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1.
Mol Immunol ; 173: 71-79, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39067087

RESUMEN

BACKGROUND: The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). METHODS: Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. RESULTS: FA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. CONCLUSIONS: The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.

2.
Immunol Res ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39034374

RESUMEN

BACKGROUND: The cause of food allergy (FA) is still a mystery. Telomerases are involved in the regulation of immune responses. This study aims to gain an understanding of the contribution of telomerase reverse transcriptase (TERT) to the pathogenesis of FA. METHODS: A murine FA model was established with ovalbumin as the specific antigen. The role of TERT in regulating dendritic cell (DC) immune tolerogenic functions was evaluated in this murine model. RESULTS: We observed that the Tert promoter was at demethylation status and the Tert expression was elevated in DCs of FA mice. The Tert expression in DCs had a positive correlation with the FA response. TERT prevented the induction of Il10 expression in DCs. The immune tolerogenic functions of DCs were diminished by TERT. The immune tolerogenic functions of DC were restored by CpG by boosting the Tert promoter methylation. Administration of CpG promoted the therapeutic effects of allergen specific immunotherapy in FA mice. CONCLUSIONS: Low levels of Il10 expression and high levels of Tert expression were observed in intestinal DCs of FA mice. CpG exposure restored the expression of Il10 and increased the therapeutic benefits of allergen-specific immunotherapy.

3.
Alzheimers Dement (Amst) ; 16(2): e12612, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38912304

RESUMEN

INTRODUCTION: Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies. METHODS: We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD. RESULTS: Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts. DISCUSSION: This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD. Highlights: Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.

4.
Immunol Lett ; 267: 106867, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38754636

RESUMEN

Chronic inflammation is the pathological feature of inflammatory bowel diseases (IBD), but its etiology is unknown. Macrophages are one of the major immune cell fractions in the colon. The objectives of this study are to characterize the immune regulatory functions of macrophages in the colon of patients with ulcerative colitis (UC). UC patients (n = 30) were recruited into this study. Colon lavage fluid (CLF) was collected. Macrophages are isolated from the cellular components of CLF. The immune suppressive functions of macrophages were assessed using immunological approaches. We observed that macrophages occupied about half of the proportions of the cellular components in CLF. Lower amounts of IL10 mRNA and proteins were detected in macrophages of the UC group than the normal control (NC) group. The expression of IL10 in CLF macrophages was positively correlated with the UC-associated cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, IFN-γ, eosinophil-derived mediators, in CLF. The immune suppressive functions of CLF macrophages in UC patients were impaired. The inducibility of IL10 expression of UC M0 cells was defective as compared with NC M0 cells. Exposure to CpG restored the inducibility of IL10 expression in UC M0 cells, and gain the potential to acquire the immune suppressive functions. To sum up, the immune suppressive functions of UC macrophages are impaired. The inducibility of IL10 expression of M0 cells is impaired, which can be restored by the treatment with CpG.


Asunto(s)
Colitis Ulcerosa , Citocinas , Interleucina-10 , Macrófagos , Humanos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Masculino , Adulto , Interleucina-10/metabolismo , Persona de Mediana Edad , Citocinas/metabolismo , Células Cultivadas , Colon/inmunología , Colon/patología , Colon/metabolismo
5.
Cell Metab ; 36(7): 1598-1618.e11, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38772364

RESUMEN

Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed ß-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum ß-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented ß-endorphin as a potential chronotherapeutic strategy for SD-related cancer.


Asunto(s)
Carcinogénesis , Ritmo Circadiano , Coenzima A Ligasas , Ácidos Grasos , Oxidación-Reducción , Ácidos Grasos/metabolismo , Humanos , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Ratones , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Masculino , Ratones Endogámicos C57BL , Proteínas CLOCK/metabolismo , Proteínas CLOCK/genética , Privación de Sueño/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética
6.
Crit Rev Oncol Hematol ; 194: 104248, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38145832

RESUMEN

Bone marrow metastasis (BMM) of solid tumors refers to a group of diseases that originate from non-hematopoietic malignant tumor cells invading the bone marrow (BM) through complex metastatic patterns. If BMM identification is delayed, the disease will rapidly develop into disseminated carcinogenesis of the BM, which manifests as a series of hematological disorders and microangiopathic hemolytic anemia, leading to serious life-threatening conditions. Although the study of solid tumor BMM is receiving increasing attention, study remains limited, and most descriptions are derived from case reports. Currently, clinicians have insufficient understanding of BMM, and BMM occurrence is often not recognized early or treated effectively, resulting in high mortality rates. In this article, we review the epidemiology, molecular mechanisms, clinical diagnosis, treatment, and prognosis of solid tumor BMM.


Asunto(s)
Neoplasias de la Médula Ósea , Neoplasias Óseas , Humanos , Médula Ósea/patología , Pronóstico , Neoplasias de la Médula Ósea/diagnóstico , Neoplasias de la Médula Ósea/terapia , Neoplasias Óseas/patología
7.
J Org Chem ; 89(1): 565-575, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38115769

RESUMEN

An array of biologically interesting tri/difluoromethylated chromones and their heteroatom analogues were conveniently synthesized from the reaction of chromones and their heteroatom analogues with CF3SO2Na or HCF2SO2Na in the presence of tert-butyl hydroperoxide under mild conditions. A mechanistic pathway involving the generation of the electrophilic tri/difluoromethyl radical, followed with the radical substitution of chromones and their heteroatom analogues, was postulated.

8.
Prog Neurobiol ; 231: 102534, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37783430

RESUMEN

N-Methyl-D-aspartate glutamate receptors (NMDARs) are involved in multiple physiopathological processes, including synaptic plasticity, neuronal network activities, excitotoxic events, and cognitive impairment. Abnormalities in NMDARs can initiate a cascade of pathological events, notably in Alzheimer's disease (AD) and even other neuropsychiatric disorders. The subunit composition of NMDARs is plastic, giving rise to a diverse array of receptor subtypes. While they are primarily found in neurons, NMDAR complexes, comprising both traditional and atypical subunits, are also present in non-neuronal cells, influencing the functions of various peripheral tissues. Furthermore, protein-protein interactions within NMDAR complexes has been linked with Aß accumulation, tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, all of which potentially served as an obligatory relay of cognitive impairment. Nonetheless, the precise mechanistic link remains to be fully elucidated. In this review, we provided an in-depth analysis of the structure and function of NMDAR, investigated their interactions with various pathogenic proteins, discussed the current landscape of NMDAR-based therapeutics, and highlighted the remaining challenges during drug development.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , N-Metilaspartato/uso terapéutico , Ácido Glutámico , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
9.
Sci China Life Sci ; 66(12): 2711-2754, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37480469

RESUMEN

Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease (AD). AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD. Each transgenic model has its unique behavioral and pathological features. This review summarizes the research progress of transgenic mouse models, and their progress in the unique mechanism of amyloid-ß oligomers, including the first transgenic mouse model built in China based on a single gene mutation (PSEN1 V97L) found in Chinese familial AD. We further summarized the preclinical findings of drugs using the models, and their future application in exploring the upstream mechanisms and multitarget drug development in AD.


Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Ratones Transgénicos , Precursor de Proteína beta-Amiloide/genética , Modelos Animales de Enfermedad , Pensamiento , Péptidos beta-Amiloides/genética
10.
J Org Chem ; 88(15): 11083-11095, 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37450647

RESUMEN

A metal-free synthesis of a series of fluoroalkyl-containing oxazoles from ß-monosubstituted enamines was developed. This fluoroacyloxylation/cyclization cascade process was mediated by fluoroalkyl-containing hypervalent iodine(III) species formed in situ from the reaction of phenyliodine(III) diacetate (PIDA) and RCF2CO2H (R = H, Cl, Br, F, CF3, CH3, Ph, SAr, OAr).

11.
Heliyon ; 9(7): e17386, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37415951

RESUMEN

The contribution of oncogenes to tumor-associated RNA splicing and the relevant molecular mechanisms therein require further elaboration. Here, we show that oncogenic Aurora kinase A (AURKA) promotes breast cancer-related RNA aberrant splicing in a context-dependent manner. AURKA regulated pan-breast cancer-associated RNA splicing events including GOLGA4, RBM4 and UBQLN1. Aberrant splicing of GOLGA4 and RBM4 was closely related to breast cancer development. Mechanistically, AURKA interacted with the splicing factor YBX1 and promoted AURKA-YBX1 complex-mediated GOLGA4 exon inclusion. AURKA binding to the splicing factor hnRNPK promoted AURKA-hnRNPK complex-mediated RBM4 exon skipping. Analysis of clinical data identified an association between the AURKA-YBX1/hnRNPK complex and poor prognosis in breast cancer. Blocking AURKA nuclear translocation with small molecule drugs partially reversed the oncogenic splicing of RBM4 and GOLGA4 in breast cancer cells. In summary, oncogenic AURKA executes its function on modulating breast cancer-related RNA splicing, and nuclear AURKA is distinguished as a hopeful target in the case of treating breast cancer.

12.
Sci Signal ; 16(791): eabm9454, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37368951

RESUMEN

Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.


Asunto(s)
Hipersensibilidad , Interleucina-2 , Humanos , Interleucina-2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Th2 , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Células Dendríticas/metabolismo , Material Particulado/metabolismo , Proteína 1 de Unión a la X-Box/genética
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(5): 391-396, 2023 May.
Artículo en Chino | MEDLINE | ID: mdl-37248832

RESUMEN

Objective To investigate the preventive therapeutic effect and possible mechanism of single chain variable fragments chimeric protein (SD) of ovalbumin epitopes internalizing receptor DEC-205 antibody on food allergy in mice. Methods Mice were randomly divided to five groups (control, PBS, scFv DEC 100 µg, SD 50 µg, SD 100 µg) and treated for 24 hours before OVA administration. After challenge, the serum level of OVA-specific IgE, IgG1, IgG2a and IL-4 were detected by ELISA. Infiltration of eosinophils and mast cells in the jejunum was observed by HE staining and toluidine blue staining respectively. The bone marrow of tibia and femur was isolated and cultured to obtain immature dendritic cells(BMDCs), which were further treated with LPS (10 ng/mL), TSLP (50 ng/mL), scFv DEC protein (1000 ng/mL) and SD protein (10,100,1000)ng/mL for 24 hours, and the IL-10 level of supernatant was assayed by ELISA. Results Compared with PBS group, the number of SD-treated mice with diarrhea was markedly reduced. The difference in rectal temperature and the levels of serum OVA-specific IgE, IgG1, IgG2a and IL-4 decreased significantly after prophylactic administration of SD; The number of eosinophils and mast cells in jejunum also decreased significantly while the IL-10 level in the supernatant of BMDCs increased significantly after SD intervention. Conclusion SD mitigates experimental FA response by fosters the immune tolerance property of dendritic cells.


Asunto(s)
Hipersensibilidad a los Alimentos , Anticuerpos de Cadena Única , Ratones , Animales , Ovalbúmina , Interleucina-10 , Anticuerpos de Cadena Única/genética , Inmunoglobulina E , Epítopos/uso terapéutico , Interleucina-4 , Hipersensibilidad a los Alimentos/prevención & control , Inmunoglobulina G , Proteínas Recombinantes de Fusión/genética , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad
14.
Neuropeptides ; 100: 102344, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37148733

RESUMEN

Arginine vasopressin (AVP) plays a hypothermic regulatory role in thermoregulation and is an important endogenous mediator in this mechanism. In the preoptic area (POA), AVP increases the spontaneous firing and thermosensitivity of warm-sensitive neurons and decreases those of cold-sensitive and temperature-insensitive neurons. Because POA neurons play a crucial role in precise thermoregulatory responses, these findings indicate that there is an association between the hypothermia and changes in the firing activity of AVP-induced POA neurons. However, the electrophysiological mechanisms by which AVP controls this firing activity remain unclear. Therefore, in the present study, using in vitro hypothalamic brain slices and whole-cell recordings, we elucidated the membrane potential responses of temperature-sensitive and -insensitive POA neurons to identify the applications of AVP or V1a vasopressin receptor antagonists. By monitoring changes in the resting potential and membrane potential thermosensitivity of the neurons before and during experimental perfusion, we observed that AVP increased the changes in the resting potential of 50% of temperature-insensitive neurons but reduced them in others. These changes are because AVP enhances the membrane potential thermosensitivity of nearly 50% of the temperature-insensitive neurons. On the other hand, AVP changes both the resting potential and membrane potential thermosensitivity of temperature-sensitive neurons, with no differences between the warm- and cold-sensitive neurons. Before and during AVP or V1a vasopressin receptor antagonist perfusion, no correlation was observed between changes in the thermosensitivity and membrane potential of all neurons. Furthermore, no correlation was observed between the thermosensitivity and membrane potential thermosensitivity of the neurons during experimental perfusion. In the present study, we found that AVP induction did not result in any changes in resting potential, which is unique to temperature-sensitive neurons. The study results suggest that AVP-induced changes in the firing activity and firing rate thermosensitivity of POA neurons are not controlled by resting potentials.


Asunto(s)
Arginina Vasopresina , Área Preóptica , Ratas , Animales , Potenciales de la Membrana , Temperatura , Arginina Vasopresina/farmacología , Ratas Sprague-Dawley , Neuronas
15.
iScience ; 26(4): 106498, 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37091242

RESUMEN

This study aims to characterize the impaired immune regulatory function of Mφ obtained from UC patient colon lavage fluid (CLF). Mφs were the largest proportion (21.3 4.0%) of the CLF-derived cellular components. Less abundant and weaker immune suppressive function were observed in M2 Mφs (M2 cells) of the ulcerative colitis (UC) group. High levels of endoplasmic reticulum (ER) stress associated molecules were detected in UC M2 cells. The spliced X box binding protein-1 (XBP1) gene was negatively correlated with programmed death ligand-1 (PD-L1) in UC M2 cells. XBP1 promoted the expression of ring-finger protein 20 (Rnf20) in M2 cells. Rnf20 reduced PD-L1 abundance in UC M2 cells and impaired the immune suppressive ability. Inhibition of Rnf20 restored the immune regulating capacity of M2 cells and suppressed experimental colitis.

16.
Sci Rep ; 13(1): 3699, 2023 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-36878963

RESUMEN

Object detection has been one of the critical technologies in autonomous driving. To improve the detection precision, a novel optimization algorithm is presented to enhance the performance of the YOLOv5 model. First, by improving the hunting behavior of the grey wolf algorithm(GWO) and incorporating it into the whale optimization algorithm(WOA), a modified whale optimization algorithm(MWOA) is proposed. The MWOA leverages the population's concentration ratio to calculate [Formula: see text] for selecting the hunting branch of GWO or WOA. Tested by six benchmark functions, MWOA is proven to possess better global search ability and stability. Second, the C3 module in YOLOv5 is substituted by G-C3, and an extra detection head is added, thus a highly optimizable detection G-YOLO network is constructed. Based on the self-built dataset, 12 initial hyperparameters in the G-YOLO model are optimized by MWOA using a score fitness function of compound indicators, thus the final hyperparameters are optimized and the whale optimization G-YOLO (WOG-YOLO) model is obtained. In comparison with the YOLOv5s model, the overall mAP increases by 1.7[Formula: see text], the mAP of pedestrians increases by 2.6[Formula: see text] and the mAP of cyclists increases by 2.3[Formula: see text].

18.
CNS Neurosci Ther ; 29(7): 1805-1816, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36852442

RESUMEN

AIMS: This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. METHODS: Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. RESULTS: Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. CONCLUSIONS: Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.


Asunto(s)
Enfermedad de Alzheimer , Mitocondrias , Fármacos Neuroprotectores , Animales , Ratones , Péptidos beta-Amiloides/metabolismo , Calcio , Modelos Animales de Enfermedad , Ratones Transgénicos , Mitocondrias/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Regulación hacia Arriba , Humanos
19.
Cancer Sci ; 114(6): 2277-2292, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36786527

RESUMEN

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.


Asunto(s)
Neoplasias Mamarias Animales , Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Mamarias Animales/genética , Complejo Mediador/genética , Complejo Mediador/metabolismo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética
20.
J Alzheimers Dis ; 91(2): 877-893, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36502323

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. OBJECTIVE: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. METHODS: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. RESULTS: We found that DAPK1 was activated after amyloid-ß oligomers (AßOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AßOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. CONCLUSION: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD.


Asunto(s)
Enfermedad de Alzheimer , Neuroblastoma , Anciano , Animales , Humanos , Ratones , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Calcio/metabolismo , Proteínas Quinasas Asociadas a Muerte Celular/genética , Ratones Transgénicos , Receptores de N-Metil-D-Aspartato/metabolismo
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