT4/GSK-3ß signaling pathway.
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Diabetes Mellitus Tipo 2 , Exosomas , Nanopartículas , Vigna , Animales , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3 beta , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Insulina , Modelos Animales de Enfermedad , Transducción de SeñalRESUMEN
This study determined the surface electromyography (sEMG) characteristics of healthy Chinese adults during swallowing to provide a reference for the clinical differential diagnosis of swallowing and dysphagia. sEMG was performed on 187 healthy adults to obtain quantitative information on normal pharyngeal swallowing. The evaluated parameters included the timing and amplitude of sEMG activity in the submental and infrahyoid muscles. A normative database was constructed for the timing and amplitude of muscle activity during pharyngeal swallowing. Results indicated that the duration of sEMG activity was related to the age of the patient; the duration gradually increasing with age. Similarly, the duration of the sEMG activity was associated with the type of swallowing. The duration of the sEMG activity was similar for dry and wet swallowing but was significantly different for excessive swallowing. The mean amplitude of sEMG activity for the submental and infrahyoid muscles was not significantly associated with patient age. A significant correlation between the mean amplitude of sEMG activity and the types of normal swallowing was observed in infrahyoid, but not in submental muscle activity. This study is the first report on the establishment of a normative database for the duration and amplitude of muscle activity based on sEMG analysis of pharyngeal swallowing in healthy Chinese adults.
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Trastornos de Deglución , Deglución , Adulto , Humanos , Deglución/fisiología , Electromiografía/métodos , Pueblos del Este de Asia , Trastornos de Deglución/diagnóstico , Músculos del CuelloRESUMEN
OBJECTIVE: The purpose of this study was to determine the effect of tripterygium glycosides (TGs) on regulating abnormal lipid deposition in nephrotic syndrome (NS) rats. METHODS: Sprague-Dawley (SD) rats were injected with 6 mg/kg doxorubicin to construct nephrotic syndrome models (n = 6 per group), and then administered with TGs (10 mg/kg·d-1), prednisone (6.3 mg/kg·d-1), or pure water for 5 weeks. Biomedical indexes, such as urine protein/creatinine ratio (PCR), blood urea nitrogen (BUN), serum creatinine (Scr), serum albumin (SA), triglycerides (TG), total cholesterol (TC)were investigated to evaluate the renal injury of rats. H&E staining experiment was used to assess the pathological alterations. Oil Red O staining was used to assess the level of renal lipid deposition. Malondialdehyde (MDA) and glutathione (GSH) were measured to assess the extent of oxidative damage to the kidney. TUNEL staining was used to assess the status of apoptosis in the kidney. Western blot analysis was performed to examine the levels of relevant intracellular signaling molecules. RESULTS: After treatment with TGs, those tested biomedical indexes were significantly improved, and the extent of kidney tissue pathological changes and lipid deposition in the kidney was diminished. Treatment with TGs decreased renal oxidative damage and apoptosis. Regarding the molecular mechanism, TGs significantly increased the protein expression levels of Bcl-2 but decreased the levels of CD36, ADFP, Bax, and Cleaved caspase-3. CONCLUSION: TGs alleviates renal injury and lipid deposition induced by doxorubicin, suggesting that it may be a new strategy for reducing renal lipotoxicity in NS.
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Síndrome Nefrótico , Ratas , Animales , Tripterygium , Ratas Sprague-Dawley , Doxorrubicina , Glutatión , Glicósidos , LípidosRESUMEN
Napabucasin (also known as BBI608) is a natural naphthoquinone originally identified as a cancer cell stemness inhibitor. Accumulated in vitro and in vivo evidence demonstrated that napabucasin showed significant anticancer effects in various types of cancers. Napabucasin inhibits cancer cell proliferation, induces apoptosis and cell cycle arrest, and suppresses metastasis and relapse. Such anticancer activities of napabucasin mainly rely on the inhibition of cancer stemness by targeting signal transducer and activator of transcription 3 (STAT3) and its related gene inhibition. However, several novel molecular targets for napabucasin, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and thioredoxin reductase 1 (TrxR1), have been reported. Napabucasin represents a promising anticancer lead for multiple cancers. In this mini review, the anticancer potential and the molecular mechanism of napabucasin will be briefly highlighted.
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Benzofuranos , Naftoquinonas , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Naftoquinonas/farmacología , Benzofuranos/farmacología , Apoptosis , Factor de Transcripción STAT3/metabolismo , Línea Celular TumoralRESUMEN
The amine submetabolome, including amino acids (AAs) and biogenic amines (BAs), is a class of small molecular compounds exhibiting important physiological activities. Here, a new pyrylium salt named 6,7-dimethoxy-3-methyl isochromenylium tetrafluoroborate ([d0]-DMMIC) with stable isotope-labeled reagents ([d3]-/[d6]-DMMIC) was designed and synthesized for amino compounds. [d0]-/[d3]-/[d6]-DMMIC-derivatized had a charged tag and formed a set of molecular ions with an increase of 3.02 m/z and the characteristic fragment ions of m/z 204.1:207.1:210.1. When DMMIC coupled with liquid chromatography-mass spectrometry (LC-MS), a systematic methodology evaluation for quantitation proved to have good linearity (R2 between 0.9904 and 0.9998), precision (interday: 2.2-21.9%; intraday: 1.0-19.7%), and accuracy (recovery: 71.8-108.8%) through the test AAs. Finally, the methods based on DMMIC and LC-MS demonstrated the advantaged application by the nontargeted screening of BAs in a common medicinal herb Senecio scandens and an analysis of metabolic differences among the amine submetabolomes between the carcinoma and paracarcinoma tissues of esophageal squamous cell carcinoma (ESCC). A total of 20 BA candidates were discovered in S. scandens as well as the finding of 13 amine metabolites might be the highest-potential differential metabolites in ESCC. The results showed the ability of DMMIC coupled with LC-MS to analyze the amine submetabolome in herbs and clinical tissues.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Aminoácidos/química , Aminas Biogénicas , Cloruro de Sodio , Isótopos de Carbono/químicaRESUMEN
The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.
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Nanocáscaras , Neoplasias , Fotoquimioterapia , Humanos , Línea Celular Tumoral , Oro , Metástasis Linfática , Neoplasias/tratamiento farmacológico , Oligopéptidos , Inhibidores de Proteasoma/farmacología , TitanioRESUMEN
BACKGROUND: Growing evidence, including our previous studies, has demonstrated that an enriched environment (EE) after cerebral ischemia/reperfusion (I/R) injury improves neurofunctional recovery in rats. However, whether EE exposure prior to injury could play a neuroprotective role in stroke has seldom been investigated. In this study, we examined the neuroprotective effects of prior exposure to EE and investigated the potential anti-apoptotic effect in rats after cerebral I/R injury. METHODS AND RESULTS: Rats were housed in EE or standard conditions (SC) for four weeks and then randomly assigned to receive 120 min of right middle cerebral occlusion (MCAO) or sham operation. Based on the housing environment and the procedure they underwent, the rats were divided into the following three groups: preischemic EE + MCAO (PIEE), preischemic SC + MCAO (PISC) and preischemic SC + sham-operated (sham). Forty-eight hours after the operation, the rats were subjected to a series of assessments. We found that prior exposure to EE improved functional outcomes, reduced infarct volume and attenuated histological damage. The apoptotic cell numbers in the ischemic penumbra cortex decreased in PIEE group, as did the p53, PUMA, Bax and AIF expression levels. The protein expression of Bcl-2 and HSP70 was increased in the PIEE group compared with the PISC group. PIEE treatment also significantly increased the BDNF level in the ischemic penumbra. In addition, inhibition of cell apoptosis and upregulation of BDNF expression levels were correlated with the improved functional recovery of MCAO rats. CONCLUSIONS: These findings suggest that EE preconditioning inhibited cell apoptosis and upregulated BDNF expression in the penumbra of MCAO rats, which may contribute to neurofunctional recovery after stroke.
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Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Accidente Cerebrovascular , Animales , Apoptosis , Isquemia Encefálica/metabolismo , Factor Neurotrófico Derivado del Encéfalo , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/terapia , Fármacos Neuroprotectores/farmacología , Ratas , Daño por Reperfusión/metabolismo , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/terapiaRESUMEN
Psoralidin (PSO) is a natural coumarin isolated from the seeds of Psoralea corylifolia Linn. Previous studies have reported that PSO exerts numerous pharmacological bioactivities including antitumor. The present study aimed to investigate its anticancer effect using colon cancer cells. Cultured HT-29 and HCT-116 colon cancer cells were treated with different concentrations of PSO, and the cell viability, the intracellular reactive oxygen species (ROS), the protein expression, and the apoptosis were determined by MTT assay, DCFH2 -DA fluorescence probe, Western blotting, and Annexin V/7-AAD staining, respectively. The activities of caspase 3/7 were determined by a commercial kit. Our study found that PSO effectively induces apoptotic cell death mediated by caspase 3/7 in HT-29 and HCT-116 colon cancer cells. PSO treatment rapidly boosts the ROS generation, which is responsible for the PSO-triggered DNA damage, mitochondria membrane potential decrease and caspase 3/7 activation, and c-Jun N-terminal kinase 1/2 activation. Collectively, these results showed that PSO triggered oxidative damage mediated apoptosis in colon cancer cells.
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Benzofuranos , Neoplasias del Colon , Cumarinas , Psoralea , Apoptosis , Benzofuranos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Cumarinas/farmacología , Humanos , Estrés Oxidativo , Psoralea/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Retinal neovascularization (RNV), a pathological process shared among diabetic retinopathy, retinopathy of prematurity and other retinopathies, has been widely studied, but the mechanism remains unclear. In this study, the mechanism by which the interleukin (IL)-23/IL-17 axis regulates RNV in oxygen-induced retinopathy (OIR) model mice and in cell experiments in vitro was characterized. In the retinas of OIR mice, IL-23/IL-17 axis activation was increased and regulated RNV formation, and this effect was accompanied by increased macrophage recruitment and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome activation. Moreover, inhibiting the IL-23/IL-17 axis reduced the number of macrophage and the expression and activation of NLRP3 inflammasome. On the other hand, recombinant (r) IL-23p19 and rIL-17A promoted the expression and activation of NLRP3 inflammasome, and the proliferation and migration of macrophages. Furthermore, macrophage elimination decreased the activation of IL-23/IL-17 axis and the expression and activation of NLRP3 inflammasome. In summary, our experiments showed that the IL-23/IL-17 axis promoted the formation of RNV by activating the NLRP3 inflammasome in retinal macrophages of an OIR mouse model.
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Retinopatía Diabética/etiología , Retinopatía Diabética/metabolismo , Inflamasomas/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neovascularización Retiniana/etiología , Neovascularización Retiniana/metabolismo , Animales , Biomarcadores , Retinopatía Diabética/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunohistoquímica , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Ratones , Neovascularización Retiniana/patologíaRESUMEN
Ocular neovascularization is the leading cause of vision impairment in a variety of ocular diseases, such as age-related macular degeneration and retinopathy of prematurity. Emerging studies have suggested that the yes-associated protein (YAP), a downstream effector of the Hippo pathway, is involved in the pathological angiogenesis, but the mechanism are largely unknown. Here, we demonstrated that hypoxic treatment triggered YAP expression and nuclear translocation in human umbilical vein endothelial cells (HUVECs). YAP acted as a transcriptional co-activator working together with transcriptional enhancer activator domain 1 (TEAD1) to binds the promoter of the key glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3), and thereby increases PFKFB3 expression. Moreover, silencing of YAP inhibited glycolysis as well as proliferation, migration, sprouting and tube formation of HUVECs under hypoxia, all of which could be reversed by enforced expression of PFKFB3. Finally, our animal study also showed that intravitreal injection of small interfering RNA of YAP or PFKFB3 dramatically suppressed the neovascular growth in mouse models of choroidal neovascularization and oxygen-induced retinopathy. These findings provide new insights into a previously unrecognized effect of YAP on endothelial glycolysis and highlight the potential of targeting YAP/PFKFB3 axis in the treatment of ocular neovascularization.