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1.
BMC Urol ; 24(1): 78, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575966

RESUMEN

BACKGROUND: Few studies are focusing on the mechanism of erastin acts on prostate cancer (PCa) cells, and essential ferroptosis-related genes (FRGs) that can be PCa therapeutic targets are rarely known. METHODS: In this study, in vitro assays were performed and RNA-sequencing was used to measure the expression of differentially expressed genes (DEGs) in erastin-induced PCa cells. A series of bioinformatic analyses were applied to analyze the pathways and DEGs. RESULTS: Erastin inhibited the expression of SLC7A11 and cell survivability in LNCaP and PC3 cells. After treatment with erastin, the concentrations of malondialdehyde (MDA) and Fe2+ significantly increased, whereas the glutathione (GSH) and the oxidized glutathione (GSSG) significantly decreased in both cells. A total of 295 overlapping DEGs were identified under erastin exposure and significantly enriched in several pathways, including DNA replication and cell cycle. The percentage of LNCaP and PC3 cells in G1 phase was markedly increased in response to erastin treatment. For four hub FRGs, TMEFF2 was higher in PCa tissue and the expression levels of NRXN3, CLU, and UNC5B were lower in PCa tissue. The expression levels of SLC7A11 and cell survivability were inhibited after the knockdown of TMEFF2 in androgen-dependent cell lines (LNCaP and VCaP) but not in androgen-independent cell lines (PC3 and C4-2). The concentration of Fe2+ only significantly increased in TMEFF2 downregulated LNCaP and VCaP cells. CONCLUSION: TMEFF2 might be likely to develop into a potential ferroptosis target in PCa and this study extends our understanding of the molecular mechanism involved in erastin-affected PCa cells.


Asunto(s)
Ferroptosis , Piperazinas , Neoplasias de la Próstata , Masculino , Humanos , Andrógenos , Ferroptosis/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Próstata/metabolismo , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Receptores de Netrina
2.
Biochem Biophys Res Commun ; 606: 75-79, 2022 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-35339755

RESUMEN

Hydroxyacyl-CoA dehydrogenase (HADH) catalyzes the third reaction of mitochondrial ß-oxidation cascade, while the regulation of its expression and function remains to be elucidated. Using the quantitative translation initiation sequencing (QTI-seq), we have identified that murine Hadh mRNA has two alternative translation start codons. We demonstrated that translation from upstream start codon encodes the mitochondrial isoform of HADH, while translation from downstream start codon produces a short isoform (HADH-S) with predominant nuclear localization. Moreover, overexpression of HADH-S inhibits the proliferation of mouse embryonic fibroblasts. Overall, our results identify a novel isoform of HADH participating in cell proliferation.


Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas , Fibroblastos , 3-Hidroxiacil-CoA Deshidrogenasas/genética , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Animales , Proliferación Celular , Codón Iniciador , Fibroblastos/metabolismo , Ratones , Isoformas de Proteínas/genética
3.
Clin Exp Rheumatol ; 40(5): 1011-1018, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34251324

RESUMEN

OBJECTIVES: To identify potential lipid biomarkers by studying changes in the blood lipid profile of patients with systemic lupus erythematosus (SLE) using lipidomics. METHODS: Serum samples were collected from 115 SLE patients and 115 age- and sex-matched healthy controls (HCs). Lipid profiles were assessed using ultrahigh-performance liquid chromatography coupled with Q Exactive spectrometry, and possible lipid biomarkers were screened and evaluated by univariate and multivariate analyses. RESULTS: Metabolic phenotypes related to SLE disease activity index (SLEDAI) scores were detected in the serum of SLE patients, and these phenotypes indicated the activity of the disease. Alterations in energy metabolism, fatty acid metabolism and other pathways were observed in patients with SLE. Phosphatidylethanolamine (16:0/18:2), lysophosphatidylethanolamine (18:0), and acylcarnitine (11:0) can be used as biomarkers for the clinical diagnosis of SLE, and receiver operating characteristic (ROC) analysis indicated their effectiveness in diagnosing this disease. CONCLUSIONS: Our study identified serum biomarkers related to disease activity in patients with SLE, providing a basis for its clinical diagnosis.


Asunto(s)
Lipidómica , Lupus Eritematoso Sistémico , Biomarcadores , Humanos , Lípidos , Lupus Eritematoso Sistémico/diagnóstico , Curva ROC
4.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(5): 919-922, 2022 Oct.
Artículo en Zh | MEDLINE | ID: mdl-36325792

RESUMEN

Studies have demonstrated that the occurrence of a variety of arrhythmias presents an obvious circadian rhythm,which may be regulated by circadian rhythm genes.Circadian cycle and light stimulation can affect circadian rhythm genes and proteins,which constitute a transcription-translation loop that can regulate the ion channels in myocardial cell membrane through nervous-humoral regulation and changes in central clock-sub-clock gene expression,thereby modulating arrhythmia.This article reviews the molecular basis,mechanism,and performance of circadian rhythm in regulating arrhythmia.


Asunto(s)
Ritmo Circadiano , Miocitos Cardíacos , Humanos , Ritmo Circadiano/genética , Arritmias Cardíacas
5.
Rheumatology (Oxford) ; 60(3): 1252-1259, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-32911538

RESUMEN

OBJECTIVE: The relationship between serum lipid variations in SS and healthy controls was investigated to identify potential predictive lipid biomarkers. METHODS: Serum samples from 230 SS patients and 240 healthy controls were collected. The samples were analysed by ultrahigh-performance liquid chromatography coupled with Q Exactive™ spectrometry. Potential lipid biomarkers were screened through orthogonal projection to latent structures discriminant analysis and further evaluated by receiver operating characteristic analysis. RESULTS: A panel of three metabolites [phosphatidylcholine (18:0/22:5), triglyceride (16:0/18:0/18:1) and acylcarnitine (12:0)] was identified as a specific biomarker of SS. The receiver operating characteristic analysis showed that the panel had a sensitivity of 84.3% with a specificity of 74.8% in discriminating patients with SS from healthy controls. CONCLUSION: Our approach successfully identified serum biomarkers associated with SS patients. The potential lipid biomarkers indicated that SS metabolic disturbance might be associated with oxidized lipids, fatty acid oxidation and energy metabolism.


Asunto(s)
Lipidómica , Síndrome de Sjögren/sangre , Biomarcadores/sangre , Carnitina/análogos & derivados , Carnitina/sangre , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Análisis Discriminante , Femenino , Humanos , Masculino , Espectrometría de Masas , Fosfatidilcolinas/sangre , Sensibilidad y Especificidad , Triglicéridos/sangre
6.
Clin Exp Rheumatol ; 39 Suppl 133(6): 23-29, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34251320

RESUMEN

OBJECTIVES: At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and discover the disturbed metabolic pathways. METHODS: Recent advances in mass spectrometry have allowed the identification of hundreds of unique metabolic signatures and the exploration of altered metabolite profiles in disease. In this study, 505 candidates including healthy controls (HCs) and SS patients were recruited and the serum samples were collected. A non-targeted gas chromatography-mass spectrometry (GC-MS) serum metabolomics method was used to explore the changes in serum metabolites. RESULTS: We found SS patients and HCs can be distinguished by 21 significant metabolites. The levels of alanine, tryptophan, glycolic acid, pelargonic acid, cis-1-2-dihydro-1-2-naphthalenediol, diglycerol, capric acid, turanose, behenic acid, dehydroabietic acid, stearic acid, linoleic acid, heptadecanoic acid, valine, and lactic acid were increased in serum samples from SS patients, whereas levels of catechol, anabasine, 3-6-anhydro-D-galactose, beta-gentiobiose, 2-ketoisocaproic acid and ethanolamine were decreased. The significantly changed pathways included the following: Linoleic acid metabolism; unsaturated fatty acid biosynthesis; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; glycerolipid metabolism; selenocompound metabolism; galactose metabolism; alanine, aspartate and glutamate metabolism; glyoxylate and dicarboxylate metabolism; glycerophospholipid metabolism; and valine, leucine and isoleucine degradation. CONCLUSIONS: These findings enhance the informative capacity of biochemical analyses through the identification of serum biomarkers and the analysis of metabolic pathways and contribute to an improved understanding of the pathogenesis of SS.


Asunto(s)
Síndrome de Sjögren , Biomarcadores , Humanos , Metabolómica , Síndrome de Sjögren/diagnóstico
7.
J Proteome Res ; 19(2): 864-872, 2020 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-31917576

RESUMEN

Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory rheumatic disease that affects 0.2% of the population. Current diagnostic criteria for disease activity rely on subjective Bath Ankylosing Spondylitis Disease Activity Index scores. Here, we aimed to discover a panel of serum protein biomarkers. First, tandem mass tag (TMT)-based quantitative proteomics was applied to identify differential proteins between 15 pooled active AS and 60 pooled healthy subjects. Second, cohort 1 of 328 humans, including 138 active AS and 190 healthy subjects from two independent centers, was used for biomarker discovery and validation. Finally, biomarker panels were applied to differentiate among active AS, stable AS, and healthy subjects from cohort 2, which enrolled 28 patients with stable AS, 26 with active AS, and 28 healthy subjects. From the proteomics study, a total of 762 proteins were identified and 46 proteins were up-regulated and 59 proteins were down-regulated in active AS patients compared to those in healthy persons. Among them, C-reactive protein (CRP), complement factor H-related protein 3 (CFHR3), α-1-acid glycoprotein 2 (ORM2), serum amyloid A1 (SAA1), fibrinogen γ (FG-γ), and fibrinogen ß (FG-ß) were the most significantly up-regulated inflammation-related proteins and S100A8, fatty acid-binding protein 5 (FABP5), and thrombospondin 1 (THBS1) were the most significantly down-regulated inflammation-related proteins. From the cohort 1 study, the best panel for the diagnosis of active AS vs healthy subjects is the combination of CRP and SAA1. The area under the receiver operating characteristic (ROC) curve was nearly 0.900, the sensitivity was 0.970%, and the specificity was 0.805% at a 95% confidence interval from 0.811 to 0.977. Using 0.387 as the cutoff value, the predictive values reached 92.00% in the internal validation set (62 with active AS vs 114 healthy subjects) and 97.50% in the external validation phase (40 with active AS vs 40 healthy subjects). From the cohort 2 study, a panel of CRP and SAA1 can differentiate well among active AS, stable AS, and healthy subjects. For active AS vs stable AS, the area under the ROC curve was 0.951, the sensitivity was 96.43%, the specificity was 88.46% at a 95% confidence interval from 0.891 to 1, and the coincidence rate was 92.30%. For stable AS vs healthy humans, the area under the ROC curve was 0.908, the sensitivity was 89.29%, the specificity was 78.57% at a 95% confidence interval from 0.836 to 0.980, and the coincidence rate was 83.93%. For active AS vs healthy subjects, the predictive value was 94.44%. The results indicated that the CRP and SAA1 combination can potentially diagnose disease status, especially for active or stable AS, which will be conducive to treatment recommendation for patients with AS.


Asunto(s)
Espondilitis Anquilosante , Biomarcadores , Proteína C-Reactiva , Proteínas de Unión a Ácidos Grasos , Humanos , Proteómica , Curva ROC , Espondilitis Anquilosante/diagnóstico , Trombospondina 1
8.
J Cell Sci ; 129(16): 3104-14, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27358480

RESUMEN

Excitatory amino acid transporter type 3 (EAAT3, also known as SLC1A1) is a high-affinity, Na(+)-dependent glutamate carrier that localizes primarily within the cell and at the apical plasma membrane. Although previous studies have reported proteins and sequence regions involved in EAAT3 trafficking, the detailed molecular mechanism by which EAAT3 is distributed to the correct location still remains elusive. Here, we identify that the YVNGGF sequence in the C-terminus of EAAT3 is responsible for its intracellular localization and apical sorting in rat hepatoma cells CRL1601 and Madin-Darby canine kidney (MDCK) cells, respectively. We further demonstrate that Numb, a clathrin adaptor protein, directly binds the YVNGGF motif and regulates the localization of EAAT3. Mutation of Y503, N505 and F508 within the YVNGGF motif to alanine residues or silencing Numb by use of small interfering RNA (siRNA) results in the aberrant localization of EAAT3. Moreover, both Numb and the YVNGGF motif mediate EAAT3 endocytosis in CRL1601 cells. In summary, our study suggests that Numb is a pivotal adaptor protein that mediates the subcellular localization of EAAT3 through binding the YxNxxF (where x stands for any amino acid) motif.


Asunto(s)
Transportador 3 de Aminoácidos Excitadores/química , Transportador 3 de Aminoácidos Excitadores/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Secuencias de Aminoácidos , Animales , Perros , Endocitosis , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones Endogámicos BALB C , Mutación/genética , Unión Proteica , Transporte de Proteínas , Ratas , Relación Estructura-Actividad , Fracciones Subcelulares/metabolismo
9.
Nucleic Acids Res ; 42(16): 10720-30, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25159612

RESUMEN

Follistatin (FST) performs several vital functions in the cells, including protection from apoptosis during stress. The expression of FST is up-regulated in response to glucose deprivation by an unknown mechanism. We herein showed that the induction of FST by glucose deprivation was due to an increase in the half-life of its mRNA. We further identified an AU-rich element (ARE) in the 3'UTR of FST mRNA that mediated its decay. The expression of FST was elevated after knocking down AUF1 and reduced when AUF1 was further expressed. In vitro binding assays and RNA pull-down assays revealed that AUF1 interacted with FST mRNA directly via its ARE. During glucose deprivation, a majority of AUF1 shuttled from cytoplasm to nucleus, resulting in dissociation of AUF1 from FST mRNA and thus stabilization of FST mRNA. Finally, knockdown of AUF1 decreased whereas overexpression of AUF1 increased glucose deprivation-induced apoptosis. The apoptosis promoting effect of AUF1 was eliminated in FST expressing cells. Collectively, this study provided evidence that AUF1 is a negative regulator of FST expression and participates in the regulation of cell survival under glucose deprivation.


Asunto(s)
Apoptosis , Folistatina/genética , Glucosa/fisiología , Ribonucleoproteína Heterogénea-Nuclear Grupo D/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo , Regiones no Traducidas 3' , Proteínas Quinasas Activadas por AMP/metabolismo , Transporte Activo de Núcleo Celular , Núcleo Celular/metabolismo , Folistatina/metabolismo , Células HeLa , Ribonucleoproteína Nuclear Heterogénea D0 , Humanos
10.
Curr Mol Med ; 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38465431

RESUMEN

Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

11.
Medicine (Baltimore) ; 102(26): e34150, 2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37390293

RESUMEN

BACKGROUND: To explore the efficacy and safety of electroacupuncture (EA) for secondary insomnia through a meta-analysis and a systematic review. METHODS: The CNKI, Wanfang, VIP database, Web of Science, EMBASE, PubMed, and Cochrane Library were retrieved. The retrieval date was February 28, 2023. Two independent reviewers conducted literature screening, data extraction, and risk of bias (ROB) assessment. The revised Cochrane ROB tool was used to assess the ROB in included studies. Data analysis was performed using RevMan 5.4 software and Stata 15.0. RESULTS: Thirteen randomized controlled studies were included, involving 820 patients, including 414 patients in EA group and 406 patients in the control group. Compared with the control group, EA could improve secondary insomnia overall responses (relative risk = 3.90, 95% confidence interval [CI] [1.87, 8.13], P < .001), reduce Pittsburgh Sleep Quality Index score (mean difference [MD] = -2.26, 95% CI [-4.14, -0.37], P = .02), reduce Athens Insomnia Scale score (MD = -0.57, 95% CI [-2.70, 1.56], P = .60), prolonged total sleep time (MD = 2.63, 95% CI [-0.59, 5.86], P = .11), and not increase adverse events (relative risk = 0.50, 95% CI [0.18, 1.44], P = .20). CONCLUSION: EA may be a promising treatment for secondary sleep disorders; however, more high-quality studies are needed to confirm our findings.


Asunto(s)
Electroacupuntura , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Electroacupuntura/efectos adversos , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Grupos Control , Análisis de Datos , Bases de Datos Factuales
12.
Front Pediatr ; 11: 1154350, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37114002

RESUMEN

Objective: This study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia. Methods: A prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission. Results: The mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h (n = 87) and >72 h (n = 16) groups. Infants who received phototherapy for >72 h had significantly higher ETCOc (2.45 vs. 1.60, P = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value. Conclusion: ETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient.

13.
J Biol Chem ; 285(47): 36857-64, 2010 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-20843798

RESUMEN

Solid tumor development is frequently accompanied by energy-deficient conditions such as glucose deprivation and hypoxia. Follistatin (FST), a secretory protein originally identified from ovarian follicular fluid, has been suggested to be involved in tumor development. However, whether it plays a role in cancer cell survival under energy-deprived conditions remains elusive. In this study, we demonstrated that glucose deprivation markedly enhanced the expression and nucleolar localization of FST in HeLa cells. The nucleolar localization of FST relied on its nuclear localization signal (NLS) comprising the residues 64-87. Localization of FST to the nucleolus attenuated rRNA synthesis, a key process for cellular energy homeostasis and cell survival. Overexpression of FST delayed glucose deprivation-induced apoptosis, whereas down-regulation of FST exerted the opposite effect. These functions depended on the presence of an intact NLS because the NLS-deleted mutant of FST lost the rRNA inhibition effect and the cell protective effect. Altogether, we identified a novel nucleolar function of FST, which is of importance in the modulation of cancer cell survival in response to glucose deprivation.


Asunto(s)
Apoptosis , Nucléolo Celular/metabolismo , Folistatina/metabolismo , Glucosa/deficiencia , ARN Ribosómico/biosíntesis , Neoplasias del Cuello Uterino/patología , Northern Blotting , Western Blotting , Inmunoprecipitación de Cromatina , Regulación hacia Abajo , Femenino , Técnica del Anticuerpo Fluorescente , Folistatina/antagonistas & inhibidores , Folistatina/genética , Células HeLa , Humanos , Señales de Localización Nuclear , ARN Mensajero/genética , ARN Ribosómico/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias del Cuello Uterino/metabolismo
14.
Front Endocrinol (Lausanne) ; 12: 637384, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34054723

RESUMEN

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays critical roles in the physiological process of oocyte mature and IVF outcomes of patients with infertility. However, the regulation of BDNF expression in the microenvironment surrounding the oocyte is still unknown. We initially predicted some microRNA (miRNA) candidates targeting bdnf with a series of bioinformatics analysis tools to determine the underlying regulatory mechanisms of BDNF, particularly the effect of miRNAs on BDNF expression. Then, we assessed whether the expression of these 14 selected miRNAs was negatively associated with BDNF expression in follicular fluid (FF) samples obtained from mature (>18 mm) or immature (<15 mm) follicles. Finally, we used the candidate miRNAs, miR-103a-3p and miR-10a-5p, to further investigate the relationship between their expression in FF and the outcomes of infertile patients undergoing IVF-ET treatment. The results of the bioinformatics analysis revealed 14 miRNAs that might directly regulate BDNF expression and might have a close relationship with oocyte development. BDNF was expressed at significantly lower levels in FF from immature follicles than in FF from mature follicles, and only the expression of miR-103a-3p and miR-10a-5p was negatively correlated with BDNF expression in FF. Moreover, in another cohort of 106 infertile women undergoing IVF-ET treatment, miR-103a-3p or miR-10a-5p expression predicted the developmental status of the corresponding oocytes in which high expression of miR-103a-3p or miR-10a-5p resulted in a poor quality of embryo on days 3 and 5 during the IVF-ET treatment. In conclusion, our study is the first to show that miR-103a-3p or miR-10a-5p negatively affects the maturation of oocytes by regulating the expression of BDNF in human FF. Additionally, the expression levels of miR-103a-3p or miR-10a-5p in FF may predict the outcomes of IVF, which are helpful for improving embryo selection and consequently the IVF success rate in the clinic.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fertilización In Vitro/métodos , Líquido Folicular/metabolismo , Perfilación de la Expresión Génica , Infertilidad Femenina/metabolismo , MicroARNs/biosíntesis , Adulto , Biomarcadores/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Oocitos/metabolismo , Folículo Ovárico/metabolismo , Estudios Prospectivos , Resultado del Tratamiento
15.
Front Mol Neurosci ; 14: 778170, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34924954

RESUMEN

Abnormality of fear memory is one of the important pathogenic factors leading to post-traumatic stress disorder (PTSD), anxiety disorder, and other mental disorders. Clinically, although exposure therapy, which is based on the principle of fear memory extinction, has a certain effect on these diseases, it still relapses frequently in some cases. These troubles can be effectively solved by retrieving the memory in a certain time window before the extinction of fear memory. Therefore, it is generally believed that the extinction of fear memory is the result of forming new safe memory to competitively inhibit the original fear memory, while the retrieval-extinction operation is the updating or erasure of the original fear memory, thus, which has greater clinical therapeutic potential. However, what are the detailed molecular networks, specifically the circular RNAs (circRNAs), involved in fear memory updating, and the differences with fear extinction, are still unknown. In this study, we systematically observed the expression of mRNAs, microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circRNAs in the basolateral amygdala of mice after fear memory formation, extinction, and updating by whole-transcriptional sequencing, then a variety of inter-group comparison and bioinformatics analysis were used to find the differential expressed RNAs, enrich the function of them, and construct the molecular interaction networks. Moreover, competing endogenous RNA (ceRNA) molecular networks and transcriptional regulatory networks for the candidate circRNAs were constructed. Through these analyses, we found that about 10% of molecules were both involved in the fear memory extinction and formation, but the molecules and their signaling pathways were almost completely different between fear memory extinction and updating. This study describes a relatively detailed molecular network for fear memory updating, which might provide some novel directions for further mechanism research, and help to develop a specific physical method for fear memory intervention, based on the regulation of these key molecules.

16.
Front Cell Dev Biol ; 9: 672564, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34485274

RESUMEN

Hemophilia A (HA), a common bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII), has long been considered an attractive target for gene therapy studies. However, full-length F8 cDNA cannot be packaged efficiently by adeno-associated virus (AAV) vectors. As the second most prevalent mutation causing severe HA, F8 intron 1 inversion (Inv1) is caused by an intrachromosomal recombination, leaving the majority of F8 (exons 2-26) untranscribed. In theory, the truncated gene could be rescued by integrating a promoter and the coding sequence of exon 1. To test this strategy in vivo, we generated an HA mouse model by deleting the promoter region and exon 1 of F8. Donor DNA and CRISPR/SaCas9 were packaged into AAV vectors and injected into HA mice intravenously. After treatment, F8 expression was restored and activated partial thromboplastin time (aPTT) was shortened. We also compared two liver-specific promoters and two types of integrating donor vectors. When an active promoter was used, all of the treated mice survived the tail-clip challenge. This is the first report of an in vivo gene repair strategy with the potential to treat a recurrent mutation in HA patients.

17.
J Exp Clin Cancer Res ; 38(1): 217, 2019 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-31122284

RESUMEN

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Diterpenos/administración & dosificación , Fenantrenos/administración & dosificación , Factor de Transcripción TFIIIB/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Diterpenos/farmacología , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Ratones , Fenantrenos/farmacología , Regiones Promotoras Genéticas , ARN Ribosómico 5S , ARN de Transferencia/genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Oncol Rep ; 38(2): 917-925, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28627627

RESUMEN

Stromal antigen 2 (STAG2) is a subunit of the cohesion complex that plays an important role in the normal segregation of sister chromatids during mitosis or meiosis. However, the effect of STAG2 on the bladder cancer cell proliferation, migration, and invasion has not yet been fully clarified. In this study, we aimed to characterize STAG2 expression and functional significance in BC and adjacent normal tissue. Notably, STAG2 expression was markedly lower in BC cells and tumor tissues than their normal counterparts at the gene and protein levels. Moreover, clinicopathological analysis showed that the low STAG2 expression is associated with TNM stage. Functional analysis demonstrated that STAG2 overexpression attenuated cell proliferation via G1-phase arrest, invasion, and migration, and promoted apoptosis in BC cell lines, while the opposite was observed with STAG2 knockdown cells. Furthermore, STAG2 overexpression upregulated E-cadherin, caspase-3, and caspase-7 and downregulated vimentin, matrix metalloproteinase (MMP)2, and MMP9. Collectively, these data suggest that STAG2 acts as a tumor suppressor gene in bladder cancer and may be a potential therapeutic target in BC.


Asunto(s)
Antígenos Nucleares/genética , Biomarcadores de Tumor/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Vejiga Urinaria/genética , Anciano , Cadherinas/genética , Caspasa 3/genética , Proteínas de Ciclo Celular , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Invasividad Neoplásica/genética , Estadificación de Neoplasias , Neoplasias de la Vejiga Urinaria/patología
19.
PLoS One ; 6(12): e28797, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22194915

RESUMEN

Angiogenin (ANG) acts on both vascular endothelial cells and cancer cells, but the underlying mechanism remains elusive. In this study, we carried out a co-immunoprecipitation assay in HeLa cells and identified 14 potential ANG-interacting proteins. Among these proteins, ß-actin, α-actinin 4, and non-muscle myosin heavy chain 9 are stress fiber components and involved in cytoskeleton organization and movement, which prompted us to investigate the mechanism of action of ANG in cell migration. Upon confirmation of the interactions between ANG and the three proteins, further studies revealed that ANG co-localized with ß-actin and α-actinin 4 at the leading edge of migrating cells. Down-regulation of ANG resulted in fewer but thicker stress fibers with less dynamics, which was associated with the enlargements of focal adhesions. The focal adhesion kinase activity and cell migration capacity were significantly decreased in ANG-deficient cells. Taken together, our data demonstrated that the existence of ANG in the cytoplasm optimizes stress fiber assembly and focal adhesion formation to accommodate cell migration. The finding that ANG promoted cancer cell migration might provide new clues for tumor metastasis research.


Asunto(s)
Movimiento Celular , Adhesiones Focales/metabolismo , Ribonucleasa Pancreática/metabolismo , Fibras de Estrés/metabolismo , Citoesqueleto/metabolismo , Regulación hacia Abajo , Activación Enzimática , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Células HeLa , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Espectrometría de Masas , Anotación de Secuencia Molecular , Fosforilación , Unión Proteica , Seudópodos/metabolismo , Ribonucleasa Pancreática/deficiencia
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