RESUMEN

It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.

Asunto(s)

Carcinogénesis , Proteínas de Unión al ARN , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , Tejido Adiposo/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Glucosa/metabolismo , Resistencia a la Insulina , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Unión al ARN/metabolismo

RESUMEN

Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.

Asunto(s)

Citocinas , Dermatitis Atópica , Macrófagos , FN-kappa B , Células Th2 , Xantonas , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Xantonas/farmacología , Xantonas/uso terapéutico , Animales , FN-kappa B/metabolismo , Células Th2/inmunología , Células Th2/efectos de los fármacos , Citocinas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Humanos , Masculino , Linfopoyetina del Estroma Tímico , Inmunoglobulina E/metabolismo , Piel/efectos de los fármacos , Piel/patología , Piel/inmunología , Piel/metabolismo

RESUMEN

A facile and efficient AgF-mediated electrophilic amination of alkoxyarylsilanes with azodicarboxylates was developed. The reaction proceeds in green solvent under simple and mild conditions to generate the corresponding aryl hydrazines. AgF acts both as a stoichiometric fluoride source and a reagent for transmetalation to the arylsilver intermediate that eventually reacts with azodicarboxylates to provide aryl hydrazines.

Asunto(s)

Hidrazinas , Aminación , Catálisis , Estructura Molecular

RESUMEN

Plasma LDL is produced from catabolism of VLDL and cleared from circulation mainly via the hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDLR degradation, increasing plasma LDL-C levels. Circulating PCSK9 is mainly secreted by the liver, whereas VLDL is exclusively secreted by hepatocytes. However, the mechanism regulating their secretion is not completely understood. Surfeit 4 (Surf4) is a cargo receptor localized in the ER membrane. It recruits cargos into coat protein complex II vesicles to facilitate their secretion. Here, we investigated the role of Surf4 in VLDL and PCSK9 secretion. We generated Surf4 liver-specific knockout mice and found that knockout of Surf4 did not affect PCSK9 secretion, whereas it significantly reduced plasma levels of cholesterol, triglyceride, and lipid-binding protein apolipoprotein B (apoB). In cultured human hepatocytes, Surf4 coimmunoprecipitated and colocalized with apolipoprotein B100, and Surf4 silencing reduced secretion of apolipoprotein B100. Furthermore, knockdown of Surf4 in LDLR knockout (Ldlr-/-) mice significantly reduced triglyceride secretion, plasma levels of apoB and non-HDL-C, and the development of atherosclerosis. However, Surf4 liver-specific knockout mice and Surf4 knockdown in Ldlr-/- mice displayed similar levels of liver lipids and plasma alanine aminotransferase activity as control mice, indicating that inhibition of Surf4 does not cause notable liver damage. Expression of stearoyl-CoA desaturase-1 was also reduced in the liver of these mice, suggesting a reduction in de novo lipogenesis. In summary, hepatic deficiency of Surf4 reduced VLDL secretion and the development of atherosclerosis but did not cause significant hepatic lipid accumulation or liver damage.

Asunto(s)

Aterosclerosis/metabolismo , Lipoproteínas VLDL/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Células Cultivadas , Proteínas de la Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proproteína Convertasa 9/deficiencia , Proproteína Convertasa 9/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/metabolismo

RESUMEN

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.

Asunto(s)

Apolipoproteína B-100/sangre , Apolipoproteínas E/sangre , Aterosclerosis/patología , Lipoproteínas LDL/sangre , Metaloproteinasa 14 de la Matriz/metabolismo , Receptores de LDL/metabolismo , Animales , Apolipoproteínas E/genética , Línea Celular Tumoral , Ésteres del Colesterol/metabolismo , Dependovirus/genética , Femenino , Células HEK293 , Células Hep G2 , Humanos , Masculino , Metaloproteinasa 14 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados

RESUMEN

Histopathological image contains rich pathological information that is valued for the aided diagnosis of many diseases such as cancer. An important issue in histopathological image classification is how to learn a high-quality discriminative dictionary due to diverse tissue pattern, a variety of texture, and different morphologies structure. In this paper, we propose a discriminative dictionary learning algorithm with pairwise local constraints (PLCDDL) for histopathological image classification. Inspired by the one-to-one mapping between dictionary atom and profile, we learn a pair of discriminative graph Laplacian matrices that are less sensitive to noise or outliers to capture the locality and discriminating information of data manifold by utilizing the local geometry information of category-specific dictionaries rather than input data. Furthermore, graph-based pairwise local constraints are designed and incorporated into the original dictionary learning model to effectively encode the locality consistency with intra-class samples and the locality inconsistency with inter-class samples. Specifically, we learn the discriminative localities for representations by jointly optimizing both the intra-class locality and inter-class locality, which can significantly improve the discriminability and robustness of dictionary. Extensive experiments on the challenging datasets verify that the proposed PLCDDL algorithm can achieve a better classification accuracy and powerful robustness compared with the state-of-the-art dictionary learning methods. Graphical abstract The proposed PLCDDL algorithm. 1) A pair of graph Laplacian matrices are first learned based on the class-specific dictionaries. 2) Graph-based pairwise local constraints are designed to transfer the locality for coding coefficients. 3) Class-specific dictionaries can be further updated.

Asunto(s)

Algoritmos , Neoplasias , Humanos

RESUMEN

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that promotes low-density lipoprotein receptor (LDLR) degradation and thereby regulating plasma levels of LDL cholesterol. Previous studies have revealed the role of the C-terminal domain (CTD) of PCSK9 in its secretion, however, how CTD regulates PCSK9 secretion is not completely understood. Additionally, SEC24A, the cargo adaptor protein of the coat protein complex II, has been implicated in the secretion of mouse PCSK9. Here, we investigated how CTD and SEC24 regulated PCSK9 secretion in humans. We found that mutant PCSK91-528, in which amino acids from 529 to the end (amino acid 692) were deleted, was maturated and secreted from cells as effectively as the wild-type protein. On the other hand, lacking amino acids 454 to 692 in mutant PCSK91-453 significantly reduced its maturation and secretion, but to a lesser extent when compared to mutants PCSK91-446, PCSK91-445 and PCSK91-444, that all markedly impaired PCSK9 maturation. However, mutant PCSK91-444 virtually eliminated PCSK9 secretion while PCSK91-446 and PCSK91-445 could still be adequately detected in culture medium. Interestingly, mutation of Pro445 to other amino acid residues considerably impaired the secretion of mutant PCSK91-445 but not the full-length protein. We also found that natural variants in CTD including S462P, S465L, E482G, R495Q and A522T impaired PCSK9 secretion. Further, the knockdown of SEC24A, SEC24B, SEC24C but not SEC24D reduced secretion of the full-length PCSK9 but not mutant PCSK91-446. Therefore, SEC24A, SEC24B, and SEC24C facilitate endogenous PCSK9 secretion from cultured human hepatocytes, that are most likely mediated by the CTD of PCSK9. Our studies also indicate that the CTD of PCSK9 may allosterically and independently modulate the stability of the hinge region. Collectively, these data revealed that the CTD of PCSK9 and the hinge region play a critical role in PCSK9 maturation and secretion.

Asunto(s)

Proproteína Convertasa 9/metabolismo , Dominios Proteicos/genética , Proteínas de Transporte Vesicular/metabolismo , Células HEK293 , Humanos , Mutagénesis Sitio-Dirigida , Proproteína Convertasa 9/genética

Asunto(s)

Proteínas de la Membrana/metabolismo , Proproteína Convertasa 9/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Células Hep G2 , Humanos , Proteínas de la Membrana/genética , ARN Interferente Pequeño/metabolismo

RESUMEN

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDL receptor (LDLR) degradation, increasing plasma levels of LDL cholesterol and the risk of cardiovascular disease. We have previously shown that, in addition to the epidermal growth factor precursor homology repeat-A of LDLR, at least three ligand-binding repeats (LRs) of LDLR are required for PCSK9-promoted LDLR degradation. However, how exactly the LRs contribute to PCSK9's action on the receptor is not completely understood. Here, we found that substitution of Asp at position 172 in the linker between the LR4 and LR5 of full-length LDLR with Asn (D172N) reduced PCSK9 binding at pH 7.4 (mimic cell surface), but not at pH 6.0 (mimic endosomal environment). On the other hand, mutation of Asp at position 203 in the LR5 of full-length LDLR to Asn (D203N) significantly reduced PCSK9 binding at both pH 7.4 and pH 6.0. D203N also significantly reduced the ability of LDLR to mediate cellular LDL uptake, whereas D172N had no detectable effect. These findings indicate that amino acid residues in the LRs of LDLR play an important role in PCSK9 binding to the receptor.

Asunto(s)

Proproteína Convertasa 9/metabolismo , Receptores de LDL/química , Receptores de LDL/metabolismo , Secuencias Repetitivas de Aminoácido , Células HEK293 , Humanos , Ligandos , Lipoproteínas LDL/metabolismo , Mutación , Unión Proteica , Receptores de LDL/genética

RESUMEN

OBJECTIVE: ATP-binding cassette transporter G1 (ABCG1) mediates cholesterol efflux to lipidated lipoproteins. Conflicting data about cellular localization of ABCG1 and its effect on cholesterol efflux have been reported. Here, we investigated the underlying mechanisms for these different observations. APPROACH AND RESULTS: Confocal microscopy and biotinylation were used to assess cell surface localization of ABCG1. We found that mouse ABCG1 (mABCG1) used in one previous study has a substitution of Leu to Pro at position 550 (mG1-L550P). When the corresponding Leu at position 562 in human ABCG1 (hABCG1) was mutated to Pro (hG1-L562P), the mutant hABCG1, like mG1-L550P, mainly resided intracellularly, whereas wild-type mABCG1 and hABCG1 were localized on the plasma membrane. However, replacement of this Leu with Pro had no significant effect on mABCG1- and hABCG1-mediated cholesterol efflux. CONCLUSIONS: Leu at position 550/562 in mABCG1/hABCG1 is critical for their plasma membrane localization but not for ABCG1-mediated cholesterol efflux. Our findings indicate that the substitution of Leu to Pro at position 550 in mABCG1 may contribute to the non-cell surface localization of mABCG1 observed in the previous study.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/metabolismo , Membrana Celular/metabolismo , Colesterol/metabolismo , Lipoproteínas/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Sustitución de Aminoácidos , Animales , Genotipo , Células HEK293 , Humanos , Leucina , Lipoproteínas/genética , Ratones , Microscopía Confocal , Mutación , Fenotipo , Transfección

RESUMEN

Currently, remote sensing technologies were widely employed in the dynamic monitoring of the land. This paper presented an algorithm named fuzzy nonlinear proximal support vector machine (FNPSVM) by basing on ETM(+) remote sensing image. This algorithm is applied to extract various types of lands of the city Da'an in northern China. Two multi-category strategies, namely "one-against-one" and "one-against-rest" for this algorithm were described in detail and then compared. A fuzzy membership function was presented to reduce the effects of noises or outliers on the data samples. The approaches of feature extraction, feature selection, and several key parameter settings were also given. Numerous experiments were carried out to evaluate its performances including various accuracies (overall accuracies and kappa coefficient), stability, training speed, and classification speed. The FNPSVM classifier was compared to the other three classifiers including the maximum likelihood classifier (MLC), back propagation neural network (BPN), and the proximal support vector machine (PSVM) under different training conditions. The impacts of the selection of training samples, testing samples and features on the four classifiers were also evaluated in these experiments.

Asunto(s)

Lógica Difusa , Dinámicas no Lineales , Tecnología de Sensores Remotos , Máquina de Vectores de Soporte , China , Geografía