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BACKGROUND: It has been confirmed that the ApoB/ApoA1 ratio is closely associated with the incidence of cardiometabolic diseases (CMD). However, due to uncontrolled confounding factors in observational studies, the causal relationship of this association remains unclear. METHODS: In this study, we extracted the ApoB/ApoA1 ratio and data on CMD and its associated risk factors from the largest European Genome-Wide Association Study. The purpose was to conduct Mendelian Randomization (MR) analysis. The causal relationship between the ApoB/ApoA1 ratio and CMD was evaluated using both univariable and multivariable MR analyses. Furthermore, bidirectional MR analysis was performed to estimate the causal relationship between the ApoB/ApoA1 ratio and risk factors for CMD. The final verification confirmed whether the ApoB/ApoA1 ratio exhibits a mediating effect in CMD and related risk factors. RESULTS: In terms of CMD, a noteworthy correlation was observed between the increase in the ApoB/ApoA1 ratio and various CMD, including ischemic heart disease, major adverse cardiovascular events, aortic aneurysm, cerebral ischemic disease and so on (all PFDR<0.05). Meanwhile, the ApoB/ApoA1 ratio was significantly associated with CMD risk factors, such as hemoglobin A1c, fasting insulin levels, waist-to-hip ratio, sedentary behavior, and various others, demonstrating a notable causal relationship (all PFDR<0.05). Additionally, the ApoB/ApoA1 ratio played a mediating role in CMD and relative risk factors. CONCLUSIONS: This MR study provides evidence supporting the significant causal relationship between the ApoB/ApoA1 ratio and CMD and its risk factors. Moreover, it demonstrates the mediating effect of the ApoB/ApoA1 ratio in CMD and its risk factors. These findings suggest that the ApoB/ApoA1 ratio may serve as a potential indicator for identifying the risk of developing CMD in participants.
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Análisis de la Aleatorización Mendeliana , Isquemia Miocárdica , Humanos , Estudio de Asociación del Genoma Completo , Biomarcadores , Factores de RiesgoRESUMEN
OBJECTIVE: Assessment of the effect of continuous cuff pressure control on airway injury in middle-aged and elderly patients undergoing endoscopic submucosal dissection (ESD). METHOD: A total of 104 eligible middle-aged and elderly patients requiring esophageal ESD from July 2022-September 2023 at the First Affiliated Hospital of Nanchang University were selected and randomly divided into two groups: the group undergoing general anesthesia tracheal intubation with continuous control of cuff pressure after intubation (Group A, n = 51) and the group undergoing general anesthesia tracheal intubation with continuous monitoring without control of cuff pressure (Group B, n = 53). After endotracheal intubation in Group A, under the guidance of an automatic cuff pressure controller, the air was used to inflate the tracheal cuff until the cuff pressure was 25-30cmH2O. The cuff pressure after intubation was recorded, and then the cuff pressure parameters were directly adjusted in the range of 25-30cmH2O until tracheal extubation after the operation. After endotracheal intubation, patients in Group B inflated the tracheal cuff with clinical experience, then monitored and recorded the cuff pressure with a handheld cuff manometer and instructed the cuff not to be loosened after being connected to the handheld cuff manometer-continuous monitoring until the tracheal extubation, but without any cuff pressure regulation. The patients of the two groups performed esophageal ESD. The left recumbent position was taken before the operation, and the cuff's pressure was recorded. Then, insert the gastrointestinal endoscope to find the lesion site and perform appropriate CO2 inflation to display the diseased esophageal wall for surgical operation fully. After determining the location, the cuff pressure of the two groups was recorded when the cuff pressure was stable. After the operation, the upper gastrointestinal endoscope was removed and the cuff pressure of the two groups was recorded. Postoperative airway injury assessment was performed in both groups, and the incidence of sore throat, hoarseness, cough, and blood in sputum was recorded. The incidence of postoperative airway mucosal injury was also observed and recorded in both groups: typical, episodic congestion spots and patchy local congestion. RESULT: The incidence of normal airway mucosa in Group A was higher than that in Group B (P < 0.05). In comparison, the incidence of occasional hyperemia and local plaque congestion in Group A was lower than in Group B (P < 0.05). CONCLUSION: Continuous cuff pressure control during operation can reduce airway injury in patients with esophageal ESD and accelerate their early recovery after the operation.
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BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.
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Cardiotoxicidad , Ferroptosis , Ratones , Animales , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Especies Reactivas de Oxígeno/metabolismo , Miocitos Cardíacos/patología , Doxorrubicina/efectos adversos , Mitocondrias/metabolismo , Estrés Oxidativo , Antioxidantes/metabolismo , ApoptosisRESUMEN
The purpose of this study was to investigate the effects of post-traumatic stress disorder (PTSD) on electrophysiological characteristics of glutamatergic and GABAergic neurons in dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) in mice, and to elucidate the mechanisms underlying the plasticity of hippocampal neurons and memory regulation after PTSD. Male C57Thy1-YFP/GAD67-GFP mice were randomly divided into PTSD group and control group. Unavoidable foot shock (FS) was applied to establish PTSD model. The spatial learning ability was explored by water maze test, and the changes in electrophysiological characteristics of glutamatergic and GABAergic neurons in dHPC and vHPC were examined using whole-cell recording method. The results showed that FS significantly reduced the movement speed, and enhanced the number and percentage of freezing. PTSD significantly prolonged the escape latency in localization avoidance training, shortened the swimming time in the original quadrant, extended the swimming time in the contralateral quadrant, and increased absolute refractory period, energy barrier and inter-spike interval of glutamatergic neurons in dHPC and GABAergic neurons in vHPC, while decreased absolute refractory period, energy barrier and inter-spike interval of GABAergic neurons in dHPC and glutamatergic neurons in vHPC. These results suggest that PTSD can damage spatial perception of mice, down-regulate the excitability of dHPC and up-regulate the excitability of vHPC, and the underlying mechanism may involve the regulation of spatial memory by the plasticity of neurons in dHPC and vHPC.
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Trastornos por Estrés Postraumático , Ratones , Masculino , Animales , Hipocampo , Aprendizaje Espacial , Neuronas GABAérgicasRESUMEN
The purpose of this study was to investigate the effects of acute fear stress on the spatial memory and neuronal plasticity of medial prefrontal cortex (mPFC) neurons in mice, and to elucidate the mechanisms underlying mPFC plasticity and post-stress memory regulation. Male C57BL/6 mice (6 weeks old) were randomly divided into control group and stress group. Foot shock stress was applied to establish an acute fear stress model. Changes in spatial memory were examined by the Morris water maze test, and the dynamic changes in the spike encoding of pyramidal neurons and GABAergic neurons in the prelimbic cortex (PrL) and infralimbic cortex (IL) of mPFC were detected by whole-cell recording. The results showed that acute fear stress significantly enhanced the percentage of freezing and the number of freezing, reduced the average speed, decreased the escape latency during acquisition phase, extended the probing time in the first quadrant and shortened the probing time in the third quadrant during probe trial, increased inter-spike interval, energy barrier and absolute refractory period of GABAergic neurons in the PrL and pyramidal neurons in the IL, while decreased inter-spike interval, energy barrier and absolute refractory period of pyramidal neurons in the PrL and GABAergic neurons in the IL. These results suggest that acute fear stress can enhance the spatial memory of mice, elevate the excitability and function of the PrL, while deteriorate the excitability and function of the IL, and the underlying mechanism may involve the role of mPFC microcircuitry plasticity in spatial memory after stress.
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Plasticidad Neuronal , Memoria Espacial , Animales , Masculino , Ratones , Miedo , Ratones Endogámicos C57BL , Corteza PrefrontalRESUMEN
BACKGROUND: Antimicrobial peptides play important roles in both plant and animal defense systems. Moreover, over-expression of CaAMP1 (Capsicum annuum antimicrobial protein 1), an antimicrobial protein gene isolated from C. annuum leaves infected with Xanthomonas campestris pv. vesicatoria, confers broad-spectrum resistance to hemibiotrophic bacterial and necrotrophic fungal pathogens in Arabidopsis. Phytophthora root and stem rot (PRR), caused by the fungus Phytophthora sojae, is one of the most devastating diseases affecting soybean (Glycine max) production worldwide. RESULTS: In this study, CaAMP1 was transformed into soybean by Agrobacterium-mediated genetic transformation. Integration of the foreign gene in the genome of transgenic soybean plants and its expression at the translation level were verified by Southern and western blot analyses, respectively. CaAMP1 over-expression (CaAMP1-OX) lines inoculated with P. sojae race 1 exhibited enhanced and stable PRR tolerance through T2-T4 generations compared with the wild-type Williams 82 plants. Gene expression analyses in the transgenic plants revealed that the expression of salicylic acid-dependent, jasmonic acid-dependent, and plant disease resistance genes (R-genes) were significantly up-regulated after P. sojae inoculation. CONCLUSIONS: These results indicate that CaAMP1 over-expression can significantly enhance PRR tolerance in soybean by eliciting resistance responses mediated by multiple defense signaling pathways. This provides an alternative approach for developing soybean varieties with improved tolerance against soil-borne pathogenic PRR.
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Capsicum/genética , Resistencia a la Enfermedad/genética , Glycine max/parasitología , Phytophthora/patogenicidad , Enfermedades de las Plantas/parasitología , Proteínas Citotóxicas Formadoras de Poros/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Enfermedades de las Plantas/genética , Plantas Modificadas Genéticamente/parasitología , Glycine max/genéticaRESUMEN
A short rod-shaped, Gram-stain-negative strain that can degrade multiple polymers was isolated from forest soil in China and designated as DSWY01T. The results of 16S rRNA gene sequence analysis showed that this isolate shared high similarities with Pseudomonas alcaliphila NBRC 102411T (99.3â%), Pseudomonas mendocina NBRC 14162T (99.2%) and Pseudomonas oleovorans NBRC 13583T (99.0%). The results of phylogenetic analysis based on 16S rRNA gene sequence and multilocus sequence analysis (recA, gyrB, nuoD, glnS and rpoD) indicated that strain DSWY01T belongs to the genus Pseudomonas and is a member of the P. oleovorans group in an independent branch. The average nucleotide identity and digital DNA-DNA hybridization between the genome of strain DSWY01T and the genomes of other species (ANIb 77.72-89.65â%; GGDC 15.50-31.10â%) showed that the isolate represents a novel species. The DNA G+C content of strain DSWY01T was 63.67 mol%, and the major cellular fatty acids (>15 %) were a mixture of C18â:â1ω7c/C18â:â1ω6c and C16â:â0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and two unidentified lipids, and the major quinone was CQ-10. The morphological, physiological and biochemical characteristics of the isolate were then compared with those of reference type strains. The isolate differed considerably from its closest relatives and is representative of a novel species of Pseudomonas, for which the name Pseudomonas hydrolytica sp. nov. is proposed. The type strain is DSWY01T (=DSM 106702T=CCTCC AB 2018053T).
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Filogenia , Pseudomonas/clasificación , Microbiología del Suelo , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , Bosques , Genes Bacterianos , Tipificación de Secuencias Multilocus , Hibridación de Ácido Nucleico , Fosfolípidos/química , Polímeros , Pseudomonas/aislamiento & purificación , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Ubiquinona/análogos & derivados , Ubiquinona/químicaRESUMEN
Gymnemic acid I (GA I) is a bioactive component of Gymnema sylvestre. It is an Indian traditional medicinal herb which has antidiabetic effect. However, the molecular mechanism is remaining to be elucidated. Here, we showed that high glucose promoted the rate of apoptosis, GA I decreased the apoptosis under the high glucose stress. Our further study explored that GA I increased the number of autophagosome and the ratio of light chain 3-I (LC3-I)/LC3-II in MIN-6 cells under the normal or high glucose stress by the methods of western blot analysis and immunofluorescence. It induced autophagy flux and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase ß-1 (p70 S6K/S6K1), which is a substrate of mTOR. GA I decreased the rate of apoptosis and the activity of caspase-3 under the high glucose stress. The inhibition of apoptosis and caspase-3 activity by GA I were increased after treating with autophagy inhibitor in mouse islet ß cells MIN-6. Our data suggested that GA I-induced autophagy protected MIN-6 cells from apoptosis under high glucose stress via inhibition the phosphorylation activity of mTOR.
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Autofagia , Citoprotección , Glucosa/toxicidad , Células Secretoras de Insulina/patología , Saponinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Triterpenos/farmacología , Animales , Línea Celular Tumoral , Citoprotección/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Saponinas/química , Triterpenos/químicaRESUMEN
OBJECTIVES: The manuscript was mainly aimed to evaluate effects of food and gender on the pharmacokinetics of ticagrelor and its main active metabolite AR-C124910XX in healthy Chinese subjects observed in the bioequivalence studies of the two formulations of ticagrelor tablets. MATERIALS AND METHODS: The single-dose, two-sequence, two-period and crossover studies were respectively conducted under fasting and fed conditions. Plasma samples were analyzed by an HPLC-MS/MS method. Log-transformed pharmacokinetic parameters of ticagrelor and AR-C124910XX obtained from the trials were compared by the mean of two one-sided t-test. RESULTS: Pharmacokinetic parameters of the two formulations were evaluated. The mean ticagrelor tmax value was delayed by 0.28 - 0.53 hours owing to meals. A 21.6 - 24.0% (p < 0.05) increase in the mean ticagrelor AUC* (body weight-normalized AUC) value was measured (fed vs. fasting). For AR-C124910XX, the mean T1/2 value was delayed by 0.84 - 1.33 hours (p < 0.05) due to meals. A 52.0 - 55.8% (p < 0.05) decrease in the mean Cmax* (body weight-normalized Cmax) value and a 15.6 - 16.9% (p < 0.05) decrease in the mean AUC* value were observed (fed vs. fasting). The female subjects exhibited higher exposures to ticagrelor and AR-C124910XX than the male subjects. Compared with other populations, the Chinese subjects in this study experienced a greater decrease in Cmax of AR-C124910XX due to meals. 21 adverse events of mild intensity occurred over the study periods. CONCLUSION: The studies showed food effects on the absorption of ticagrelor and the formation of AR-C124910XX, and gender effects on exposures to the drug after single oral-dose administration.â©.
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Adenosina/análogos & derivados , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Adenosina/efectos adversos , Adenosina/sangre , Adenosina/farmacocinética , Adulto , Pueblo Asiatico , Estudios Cruzados , Composición de Medicamentos , Ayuno , Femenino , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Absorción Intestinal , Masculino , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Seguridad , Caracteres Sexuales , Equivalencia Terapéutica , Ticagrelor , Adulto JovenRESUMEN
Organosulfur compounds (OSCs) are the bioactive components of garlic. Some OSCs have apoptotic or autophagy-inducing effects. Autophagy plays roles in both cytoprotection and apoptosis-related cell death, and the interaction between autophagy and apoptosis is important in the modulation of immune responses. The mechanism of an OSC-mediated effect via the interaction of autophagy and apoptosis is unknown. In this study, the effects of five OSC compounds on autophagy in the macrophage cell line RAW264.7 and primary macrophages were investigated. We found that S-allylcysteine (SAC), diallyl disulde (DADS) and diallyl tetrasulfide (DTS) treatment increased the number of autophagosomes of RAW264.7 cells, inhibited the phosphorylation of ribosomal protein S6 kinase beta-1 (p70S6K/S6K1) which is a substrate of mammalian target of rapamycin (mTOR), and significantly enhanced autophagy flux. The induction of autophagy by SAC, DADS and DTS was inhibited by stably knocking down the expression of autophagy-related gene 5 (ATG5) with short hairpin RNA (shRNA). Further experiments confirmed that SAC, DADS and DTS also induced apoptosis in RAW264.7 cells. The induction of apoptosis and Caspase 3 activity by SAC, DADS and DTS were increased by stably knocking down of ATG5 expression with shRNA in RAW264.7 cells or treating with 5 mM 3-MA in primary macrophages. Our results suggest that SAC, DADS and DTS induce both autophagy and apoptosis. The autophagy induction protects macrophages from apoptosis by inhibiting mTOR phosphorylation activity to maintain the mass of immune cells.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Macrófagos/efectos de los fármacos , Compuestos Orgánicos/farmacología , Compuestos de Azufre/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Compuestos Alílicos/farmacología , Animales , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Células Cultivadas , Cisteína/análogos & derivados , Cisteína/farmacología , Disulfuros/farmacología , Ajo/química , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Sustancias Protectoras/farmacología , Células RAW 264.7 , Sulfuros/farmacologíaRESUMEN
Simo decoction (SMD), as a traditional medicine, is widely used in the treatment of gastrointestinal dysmotility in China. In this study, a combined method of liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) and ultrafiltration high-performance liquid chromatography molecular docking (UF-HPLC-MD) was efficiently employed to identify and screen bioactive ingredients in SMD. Ninety-four major constituents were identified or tentatively characterized by comparing their retention times and mass spectra with standards or literature data by using LC-Q-TOF-MS, and the ascription of those compounds were classified for the first time. Among them, 13 bioactive ingredients, including norisoboldine, eriocitrin, neoeriocitrin, narirutin, hesperidin, naringin, neohesperidin, hesperitin-7-O-glucoside, linderane, poncirin, costunolide, nobiletin, and tangeretin, were primarily identified as the human serum albumin (HSA) ligands at a range of docking scores from -29.7 to -40.6 kJ/mol by UF-HPLC-MD. The results indicate the systematic identification and screening of HSA ligands from Simo decoction guided by LC-Q-TOF-MS and UF-HPLC-MD represents a feasible and efficient method that could be extended for the identification and screening of other bioactive ingredients from natural medicines.
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Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Sitios de Unión , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Ligandos , Modelos Moleculares , Conformación Molecular , Reproducibilidad de los Resultados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , UltrafiltraciónRESUMEN
We explored the expression and function of miR-181d (microRNA-181d) in human pancreatic cancer. Quantitative real-time polymerase chain reaction was used to probe miR-181d expression in both pancreatic cancer cell lines and human pancreatic carcinoma. Pancreatic cancer cell lines, PANC-1 and AsPC-1 cells, were engineered to stably downregulate endogenous miR-181d through lentiviral transduction. The mechanistic effects of miR-181d downregulation on pancreatic cancer development were tested by proliferation, migration, fluorouracil chemosensitivity assays in vitro, and explant assay in vivo. Possible miR-181d downstream gene, NKAIN2 (Na+/K+ transporting ATPase interacting 2), was tested by dual-luciferase activity assay and quantitative real-time polymerase chain reaction. Functional involvement of NKAIN2 in miR-181d-regulated pancreatic cancer development was tested by small interfering RNA-mediated NKAIN2 knockdown in miR-181d-downregulated PANC-1 and AsPC-1 cells. MiR-181d was upregulated in both pancreatic cancer cell lines and human pancreatic carcinoma. Lentivirus-induced miR-181d downregulation decreased pancreatic cancer proliferation, migration, and fluorouracil resistance in vitro and inhibited the growth of cancer explant in vivo. NKAIN2 was directly targeted by miR-181d in pancreatic cancer. Small interfering RNA-mediated NKAIN2 knockdown reversed the inhibition of miR-181d downregulation on pancreatic cancer development. MiR-181d is aberrantly overexpressed in pancreatic cancer. Inhibiting miR-181d may suppress pancreatic cancer development, possibly through the inverse regulation on NKAIN2.
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Genes Supresores de Tumor/fisiología , Proteínas de la Membrana/fisiología , MicroARNs/fisiología , Neoplasias Pancreáticas/etiología , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , MicroARNs/antagonistas & inhibidores , Neoplasias Pancreáticas/prevención & controlRESUMEN
BACKGROUND: Chronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors. LPTS is a well-identified tumor suppressor by inhibiting telomerase activity and cancer cell growth. However, whether and how LPTS is regulated by inflammation signaling is still incompletely elucidated. METHODS: Real-time PCR and western blotting were used to determine the expression of p65 and LPTS. Reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation were performed to decipher the regulatory mechanism between p65 and LPTS. Cell counting kit-8 assays and xenograt models were used to detect p65-LPTS-regulated cancer cell growth in vitro and in vivo, respectively. RESULTS: Here we for the first time demonstrated that NF-κB could inhibit LPTS expression in the mRNA and protein levels in multiple cancer cells (e.g. cervical cancer and colon cancer cells). Mechanistically, NF-κB p65 could bind to two consensus response elements locating at -1143/-1136 and -888/-881 in the promoter region of human LPTS gene according to EMSA and ChIP assays. Mutation of those two binding sites rescued p65-suppressed LPTS promoter activity. Functionally, NF-κB regulated LPTS-dependent cell growth of cervical and colon cancers in vitro and in xenograft models. In translation studies, we verified that increased p65 expression was associated with decreased LPTS level in multiple solid cancers. CONCLUSIONS: Taken together, we revealed that NF-κB p65 potentiated tumor growth via suppressing a novel target LPTS. Modulation of NF-κB-LPTS axis represented a potential strategy for treatment of those inflammation-associated malignancies.
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Terapia Molecular Dirigida , Factor de Transcripción ReIA/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Proteínas Oncogénicas Virales/metabolismo , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/genéticaRESUMEN
In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.
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Quinasa I-kappa B/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/enzimología , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Adenina/análogos & derivados , Animales , Azepinas/farmacología , Azepinas/toxicidad , Proteínas de Ciclo Celular , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular , Sinergismo Farmacológico , Humanos , Quinasa I-kappa B/química , Quinasa I-kappa B/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones SCID , Proteínas Nucleares/metabolismo , Piperidinas , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirazoles/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Triazoles/farmacología , Triazoles/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT-mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Linfocitos B/inmunología , Linfoma de Células B Grandes Difuso/patología , Pirazoles/farmacología , Pirimidinas/farmacología , Adenina/análogos & derivados , Línea Celular Tumoral , Ensayos Analíticos de Alto Rendimiento , Humanos , Linfoma de Células B Grandes Difuso/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , PiperidinasRESUMEN
BACKGROUND: Conventional scientific studies had supported the use of polysaccharides and ß-glucans from a number of fungi, including Ganoderma lucidum for the treatment of recurrent oral ulceration (ROU). Our aim of the present study was to evaluate whether freeze-dried powder from G. lucidum mycelia (FDPGLM) prevents ROU in rats. METHODS: A Sprague-Dawley (SD) rat model with ROU was established by autoantigen injection. The ROU rats were treated with three different dosages of FDPGLM and prednisone acetate (PA), and their effects were evaluated according to the clinical therapeutic evaluation indices of ROU. RESULTS: High-dose FDPGLM induced significantly prolonged total intervals and a reduction in the number of ulcers and ulcer areas, thereby indicating that the treatment was effective in preventing ROU. Enzyme-linked immunosorbent assay (ELISA) showed that high-dose FDPGLM significantly enhanced the serum transforming growth factor-ß1 (TGF-ß1) levels, whereas reduced those of interleukin-6 (IL-6) and interleukin-17 (IL-17). Flow cytometry (FCM) showed that the proportion of CD4+ CD25+ Foxp3+ (forkhead box P3) regulatory T cells (Tregs) significantly increased by 1.5-fold in the high-dose FDPGLM group compared to that in the rat model group (P < 0.01). The application of middle- and high-dose FDPGLM also resulted in the upregulation of Foxp3 and downregulation of retinoid-related orphan receptor gamma t(RORγt) mRNA. CONCLUSION: High-dose FDPGLM possibly plays a role in ROU by promoting CD4+ CD25+ Foxp3+ Treg and inhibiting T helper cell 17 differentiation. This study also shows that FDPGLM may be potentially used as a complementary and alternative medicine treatment scheme for ROU.
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Productos Biológicos/uso terapéutico , Ganoderma/química , Micelio/química , Úlceras Bucales/tratamiento farmacológico , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Citocinas/sangre , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Liofilización , Mucosa Bucal/química , Mucosa Bucal/patología , Prednisona/farmacología , Prednisona/uso terapéutico , Ratas , Ratas Sprague-Dawley , RecurrenciaRESUMEN
Motor imagery (MI)-based brain-computer interfaces (BCIs) have been widely used for rehabilitation of motor abilities and prosthesis control for patients with motor impairments. However, MI-BCI performance exhibits a wide variability across subjects, and the underlying neural mechanism remains unclear. Several studies have demonstrated that both the fronto-parietal attention network (FPAN) and MI are involved in high-level cognitive processes that are crucial for the control of BCIs. Therefore, we hypothesized that the FPAN may play an important role in MI-BCI performance. In our study, we recorded multi-modal datasets consisting of MI electroencephalography (EEG) signals, T1-weighted structural and resting-state functional MRI data for each subject. MI-BCI performance was evaluated using the common spatial pattern to extract the MI features from EEG signals. One cortical structural feature (cortical thickness (CT)) and two measurements (degree centrality (DC) and eigenvector centrality (EC)) of node centrality were derived from the structural and functional MRI data, respectively. Based on the information extracted from the EEG and MRI, a correlation analysis was used to elucidate the relationships between the FPAN and MI-BCI performance. Our results show that the DC of the right ventral intraparietal sulcus, the EC and CT of the left inferior parietal lobe, and the CT of the right dorsolateral prefrontal cortex were significantly associated with MI-BCI performance. Moreover, the receiver operating characteristic analysis and machine learning classification revealed that the EC and CT of the left IPL could effectively predict the low-aptitude BCI users from the high-aptitude BCI users with 83.3% accuracy. Those findings consistently reveal that the individuals who have efficient FPAN would perform better on MI-BCI. Our findings may deepen the understanding of individual variability in MI-BCI performance, and also may provide a new biomarker to predict individual MI-BCI performance.
Asunto(s)
Atención/fisiología , Interfaces Cerebro-Computador , Lóbulo Frontal/anatomía & histología , Lóbulo Frontal/fisiología , Imaginación/fisiología , Lóbulo Parietal/anatomía & histología , Lóbulo Parietal/fisiología , Desempeño Psicomotor , Adulto , Mapeo Encefálico , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiología , Adulto JovenRESUMEN
How mesenchymal stem cells (MSCs) promote tumor growth remains incompletely understood. Here, we show that mesenchymal stem-like cells (MSLCs) are commonly present in malignant pleural effusion or ascites of cancer patients, where they directly interact with tumor cells. Chemokines and chemokine receptors, especially the CCL2/CCR2 pathway, are involved in this interaction. As a result, MSLCs exert tumor-promoting effects by enhancing the proliferation and colony formation of tumor-repopulating cells. The underlying molecular basis involves MSLC release of glutamine to tumorigenic cells. Inhibition of glutamine uptake impedes MSC-mediated tumor-promoting effects. More intriguingly, MSLCs take up tumor cell-released ammonium that, in turn, favors MSLC growth. Thus, glutamine and ammonium form a vicious cycle between MSLCs and tumorigenic cells. These findings suggest a potential clinical application by targeting MSLCs in patients with malignant pleural effusions or ascites.
Asunto(s)
Compuestos de Amonio/metabolismo , Carcinogénesis/metabolismo , Proliferación Celular/fisiología , Glutamina/farmacología , Células Madre Mesenquimatosas/metabolismo , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Células MCF-7 , Células Madre Mesenquimatosas/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
An extracellular alkaline protease produced by the alkali-tolerant Cellulomonas bogoriensis was purified by a combination of ammonium sulfate precipitation and cation exchange chromatography. The purity of the protease was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its molecular weight was confirmed to be 18.3 kDa. The enzyme showed optimum activity at 60 °C and pH 11. The stability of the protease was maintained at a wide temperature range of 4-60 °C and pH range of 3-12. Irreversible inhibition of the enzyme activity by phenylmethylsulfonyl fluoride and tosyl-l-phenylalanine chloromethyl ketone demonstrated that the purified enzyme is a chymotrypsin of the serine protease family. The Km and Vmax of the protease activity on casein were 19.2 mg/mL and 25000 µg/min/mg, respectively. The broad substrate specificity and remarkable stability in the presence of organic solvents, salt, and commercial detergents, as well as its excellent stain removal and dehairing capability, make the purified alkaline protease a promising candidate for industrial applications.
Asunto(s)
Proteínas Bacterianas/química , Proteínas Bacterianas/aislamiento & purificación , Cellulomonas/enzimología , Endopeptidasas/química , Endopeptidasas/aislamiento & purificación , Sulfato de Amonio/química , Proteínas Bacterianas/antagonistas & inhibidores , Estabilidad de Enzimas , Cinética , Fluoruro de Fenilmetilsulfonilo/farmacología , Solventes/químicaRESUMEN
Action video games (AVGs) have attracted increasing research attention as they offer a unique perspective into the relation between active learning and neural plasticity. However, little research has examined the relation between AVG experience and the plasticity of neural network mechanisms. It has been proposed that AVG experience is related to the integration between Salience Network (SN) and Central Executive Network (CEN), which are responsible for attention and working memory, respectively, two cognitive functions essential for AVG playing. This study initiated a systematic investigation of this proposition by analyzing AVG experts' and amateurs' resting-state brain functions through graph theoretical analyses and functional connectivity. Results reveal enhanced intra- and internetwork functional integrations in AVG experts compared to amateurs. The findings support the possible relation between AVG experience and the neural network plasticity.