RESUMEN
Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.
RESUMEN
BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS: Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.
Asunto(s)
Aterosclerosis , ARN Largo no Codificante , Animales , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Colesterol/metabolismo , Células Endoteliales/metabolismo , Aterosclerosis/patología , Macrófagos/metabolismo , Ratones NoqueadosRESUMEN
BACKGROUND: Neurometabolite concentrations provide a direct index of infarction progression in stroke. However, their relationship with stroke onset time remains unclear. PURPOSE: To assess the temporal dynamics of N-acetylaspartate (NAA), creatine, choline, and lactate and estimate their value in predicting early (<6 hours) vs. late (6-24 hours) hyperacute stroke groups. STUDY TYPE: Cross-sectional cohort. POPULATION: A total of 73 ischemic stroke patients scanned at 1.8-302.5 hours after symptom onset, including 25 patients with follow-up scans. FIELD STRENGTH/SEQUENCE: A 3 T/magnetization-prepared rapid acquisition gradient echo sequence for anatomical imaging, diffusion-weighted imaging and fluid-attenuated inversion recovery imaging for lesion delineation, and 3D MR spectroscopic imaging (MRSI) for neurometabolic mapping. ASSESSMENT: Patients were divided into hyperacute (0-24 hours), acute (24 hours to 1 week), and subacute (1-2 weeks) groups, and into early (<6 hours) and late (6-24 hours) hyperacute groups. Bayesian logistic regression was used to compare classification performance between early and late hyperacute groups by using different combinations of neurometabolites as inputs. STATISTICAL TESTS: Linear mixed effects modeling was applied for group-wise comparisons between NAA, creatine, choline, and lactate. Pearson's correlation analysis was used for neurometabolites vs. time. P < 0.05 was considered statistically significant. RESULTS: Lesional NAA and creatine were significantly lower in subacute than in acute stroke. The main effects of time were shown on NAA (F = 14.321) and creatine (F = 12.261). NAA was significantly lower in late than early hyperacute patients, and was inversely related to time from symptom onset across both groups (r = -0.440). The decrease of NAA and increase of lactate were correlated with lesion volume (NAA: r = -0.472; lactate: r = 0.366) in hyperacute stroke. Discrimination was improved by combining NAA, creatine, and choline signals (area under the curve [AUC] = 0.90). DATA CONCLUSION: High-resolution 3D MRSI effectively assessed the neurometabolite changes and discriminated early and late hyperacute stroke lesions. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 2.
Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Creatina , Teorema de Bayes , Estudios Transversales , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Ácido Láctico , Colina , Ácido AspárticoRESUMEN
Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 µM) and THBru (20, 40 µM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.
Asunto(s)
Berberina , Cardiomiopatías , Animales , Ratones , Transducción de Señal , Berberina/farmacología , Berberina/uso terapéutico , Mitofagia , EnvejecimientoRESUMEN
Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antraquinonas/farmacología , Emodina/farmacología , Cardiopatías/patología , Mitofagia/efectos de los fármacos , Animales , Benzofuranos , Modelos Animales de Enfermedad , Femenino , Galactosa/farmacología , Ratones , Simulación del Acoplamiento Molecular , Miocitos Cardíacos/efectos de los fármacos , Quinolinas , Distribución Aleatoria , Ubiquitina-Proteína Ligasas/efectos de los fármacosRESUMEN
PURPOSE: To accelerate T2 mapping with highly sparse sampling by integrating deep learning image priors with low-rank and sparse modeling. METHODS: The proposed method achieves high-speed T2 mapping by highly sparsely sampling (k, TE)-space. Image reconstruction from the undersampled data was done by exploiting the low-rank structure and sparsity in the T2 -weighted image sequence and image priors learned from training data. The image priors for a single TE were generated from the public Human Connectome Project data using a tissue-based deep learning method; the image priors were then transferred to other TEs using a generalized series-based method. With these image priors, the proposed reconstruction method used a low-rank model and a sparse model to capture subject-dependent novel features. RESULTS: The proposed method was evaluated using experimental data obtained from both healthy subjects and tumor patients using a turbo spin-echo sequence. High-quality T2 maps at the resolution of 0.9 × 0.9 × 3.0 mm3 were obtained successfully from highly undersampled data with an acceleration factor of 8. Compared with the existing compressed sensing-based methods, the proposed method produced significantly reduced reconstruction errors. Compared with the deep learning-based methods, the proposed method recovered novel features better. CONCLUSION: This paper demonstrates the feasibility of learning T2 -weighted image priors for multiple TEs using tissue-based deep learning and generalized series-based learning. A new method was proposed to effectively integrate these image priors with low-rank and sparse modeling to reconstruct high-quality images from highly undersampled data. The proposed method will supplement other acquisition-based methods to achieve high-speed T2 mapping.
Asunto(s)
Aprendizaje Profundo , Algoritmos , Encéfalo/diagnóstico por imagen , Voluntarios Sanos , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia MagnéticaRESUMEN
Sesamin is a lignan compound in plants that has various pharmacological effects, including reducing diabetes-associated injuries, regulating fatty acid and cholesterol metabolism, and exerting antiinflammatory and antitumour effects. Previous studies have reported that sesamin can inhibit the proliferation of several types of tumour cells and exert antitumour effects. However, the antitumour effect of sesamin on T-cell lymphoma is still unknown. In this study, we selected a T-cell lymphoma mouse model to investigate the mechanism of sesamin against T-cell lymphoma via programmed cell death in vivo and in vitro. We found that sesamin could significantly inhibit the growth of EL4 cells in a tumour-bearing mouse model. Sesamin markedly inhibited the proliferation of EL4 cells by inducing apoptosis, pyroptosis and autophagy. Autophagy occurred earlier than apoptosis and pyroptosis in EL4 cells after sesamin treatment. Blocking autophagy inhibited apoptosis and pyroptosis in EL4 cells after sesamin treatment. Taken together, these results suggested that sesamin promoted apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma. This study expands our knowledge of the pharmacological effects of sesamin on T-cell lymphoma, and provides a theoretical basis for the development of new antitumour drugs and treatments for T-cell lymphoma.
Asunto(s)
Antineoplásicos , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Dioxoles/farmacología , Dioxoles/uso terapéutico , Lignanos/farmacología , Lignanos/uso terapéutico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Fitoterapia , Piroptosis/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos BALB C , Estimulación QuímicaRESUMEN
Impaired oxygen and cellular metabolism is a hallmark of ischaemic injury in acute stroke. Magnetic resonance spectroscopic imaging (MRSI) has long been recognized as a potentially powerful tool for non-invasive metabolic imaging. Nonetheless, long acquisition time, poor spatial resolution, and narrow coverage have limited its clinical application. Here we investigated the feasibility and potential clinical utility of rapid, high spatial resolution, near whole-brain 3D metabolic imaging based on a novel MRSI technology. In an 8-min scan, we simultaneously obtained 3D maps of N-acetylaspartate and lactate at a nominal spatial resolution of 2.0 × 3.0 × 3.0 mm3 with near whole-brain coverage from a cohort of 18 patients with acute ischaemic stroke. Serial structural and perfusion MRI was used to define detailed spatial maps of tissue-level outcomes against which high-resolution metabolic changes were evaluated. Within hypoperfused tissue, the lactate signal was higher in areas that ultimately infarcted compared with those that recovered (P < 0.0001). Both lactate (P < 0.0001) and N-acetylaspartate (P < 0.001) differed between infarcted and other regions. Within the areas of diffusion-weighted abnormality, lactate was lower where recovery was observed compared with elsewhere (P < 0.001). This feasibility study supports further investigation of fast high-resolution MRSI in acute stroke.
Asunto(s)
Imagenología Tridimensional/métodos , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/metabolismo , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Neuroimagen/métodos , Adulto , Anciano , Anciano de 80 o más Años , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Estudios de Cohortes , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Ácido Láctico/metabolismo , Masculino , Persona de Mediana Edad , Imagen de Perfusión/métodos , Estudios Prospectivos , Marcadores de SpinRESUMEN
BACKGROUND Loss of the epithelial barrier is characterized by a reduction in E-cadherin expression and is a hallmark of asthma. Qi-xian decoction (QXT) is a Chinese medicinal formula that has been used to effectively treat asthma. This study aimed to investigate the effect of QXT on E-cadherin expression in human lung epithelial 16HBE cells and ovalbumin-challenged mice and to explore the underlying molecular mechanism. MATERIAL AND METHODS Ovalbumin (OVA)-induced mice were used as a model of asthma. Real-time PCR and Western blotting were utilized to examine mRNA and protein levels. Lung tissue reactive oxygen species (ROS) levels were evaluated using dichloro-dihydro-fluorescein diacetate (DCFH-DA). Serum superoxide dismutase (SOD) and the total antioxidant capacity (TAOC) were measured via enzyme-linked immunosorbent assay (ELISA)-based analyses. 16HBE cells were utilized to explore the effect of QXT or hydrogen peroxide (H2O2) on the expression of E-cadherin in vitro. RESULTS We found that QXT treatment increased E-cadherin expression and decreased extracellular-signal-regulated kinase (ERK) phosphorylation levels in the lung tissues of OVA-challenged mice. QXT also downregulated ROS levels and increased serum SOD and TAOC levels in OVA-challenged mice. In vitro studies demonstrated that increased ROS generation induced by H2O2 resulted in decreased E-cadherin expression levels in 16HBE cells, which was attenuated by inhibition of ERK signaling. Moreover, the H2O2-induced downregulation of E-cadherin expression, increased ROS generation, and ERK activation in 16HBE cells were restored by treatment with QXT water or ethanol extract. CONCLUSIONS These data demonstrate that one mechanism by which QXT protects against asthma is to restore E-cadherin expression in vivo and in vitro by inhibiting ROS-mediated ERK activation.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Pulmón/efectos de los fármacos , Ovalbúmina/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , Asma/metabolismo , Cadherinas/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Células Epiteliales/efectos de los fármacos , Femenino , Humanos , Peróxido de Hidrógeno/farmacología , Pulmón/citología , Ratones , Ratones Endogámicos BALB C , FosforilaciónRESUMEN
AIMS/HYPOTHESIS: Many studies have shown that tissue kallikrein has effects on diabetic vascular complications such as nephropathy, cardiomyopathy and neuropathy, but its effects on diabetic retinopathy are not fully understood. Here, we investigated the retinoprotective role of exogenous pancreatic kallikrein and studied potential mechanisms of action. METHODS: We used KK Cg-Ay/J (KKAy) mice (a mouse model of spontaneous type 2 diabetes) and mice with high-fat diet/streptozotocin (STZ)-induced type 2 diabetes as our models. After the onset of diabetes, both types of mice were injected intraperitoneally with either pancreatic kallikrein (KKAy + pancreatic kallikrein and STZ + pancreatic kallikrein groups) or saline (KKAy + saline and STZ + saline groups) for 12 weeks. C57BL/6J mice were used as non-diabetic controls for both models. We analysed pathological changes in the retina; evaluated the effects of pancreatic kallikrein on retinal oxidative stress, inflammation and apoptosis; and measured the levels of bradykinin and B1 and B2 receptors in both models. RESULTS: In both models, pancreatic kallikrein improved pathological structural features of the retina, increasing the thickness of retinal layers, and attenuated retinal acellular capillary formation and vascular leakage (p < 0.05). Furthermore, pancreatic kallikrein ameliorated retinal oxidative stress, inflammation and apoptosis in both models (p < 0.05). We also found that the levels of bradykinin and B1 and B2 receptors were increased after pancreatic kallikrein in both models (p < 0.05). CONCLUSIONS/INTERPRETATION: Pancreatic kallikrein can protect against diabetic retinopathy by activating B1 and B2 receptors and inhibiting oxidative stress, inflammation and apoptosis. Thus, pancreatic kallikrein may represent a new therapeutic agent for diabetic retinopathy.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Calicreínas/uso terapéutico , Estreptozocina/toxicidad , Animales , Apoptosis/efectos de los fármacos , Diabetes Mellitus Tipo 2/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Retina/efectos de los fármacos , Retina/metabolismoRESUMEN
BACKGROUND: Steatosis is an important clinical manifestation associated with chronic hepatitis C virus (HCV) infection. AMP-activated protein kinase (AMPK), a major mediator of lipid metabolism, regulates HCV-associated hepatic steatosis, but the underlying mechanisms remain obscure. Here we investigated the mechanism of HCV nonstructural protein 5A (NS5A)-induced lipid accumulation by the AMPK/SREBP-1c pathway. METHODS: We generated model mice by injecting recombinant lentiviral particles expressing the NS5A protein (genotype 3a) via the tail vein. The serum levels of alanine aminotransferase (ALT), free fatty acids (FFAs) and triglycerides (TG) were examined. H&E and Oil Red O staining were used to examine lipid droplets. Immunohistochemistry staining, quantitative real-time PCR and Western blotting were used to determine the expression of lipogenic genes. RESULTS: Our results showed that the serum levels of ALT, FFAs and TG, as well as the accumulation of hepatic lipid droplets, were increased significantly in mice infected with NS5A-expressing lentiviral particles. NS5A inhibited AMPK phosphorylation and increased the expression levels of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-coenzyme A carboxylase 1 (ACC1) and fatty acid synthase (FASN) in vivo and in vitro. Further investigation revealed that pharmacological activation or ectopic expression of AMPK neutralized the upregulation of SREBP-1c, ACC1 and FASN, and ameliorated hepatic lipid accumulation induced by NS5A. Ectopic expression of SREBP-1c enhanced NS5A-induced hepatic lipid accumulation, which was dramatically reversed by pharmacological activation of AMPK. CONCLUSIONS: Collectively, we demonstrate that NS5A induces hepatic lipid accumulation via the AMPK/SREBP-1c pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteínas no Estructurales Virales/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Western Blotting , Línea Celular , Femenino , Células Hep G2 , Humanos , Inmunohistoquímica , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
OBJECTIVE: The imbalance in neurotransmitter and neuronal metabolite concentration within cortico-striato-thalamo-cortical (CSTC) circuit contributes to obsessive-compulsive disorder's (OCD) onset. Previous studies showed that glutamate mediated upregulation of resting-state activity in healthy people. However, there have been few studies investigating the correlational features between functional and neurochemical alterations in OCD. METHODS: We utilize a combined resting-state functional magnetic resonance imaging (rs-fMRI) and proton magnetic resonance spectroscopy (1H-MRS) approach to investigate the altered functional connectivity (FC) in association with glutamatergic dysfunction in OCD pathophysiology. Three regions of interest are investigated, i.e., medial prefrontal cortex and bilateral thalamus, for seed-based whole-brain FC analysis as well as MRS data acquisition. There are 23 unmedicated adult OCD patients and 23 healthy controls recruited for brain FC analysis. Among them, 12 OCD and 8 controls are performed MRS data acquisition. RESULTS: Besides abnormal FC within CSTC circuit, we also find altered FCs in large-scale networks outside CSTC circuit, including occipital area and limbic and motor systems. The decreased FC between right thalamus and right middle occipital gyrus (MOG) is correlated with glutamatergic signal within right thalamus in OCD patients. Moreover, the FC between right thalamus and right dorsal anterior cingulate cortex (dACC) is associated with glutamate level in right thalamus, specifically in patient's group. Finally, the FC between right thalamus and right MOG is correlated with patient's Yale-Brown Obsessive Compulsive Scale (YBOCS) compulsion and total scores, while the right thalamic glutamatergic signal is associated with YBOCS-compulsion score. CONCLUSION: Our findings showed that the coupled intrinsic functional-biochemical alterations existed both within CSTC circuit and from CSTC to occipital lobe in OCD pathophysiology.
Asunto(s)
Ácido Glutámico/metabolismo , Giro del Cíngulo/fisiología , Trastorno Obsesivo Compulsivo/metabolismo , Trastorno Obsesivo Compulsivo/fisiopatología , Lóbulo Occipital/fisiología , Corteza Prefrontal/fisiología , Tálamo/metabolismo , Adulto , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiología , Espectroscopía de Protones por Resonancia Magnética , Adulto JovenRESUMEN
Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between γδ T cells and liver damage in patients with hepatitis B virus (HBV). However, whether γδ T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation-induced hepatitis is unknown. In this study, using HBV transgenic (HBs-Tg) and HBs-Tg T-cell receptor-δ-deficient (TCR-δ-/- ) mice, we found that mice genetically deficient in γδ T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon-γ (IFN-γ) levels and more extensive necrosis. γδ T-cell deficiency resulted in elevated IFN-γ in CD4+ T cells but not in natural killer or natural killer T cells. The depletion of CD4+ T cells and neutralization of IFN-γ reduced liver damage in HBs-Tg and HBs-Tg-TCR-δ-/- mice to a similar extent. Further investigation revealed that HBs-Tg mice showed an enhanced interleukin-17 (IL-17) signature. The administration of exogenous IL-23 enhanced IL-17A production from Vγ4 γδ T cells and ameliorated liver damage in HBs-Tg mice, but not in HBs-Tg-TCR-δ-/- mice. In summary, our results demonstrated that γδ T cells played a protective role in restraining Con A-induced hepatitis by inhibiting IFN-γ production from CD4+ T cells and are indispensable for IL-23-mediated protection against Con A-induced hepatitis in HBs-Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation-induced liver damage.
Asunto(s)
Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/fisiología , Hepatitis B/inmunología , Hígado/patología , Linfocitos T/inmunología , Animales , Células Cultivadas , Concanavalina A/inmunología , Hepatitis B/terapia , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-23/uso terapéutico , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Necrosis , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/virologíaRESUMEN
BACKGROUND/AIMS: A growing number of studies have demonstrated that the activity and expression level of sirtuin-1 (SIRT1) are decreased in asthma patients; however, the mechanisms underlying decreased SIRT1 expression and function are still not completely understood. Interleukin (IL)-6 plays important roles in inflammation during allergic asthma. In this study, we examined whether loss of SIRT1 activity regulated the expression of IL-6 and further verified the underlying mechanisms. METHODS: The human airway epithelial cell line 16HBE was used to test the effects of the SIRT1 inhibitor (salermide) on expression of IL-6. IL-6 mRNA and protein expression were assessed with real-time polymerase chain reaction (PCR), immunochemistry, and ELISA. OVA-challenged mice were used as an asthma model to investigate the effect of SIRT1 activation on IL-6 and relative Akt phosphorylation level. RESULTS: We found that inhibition of SIRT1 increased IL-6 mRNA and protein levels in a time-dependent manner, which was accompanied by increased Akt pathway activation in 16HBE cells. Furthermore activation of Akt showed upregulated expression of the IL-6 protein whereas Akt inhibitor, LY294002 or Akt siRNA significantly inhibited SIRT1-regulated IL-6 expression. Conversely, activation of SIRT1 inhibited Akt activation and IL-6 expression in an asthmatic mice model and 16HBE cells. CONCLUSION: Our results indicate the potential role of SIRT1 in regulating inflammation by modulation of IL-6 expression in an Akt-dependent manner during allergic asthma.
Asunto(s)
Asma/metabolismo , Interleucina-6/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirtuina 1/metabolismo , Animales , Asma/tratamiento farmacológico , Western Blotting , Línea Celular , Cromonas/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Inmunohistoquímica , Interleucina-6/genética , Pulmón/citología , Morfolinas/farmacología , Naftoles/farmacología , Fenilpropionatos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , ARN Interferente Pequeño/genética , Resveratrol , Transducción de Señal/efectos de los fármacos , Sirtuina 1/antagonistas & inhibidores , Estilbenos/uso terapéuticoRESUMEN
With aging and the increasing incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD mainly includes simple hepatic steatosis, nonalcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma (HCC). An imbalance in hepatic iron homeostasis is usually associated with the progression of NAFLD and induces iron overload, reactive oxygen species (ROS) production, and lipid peroxide accumulation, which leads to ferroptosis. Ferroptosis is a unique type of programmed cell death (PCD) that is characterized by iron dependence, ROS production and lipid peroxidation. The ferroptosis inhibition systems involved in NAFLD include the solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10)/nicotinamide adenine dinucleotide phosphate (NADPH) regulatory axes. The main promotion system involved is the acyl-CoA synthetase long-chain family (ACSL4)/arachidonic lipoxygenase 15 (ALOX15) axis. In recent years, an increasing number of studies have focused on the multiple roles of iron homeostasis imbalance and ferroptosis in the progression of NAFLD. This review highlights the latest studies about iron homeostasis imbalance- and ferroptosis-associated NAFLD, mainly including the physiology and pathophysiology of hepatic iron metabolism, hepatic iron homeostasis imbalance during the development of NAFLD, and key regulatory molecules and roles of hepatic ferroptosis in NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD.
Asunto(s)
Ferroptosis , Homeostasis , Hierro , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Homeostasis/fisiología , Hierro/metabolismo , Ferroptosis/fisiología , AnimalesRESUMEN
Background: Milk Fat Globule-Epidermal Growth Factor 8 (MFG-E8) has been reported to play an oncogenic role in a variety of tumors. However, its involvement in gastric cancer (GC) development has not been described. Methods: The cancer genome atlas (TCGA) and the gene expression omnibus database (GEO) databases were used to analyze the expression of MFG-E8 in GC. These findings were further validated using immunohistochemistry (IHC) and western blotting assay (WB). Kaplan-Meier method, univariate logistic regression, and Christopher Cox regression were used to study the relationship between MFG-E8 and clinical pathology. In addition, the potential signaling pathways involved in MFG-E8 and its potential correlation with levels of immune cell infiltration were investigated. Finally, the biological function of MFG-E8 in GC cells was revealed. Results: MFG-E8 was highly expressed in GC patients and cells, and the high level of MFG-E8 was associated with poor overall survival (OS). KEGG analysis indicated that MFG-E8 may play an important role in the cAMP signaling pathway. The expression of MFG-E8 was positively correlated with the infiltration of M2 macrophages. The patients with high MFG-E8 were easy to develop chemotherapy resistance. Furthermore, the knockdown of MFG-E8 significantly inhibited the proliferation and invasion of GC cells. Conclusion: MFG-E8 in GC may serve as a prognostic marker and a potential immunotherapy target for GC.
RESUMEN
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Due to the insidious onset of HCC, early diagnosis is relatively difficult. HCC also exhibit strong resistance to first-line therapeutic drugs. Therefore, novel precise diagnostic and prognostic biomarkers for HCC are urgently needed. We employed a combination methods of bioinformatic analysis, cell functional experiments in vitro and a xenograft tumour model in vivo to systematically investigate the role of solute carrier family 37 member 3 (SLC37A3) in HCC progression. First, bioinformatic analysis demonstrated that SLC37A3 expression was significantly increased in HCC tissues compared with normal tissues. SLC37A3 expression was also associated with tumour stages and various clinical and pathological features. Similar trends in SLC37A3 expression levels were verified in HCC cells and by using IHC experiments. Next, survival analysis showed that the overall, 1-year, 3-year and 5-year survival rates were decreased in HCC patients with high SLC37A3 expression compared with HCC patients low SLC37A3 expression. Xenograft tumour experiments also suggested that SLC37A3 knockdown significantly inhibited HCC tumourigenesis in vivo. Cell functional experiments suggested that SLC37A3 knockdown inhibited HCC cell proliferation and metastasis, but promoted apoptosis. Furthermore, RNA-seq analysis of SLC37A3-knockdown HCC cells indicated that the type 1 diabetes mellitus (T1DM)-related signalling pathway was significantly altered. The expression levels of insulin secretion-related and glycolysis/gluconeogenesis-related genes were also altered, suggesting that SLC37A3 might be involved in the regulation of glucose homeostasis. In summary, SLC37A3 represents a prospective diagnostic and prognostic biomarker for HCC that functions in glucose metabolism regulation.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Biomarcadores , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Glucosa , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Pronóstico , Estudios ProspectivosRESUMEN
Image reconstruction from limited and/or sparse data is known to be an ill-posed problem and a priori information/constraints have played an important role in solving the problem. Early constrained image reconstruction methods utilize image priors based on general image properties such as sparsity, low-rank structures, spatial support bound, etc. Recent deep learning-based reconstruction methods promise to produce even higher quality reconstructions by utilizing more specific image priors learned from training data. However, learning high-dimensional image priors requires huge amounts of training data that are currently not available in medical imaging applications. As a result, deep learning-based reconstructions often suffer from two known practical issues: a) sensitivity to data perturbations (e.g., changes in data sampling scheme), and b) limited generalization capability (e.g., biased reconstruction of lesions). This paper proposes a new method to address these issues. The proposed method synergistically integrates model-based and data-driven learning in three key components. The first component uses the linear vector space framework to capture global dependence of image features; the second exploits a deep network to learn the mapping from a linear vector space to a nonlinear manifold; the third is an unrolling-based deep network that captures local residual features with the aid of a sparsity model. The proposed method has been evaluated with magnetic resonance imaging data, demonstrating improved reconstruction in the presence of data perturbation and/or novel image features. The method may enhance the practical utility of deep learning-based image reconstruction.
Asunto(s)
Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , AlgoritmosRESUMEN
Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague-Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of Ë16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.
RESUMEN
OBJECTIVE: The purpose of this work is to develop a multispectral imaging approach that combines fast high-resolution 3D magnetic resonance spectroscopic imaging (MRSI) and fast quantitative T2 mapping to capture the multifactorial biochemical changes within stroke lesions and evaluate its potentials for stroke onset time prediction. METHODS: Special imaging sequences combining fast trajectories and sparse sampling were used to obtain whole-brain maps of both neurometabolites (2.0 × 3.0 × 3.0 mm3) and quantitative T2 values (1.9 × 1.9 × 3.0 mm3) within a 9-minute scan. Participants with ischemic stroke at hyperacute (0-24 h, n = 23) or acute (24 h-7d, n = 33) phase were recruited in this study. Lesion N-acetylaspartate (NAA), lactate, choline, creatine, and T2 signals were compared between groups and correlated with patient symptomatic duration. Bayesian regression analyses were employed to compare the predictive models of symptomatic duration using multispectral signals. RESULTS: In both groups, increased T2 and lactate levels, as well as decreased NAA and choline levels were detected within the lesion (all p < 0.001). Changes in T2, NAA, choline, and creatine signals were correlated with symptomatic duration for all patients (all p < 0.005). Predictive models of stroke onset time combining signals from MRSI and T2 mapping achieved the best performance (hyperacute: R2 = 0.438; all: R2 = 0.548). CONCLUSION: The proposed multispectral imaging approach provides a combination of biomarkers that index early pathological changes after stroke in a clinical-feasible time and improves the assessment of the duration of cerebral infarction. SIGNIFICANCE: Developing accurate and efficient neuroimaging techniques to provide sensitive biomarkers for prediction of stroke onset time is of great importance for maximizing the proportion of patients eligible for therapeutic intervention. The proposed method provides a clinically feasible tool for the assessment of symptom onset time post ischemic stroke, which will help guide time-sensitive clinical management.