RESUMEN
Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors1-6. LEPR+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin13,14, distinguishes peri-arteriolar LEPR+ cells poised to undergo osteogenesis from peri-sinusoidal LEPR+ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR+osteolectin+ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin+ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin+ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin+ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin+ cells depleted osteolectin+ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing.
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Arteriolas , Linfopoyesis , Osteogénesis , Nicho de Células Madre , Tejido Adiposo/citología , Envejecimiento , Animales , Células de la Médula Ósea/citología , Huesos/citología , Femenino , Factores de Crecimiento de Célula Hematopoyética/metabolismo , Lectinas Tipo C/metabolismo , Linfocitos/citología , Masculino , Ratones , Receptores de Leptina/metabolismo , Factor de Células Madre , Células del Estroma/citologíaRESUMEN
Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.
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Cardiomiopatías Diabéticas , GTP Fosfohidrolasas , Miocitos Cardíacos , Fosfofructoquinasa-2 , Ubiquitinación , Fosfofructoquinasa-2/metabolismo , Fosfofructoquinasa-2/genética , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/genética , Ratones , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Estrés Oxidativo , Apoptosis/genética , Miocardio/metabolismo , Miocardio/patología , Ratones Endogámicos C57BL , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Glucólisis , Humanos , Estabilidad ProteicaRESUMEN
BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.
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Caveolina 3 , Cardiomiopatías Diabéticas , Complejo I de Transporte de Electrón , Mitocondrias , Miocitos Cardíacos , Animales , Masculino , Ratones , Apoptosis , Caveolina 3/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Complejo I de Transporte de Electrón/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.
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Adenocarcinoma Mucinoso , Neoplasias del Apéndice , Quimioterapia Intraperitoneal Hipertérmica , Humanos , Estudios Retrospectivos , Masculino , Femenino , Neoplasias del Apéndice/terapia , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/patología , Persona de Mediana Edad , Adulto , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Anciano , Terapia Combinada , Resultado del Tratamiento , Tasa de Supervivencia , Clasificación del Tumor , Perforación Intestinal/etiología , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/mortalidadRESUMEN
The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.
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Neoplasias del Colon/enzimología , Mucosa Intestinal/enzimología , Proteínas de Neoplasias/metabolismo , Nucleotidiltransferasas/metabolismo , Animales , Neoplasias del Colon/genética , Ratones , Ratones Noqueados , Células Supresoras de Origen Mieloide/enzimología , Proteínas de Neoplasias/genética , Nucleotidiltransferasas/genética , Células Madre/enzimología , Células Th17/enzimologíaRESUMEN
Thermal insulating fibers can effectively regulate the human body temperature and decrease indoor energy consumption. However, designing super thermal insulating fibers integrating a sponge and aerogel structure based on biomass resources is still a challenge. Herein, a flow-assisted dynamic dual-cross-linking strategy is developed to realize the steady fabrication of regenerated all-cellulose graded sponge-aerogel fibers (CGFs) in a microfluidic chip. The chemically cross-linked cellulose solution is used as the core flow, which is passed through two sheath flow channels, containing either a diffusion solvent or a physical cross-linking solvent, resulting in CGFs with a porous sponge outer layer and a dense aerogel inner layer. By regulating and simulating the flow process in the microfluidic chip, CGFs with adjustable sponge thicknesses, excellent toughness (26.20 MJ m-3), and ultralow thermal conductivity (0.023 W m-1 K-1) are fabricated. This work provides a new method for fabricating graded biomass fibers and inspires attractive applications for thermal insulation in textiles.
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Celulosa , Nanoestructuras , Celulosa/química , Humanos , Porosidad , Solventes , Conductividad TérmicaRESUMEN
The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF-HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF-HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/ß/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/ß/NF-κB-induced inflammatory response.
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Epóxido Hidrolasas/antagonistas & inhibidores , Regulación de la Expresión Génica , Hipertensión/prevención & control , Resistencia a la Insulina , Riñón/metabolismo , Enfermedades Metabólicas/prevención & control , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Regulación hacia Abajo , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/patología , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/patología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Transportador 2 de Sodio-Glucosa/genéticaRESUMEN
Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice (Ephx2-/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.
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Aorta/efectos de los fármacos , Epóxido Hidrolasas/genética , Niacinamida/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Sirtuina 1/metabolismo , Rigidez Vascular/efectos de los fármacos , Complejo Vitamínico B/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacología , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Aorta/metabolismo , Aorta/fisiopatología , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/genética , Ratones , Ratones Noqueados , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/efectos de los fármacos , Rigidez Vascular/genética , Vasodilatadores/farmacología , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: The etiology of reflux esophagitis (RE) is multi-factorial. This study analyzed the relationship of depression, anxiety, lifestyle and eating habits with RE and its severity and further explored the impact of anxiety and depression on patients' symptoms and quality of life. METHODS: From September 2016 to February 2018, a total of 689 subjects at Xuanwu Hospital Capital Medical University participated in this survey. They were divided into the RE group (patients diagnosed with RE on gastroscopy, n = 361) and the control group (healthy individuals without heartburn, regurgitation and other gastrointestinal symptoms, n = 328). The survey included general demographic information, lifestyle habits, eating habits, comorbidities, current medications, the gastroesophageal reflux disease (GERD) questionnaire (GerdQ), the Patient Health Questionnaire-9 depression scale and the General Anxiety Disorder-7 anxiety scale. RESULTS: The mean age and sex ratio of the two groups were similar. Multivariate logistic regression analysis identified the following factors as related to the onset of RE (p < 0.05): low education level; drinking strong tea; preferences for sweets, noodles and acidic foods; sleeping on a low pillow; overeating; a short interval between dinner and sleep; anxiety; depression; constipation; history of hypertension; and use of oral calcium channel blockers. Ordinal logistic regression analysis revealed a positive correlation between sleeping on a low pillow and RE severity (p = 0.025). Depression had a positive correlation with the severity of symptoms (rs = 0.375, p < 0.001) and patients' quality of life (rs = 0.306, p < 0.001), whereas anxiety showed no such association. CONCLUSIONS: Many lifestyle factors and eating habits were correlated with the onset of RE. Notably, sleeping on a low pillow was positively correlated with RE severity, and depression was positively related to the severity of symptoms and patients' quality of life.
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Esofagitis Péptica , Ansiedad/epidemiología , Trastornos de Ansiedad , Depresión/epidemiología , Esofagitis Péptica/epidemiología , Conducta Alimentaria , Humanos , Estilo de Vida , Calidad de Vida , Encuestas y CuestionariosRESUMEN
cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.
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Inmunidad Innata/inmunología , Melanoma Experimental/inmunología , Nucleótidos Cíclicos/inmunología , Nucleotidiltransferasas/inmunología , Animales , Anticuerpos/administración & dosificación , Anticuerpos/inmunología , Anticuerpos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Células Cultivadas , Reactividad Cruzada/efectos de los fármacos , Reactividad Cruzada/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunidad Innata/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleótidos Cíclicos/administración & dosificación , Nucleótidos Cíclicos/farmacología , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Análisis de SupervivenciaRESUMEN
Microvilli are a common structure found on epithelial cells that increase the apical surface thus enhancing the transmembrane transport capacity and also serve as one of the cell's mechanosensors. These structures are composed of microfilaments and cytoplasm, covered by plasma membrane. Epithelial cell function is usually coupled to the density of microvilli and its individual size illustrated by diseases, in which microvilli degradation causes malabsorption and diarrhea. Atomic force microscopy (AFM) has been widely used to study the topography and morphology of living cells. Visualizing soft and flexible structures such as microvilli on the apical surface of a live cell has been very challenging because the native microvilli structures are displaced and deformed by the interaction with the probe. PeakForce Tapping® is an AFM imaging mode, which allows reducing tip-sample interactions in time (microseconds) and controlling force in the low pico-Newton range. Data acquisition of this mode was optimized by using a newly developed PeakForce QNM-Live Cell probe, having a short cantilever with a 17-µm-long tip that minimizes hydrodynamic effects between the cantilever and the sample surface. In this paper, we have demonstrated for the first time the visualization of the microvilli on living kidney cells with AFM using PeakForce Tapping. The structures observed display a force dependence representing either the whole microvilli or just the tips of the microvilli layer. Together, PeakForce Tapping allows force control in the low pico-Newton range and enables the visualization of very soft and flexible structures on living cells under physiological conditions.
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Células Epiteliales/ultraestructura , Procesamiento de Imagen Asistido por Computador/métodos , Microvellosidades/ultraestructura , Animales , Perros , Riñón/citología , Células de Riñón Canino Madin Darby , Microscopía de Fuerza Atómica/métodosRESUMEN
Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Modelos Biológicos , Preparaciones Farmacéuticas/química , Teorema de Bayes , Descubrimiento de Drogas , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) initially emerged as oral antidiabetic medication but were subsequently discovered to exhibit pleiotropic actions. Insomnia is a prevalent and debilitating sleep disorder. To date, the causality between SGLT2 inhibitors and insomnia remains unclear. This study aims to evaluate the causality between SGLT2 inhibitors and insomnia and identify potential plasma protein mediators. METHODS: Using a two-sample Mendelian Randomization (MR) analysis, we estimated the causality of SGLT2 inhibition on insomnia and sleep duration. Additionally, employing a two-step and proteome-wide MR analysis, we evaluated the causal link of SGLT2 inhibition on 4907 circulating proteins and the causality of SGLT2 inhibition-driven plasma proteins on insomnia. We applied a false discovery rate (FDR) correction for multiple comparisons. Furthermore, mediation analyses were used to identify plasma proteins that mediate the effects of SGLT2 inhibition on insomnia. RESULTS: SGLT2 inhibition was negatively correlated with insomnia (odds ratio [OR] = 0.791, 95 % confidence interval [CI] [0.715, 0.876], P = 5.579*10^-6) and positively correlated with sleep duration (ß = 0.186, 95 % CI [0.059, 0.314], P = 0.004). Among the 4907 circulating proteins, diadenosine tetraphosphatase (Ap4A) was identified as being linked to both SGLT2 inhibition and insomnia. Mediation analysis indicated that the effect of SGLT2 inhibition on insomnia partially operates through Ap4A (ß = -0.018, 95 % CI [-0.036, -0.005], P = 0.023), with a mediation proportion of 7.7 %. CONCLUSION: The study indicated a causality between SGLT2 inhibition and insomnia, with plasma Ap4A potentially serving as a mediator.
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Análisis de la Aleatorización Mendeliana , Trastornos del Inicio y del Mantenimiento del Sueño , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Proteínas SanguíneasRESUMEN
Objective: To investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF. Methods: Applying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium. Results: SGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [ß = -0.20, 95% CI (-0.39, -0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF. Conclusion: The study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.
RESUMEN
BACKGROUND: BRD4 is a member of the bromodomain and extra terminal domain (BET) family of proteins, containing two bromodomains and one extra terminal domain, and is overexpressed in several human malignancies. However, its expression in gastric cancer has not yet been well illustrated. OBJECTIVE: This study aimed to elucidate the overexpression of BRD4 in gastric cancer and its clinical significance as a novel therapeutic target. METHODS: Fresh gastric cancer tissues and paraffin-embedded specimens of gastric cancer patients were collected, and the BRD4 expression was examined by Western Blot Analysis (WB) and Immunohistochemistry Analysis (IHC), respectively. The possible relationship between BRD4 expression and the clinicopathological features as well as survival in gastric cancer patients was analyzed. The effect of BRD4 silencing on human gastric cancer cell lines was investigated by MTT assay, WB, wound healing assay, and Transwell invasion. RESULTS: The results showed that the expression level in tumor tissues and adjacent tissues was significantly higher than that in normal tissues, respectively (P < 0.01). BRD4 expression level in gastric cancer tissues was strongly correlated with the degree of tumor differentiated degree (P = 0.033), regional lymph nodes metastasis (P = 0.038), clinical staging (P = 0.002), and survival situation (P = 0.000), while the gender (P = 0.564), age (P = 0.926) and infiltrating depth (P = 0.619) of patients were not associated. Increased BRD4 expression resulted in poor overall survival (P = 0.003). In in vitro assays, BRD4 small interfering RNA resulted in significantly decreased BRD4 protein expression, therefore inhibiting proliferation, migration, and invasion of gastric cancer cells. CONCLUSION: BRD4 might be a novel biomarker for the early diagnosis, prognosis, and therapeutic target in gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Relevancia Clínica , Línea Celular Tumoral , Proliferación Celular , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismoRESUMEN
AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer a novel therapeutic avenue for myocardial infarction (MI). However, the exact nature of this relationship and the underlying mechanisms are not fully understood. METHODS: Utilizing a two-sample Mendelian Randomization (MR) analysis, we elucidated the causal effects stemming from the inhibition of SGLT2 on MI. Then, The pool of 4907 circulating proteins within the plasma proteome were utilized to explore the mediators of SGLT2 inhibitors on MI. Protein-protein network and enrichment analysis were conducted to clarify the potential mechanism. Finally, employing MR analysis and meta-analysis techniques, we systematically assessed the causal associations between SGLT2 inhibition and coronary heart diseases (CHD). RESULTS: SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of MI (odds ratio [OR] = 0.462, [95% CI 0.222, 0.958], P = 0.038). Among 4907 circulating proteins, we identified APOB and CCL17 which were related to both SGLT2 inhibition and MI. Mediation analysis showed evidence of the indirect effect of SGLT2 inhibition on MI through APOB (ß = -0.557, 95%CI [-1.098, -0.155]) with a mediated proportion of 72%, and CCL17 (ß = -0.176, 95%CI [-0.332, -0.056]) with a mediated proportion of 17%. The meta-analysis result showed that SGLT2 inhibition was associated with a lower risk of CHD. CONCLUSION: Based on proteome-wide mendelian randomization, APOB and CCL17 were seen as mediators in the protective effect of SGLT2 inhibition against myocardial infarction.
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Apolipoproteínas B , Análisis de la Aleatorización Mendeliana , Infarto del Miocardio , Proteoma , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Infarto del Miocardio/prevención & control , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Proteoma/metabolismo , Apolipoproteínas B/sangre , Apolipoproteínas B/genéticaRESUMEN
Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL-33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 µg/mL) and GA (10 µg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33-activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-kB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects.
Asunto(s)
Antialérgicos/farmacología , Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Ácido Gálico/farmacología , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Quimiocinas/biosíntesis , Dexametasona/farmacología , Humanos , Interleucina-33 , Interleucina-6/biosíntesis , Interleucinas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Paeonia , Fosforilación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Polymer gels suffer from a serious syneresis issue when exposed to high-temperature and high-salinity (HTHS) conditions, which limits their use as water-treatment agents in this type of reservoir. In this paper, the effects of the polymer type/concentration, deoxidizers, and stabilizers on the long-term stability of polymer gels were systematically studied; thus, the methods to develop stable polymer gels for two typical levels of salinity were optimized. The results show the following: (1) For a medium-salinity condition (TDS: 33,645.0 mg/L) at 125 °C, conventional HPAM gels completely dehydrate within only 1 day, and the addition of a deoxidizer hardly improved their stability. Some special polymers, e.g., AP-P5, MKY, and CPAM, are able to form stable gels if a high concentration of 0.8% is used; the syneresis rate of these gels is about 10% after 30 days. However, the addition of the complexant sodium oxalate significantly improves the stability of gels formed by all five of these different polymers, which behave with a 0% syneresis rate after 30 days pass. Complexants are the most economical and feasible agents to develop stable gels in medium-salinity water. (2) Gels enhanced using the methods above all become unstable in a more challenging ultra-high-saline condition (TDS: 225,068.0 mg/L). In this case, special calcium- and magnesium-resistant polymers are required to prepare stable gels, which show 0% syneresis rates after 30 days, have relatively low strengths, but do produce a good plugging effect in high-permeability cores.
RESUMEN
Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP-STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.
Asunto(s)
Neoplasias , Podofilotoxina , Animales , Ratones , Podofilotoxina/farmacología , Proteínas de la Membrana/metabolismo , Transducción de Señal , Inmunidad InnataRESUMEN
Diabetic cardiomyopathy (DCM), characterized by mitochondrial dysfunction and impaired energetics as contributing factors, significantly contributes to high mortality in patients with diabetes. Targeting key proteins involved in mitochondrial dysfunction might offer new therapeutic possibilities for DCM. Lentinan (LNT), a ß-(1,3)-glucan polysaccharide obtained from lentinus edodes, has demonstrated biological activity in modulating metabolic syndrome. In this study, the authors investigate LNT's pharmacological effects on and mechanisms against DCM. The results demonstrate that administering LNT to db/db mice reduces cardiomyocyte apoptosis and mitochondrial dysfunction, thereby preventing DCM. Notably, these effects are fully negated by Caveolin-1 (CAV1) overexpression both in vivo and in vitro. Further studies and bioinformatics analysis uncovered that CAV1 bound with Succinate dehydrogenase subunit A (SDHA), triggering the following ubiquitination and degradation of SDHA, which leads to mitochondrial dysfunction and mitochondria-derived apoptosis under PA condition. Silencing CAV1 leads to reduced apoptosis and improved mitochondrial function, which is blocked by SDHA knockdown. In conclusion, CAV1 directly interacts with SDHA to promote ubiquitination and proteasomal degradation, resulting in mitochondrial dysfunction and mitochondria-derived apoptosis, which was depressed by LNT administration. Therefore, LNT may be a potential pharmacological agent in preventing DCM, and targeting the CAV1/SDHA pathway may be a promising therapeutic approach for DCM.