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1.
Phytomedicine ; 129: 155574, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38643715

RESUMEN

BACKGROUND: Appropriate conditions for storage of Artemisia argyi leaves reduce irritation during treatment and increase the active ingredient content. Naturally aged A. argyi leaves (≥1 year) are optimal for moxibustion; however, this process is time-consuming and costly. A comprehensive understanding of the conditions for artificial aging of A. argyi leaves and the mechanism of quality-marker conversion are required to guarantee A. argyi quality and moxibustion efficacy. OBJECTIVE: To identify the optimal conditions for artificial aging of A. argyi leaves and clarify the mechanism of quality-marker conversion. METHOD: Gas chromatography (GC), high-performance liquid chromatography (HPLC), colorimeter (CD), and near-infrared spectroscopy (NIRS) were used to determine the chemical composition of A. argyi leaves before and after artificial and natural (1 year) aging and to determine the optimal artificial aging conditions. The effects of both artificially and naturally aged A. argyi leaves were then evaluated in a mouse model of ulcerative colitis (UC). The main chemical components of aged A. argyi leaves were then analyzed to determine quality-markers and the transformation mechanism. RESULTS: Comprehensive analysis of volatile and non-volatile components, color values, and characteristic near-infrared spectra revealed that the quality of artificially aged A. argyi leaves was similar to that of naturally aged A. argyi leaves. In the mouse model, artificially and naturally aged A. argyi leaves not only improved the symptoms of UC with the same therapeutic effects, but also safeguarded the barrier of the colonic mucosa and prevented the release of colitis-related substances. In addition, the content of caffeic acid converted from L-phenylalanine in A. argyi leaves increased during the aging process. CONCLUSION: Conditions for artificial aging of A. argyi leaves were identified for the first time, and the equivalent efficacy of artificially aged A. argyi leaves and naturally aged A. argyi leaves for improving UC was confirmed. This method for artificial aging of A. argyi leaves not only reduces the time and cost associated with this process, but also provides technical support to ensure the quality and stability of artificially aged A. argyi leaves. In addition, caffeic acid was identified as a potential quality-marker for establishing standards and specifications for aging A. argyi leaves for the first time, and its possible transformation mechanism was preliminarily elucidated.


Asunto(s)
Artemisia , Hojas de la Planta , Artemisia/química , Hojas de la Planta/química , Animales , Masculino , Ratones , Moxibustión/métodos , Cromatografía Líquida de Alta Presión/métodos , Modelos Animales de Enfermedad , Espectroscopía Infrarroja Corta/métodos
2.
Nat Commun ; 14(1): 7526, 2023 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-37980347

RESUMEN

Glioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal and tumorigenicity through control of rRNA 2'-O-methylation. INHEG induces the interaction between SUMO2 E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2'-O-methylation, thereby increasing the expression of oncogenic proteins including EGFR, IGF1R, CDK6 and PDGFRB in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs, supporting an axis for potential therapeutic targeting of gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Metilación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Ribonucleoproteínas Nucleolares Pequeñas/metabolismo , Células Madre Neoplásicas/metabolismo , Glioma/genética , Glioma/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Línea Celular Tumoral
3.
J Agric Food Chem ; 2023 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-37861444

RESUMEN

Plant-derived polysaccharides, such as Atractylodes lancea rhizome polysaccharide (ALP), are good immune regulators. However, the immune regulatory mechanism of the ALP is unknown. This study aimed to evaluate the effects of ALP on the intestinal mucosal barrier and intestinal mucosal immunity of immunosuppressed mice. We also compared the activity of raw Atractylodes lancea rhizome polysaccharide (SALP) with wheat bran processed bran-fried Atractylodes lancea rhizome polysaccharide (FALP; both at 1.2 g/kg/d for mice). Our results showed that ALP effectively increased the immune organ index and blood cell count, stimulated the secretion of cytokines, and promoted the expression of occludin and zonula occludens-1 (ZO-1). ALP also promoted the expression of T cells and the secretion of sIgA. Furthermore, ALP alleviated the gut microbiota disorder in Cy-treated mice and increased the relative abundances of Lactobacillus and Faecalibaculum. ALP reversed the decrease in the level of SCFAs and promoted the expression of G protein-coupled receptor 43 (GPR43). To our knowledge, this study was the first to explore how the ALP protects the intestinal mucosal barrier and enhances intestinal mucosal immunity by alleviating the gut microbiota imbalance and metabolic disorders of SCFAs. FALP was more therapeutic than SALP, suggesting that FALP could be developed as a promising functional food component.

4.
J Ethnopharmacol ; 303: 115945, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36435407

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Radix Praeparata (Zhiheshouwu) has been a Wudang Taoist medicine for tonifying the liver and kidney, resolving turbidity and reducing lipid. Emodin is one of the active anthraquinones in Zhiheshouwu. Our previous studies showed that emodin (EM) and the other anthraquinones in Zhiheshouwu extract (HSWE) exerted similar inhibitory effects on liver cancer cells in vitro. However, it is still unknown if the other anthraquinones enhance pharmacokinetics (PK) of EM in HSWE in vivo. AIM OF THE STUDY: In this study, we compared the PK characteristics of EM alone with that in Zhiheshouwu aiming to explore which anthraquinones in HSWE contribute to the changed PK of EM in rats. MATERIALS AND METHODS: Quality control of HSWE was determined using high performance liquid chromatography (HPLC). The ratios of emodin to other anthraquinones, physcion (PH), chrysophanol (CH), rhein (RH), aloe-emodin (AE), emodin-8-O-ß-D-glycoside (EMG), physcion-1-O-ß-D-glycoside (PHG) and chrysophanol-8-O-ß-D-glycoside (CHG) in HSWE were determined and analyzed using UPLC combined with tandem mass spectrometry (UPLC/MS). The PK parameters and intestinal tissue concentration of EM alone, EM in HSWE, or with other anthraquinones in SD rats were analyzed using UPLC/MS. RESULTS: The quality of the Zhiheshouwu samples met the quality standard of the Chinese Pharmacopoeia (Version 2020). The PK results showed that compared with EM alone, Cmax (239.90 ± 146.71 vs. 898.46 ± 291.62, P < 0.001), Tmax (0.26 ± 0.15 vs. 12.55 ± 1.33, P < 0.001), AUC0-t (1575.09 ± 570.46 vs. 12154.96 ± 5394.25, P < 0.001), and AUC0-∞ (4742.51 ± 1837.62 vs. 37131.34 ± 21647.39, P < 0.001) of EM in HSWE were decreased due to PH and EMG, while the values of Vd (380.75 ± 217.74 vs. 11.75 ± 7.35, P < 0.001), T1/2 (10.81 ± 1.99 vs. 6.65 ± 2.76, P < 0.05) and CL (19.30 ± 7.82 vs. 2.78 ± 1.88, P < 0.001) of EM in HSWE were increased due to PH and AE. In addition, the intestinal tissue concentration of emodin in HSWE was decreased compared with that of EM alone in 20 and 780 min (25.37 ± 5.98 vs. 43.29 ± 4.16 and 26.72 ± 4.03 vs. 43.40 ± 14.19, respectively. P < 0.05) dominantly due to RH and PH. CONCLUSION: In conclusion, compared with treatment of EM alone, the AUC0-t value of EM in HSWE was decreased with different ways in rats. PH shortened Tmax, and increased Vd and CL. While AE prolonged T1/2 of EM. This indicated that the other anthraquinones in HSWE changed the PK of EM in rats and participated in the complex effects of EM on liver cancer. Besides the other anthraquinones, other components (e.g., 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside) in Zhiheshouwu may contribute in the pharmacokinetic and pharmacodynamic interactions with EM for anti-liver cancer.


Asunto(s)
Emodina , Polygonum , Ratas , Animales , Emodina/farmacocinética , Polygonum/química , Ratas Sprague-Dawley , Antraquinonas , Glicósidos , Cromatografía Líquida de Alta Presión
5.
Int J Mol Sci ; 23(24)2022 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-36555773

RESUMEN

Acute lung injury (ALI) is a syndrome caused by an excessive inflammatory response characterized by intractable hypoxemia both inside and outside the lung, for which effective therapeutic drugs are lacking. Atractylodis rhizoma, a traditional Chinese medicine, has excellent anti-inflammatory and antiviral properties in addition to protecting the integrity of the cellular barrier. However, few studies of Atractylodis rhizoma for the treatment of ALI have been published, and its mechanism of action remains unclear. In the present study, the chemical composition of the ethanolic extract of Atractylodis rhizoma (EEAR) was initially clarified by high performance liquid chromatography (HPLC), after which it was studied in vivo using a lipopolysaccharide (LPS)-induced ALI rat model. Treatment with EEAR significantly reduced the lung wet/dry (W/D) ratio, neutrophil infiltration, and malondialdehyde (MDA) and myeloperoxidase (MPO) formation, and enhanced superoxide dismutase (SOD) and glutathione (GSH) depletion in rats with ALI, thereby improving lung barrier function and effectively reducing lung injury. In addition, EEAR significantly reduced histopathological changes, decreased the expression of inflammatory factors (such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), inducible nitric oxide synthase (INOS), and cyclooxygenase-2 (COX-2)), and inhibited the activation of the NF-κB signaling pathway, thus reducing inflammation. In addition, EEAR was found to also reduce oxidative stress in ALI by upregulating the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NADPH quinone acceptor oxidoreductase 1 (NQO-1). EEAR also reduced LPS-induced inflammatory factor expression in THP-1 cells in vitro by inhibition of the NF-κB signaling pathway, and reduced damage from lipopolysaccharide (LPS)-induced oxidative stress in THP-1 cells by promoting the expression of Nrf2 and its downstream targets HO-1 and NQO-1, the molecular mechanism of which was consistent with in vivo observations. Therefore, we conclude that EEAR attenuates oxidative stress and inflammatory responses via TLR4/NF-κB and Keap1/Nrf2 signaling pathways to alleviate LPS-induced ALI, suggesting that Atractylodis rhizoma is a potential drug candidate for the treatment of ALI.


Asunto(s)
Lesión Pulmonar Aguda , FN-kappa B , Receptor Toll-Like 4 , Animales , Ratas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Glutatión/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/patología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Extractos Vegetales/farmacología , Atractylodes/química
6.
Science ; 378(6623): 983-989, 2022 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-36454826

RESUMEN

Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage, a process that normally safeguards cell identity but can also provoke neurotoxicity after anticancer treatments.


Asunto(s)
Roturas del ADN de Cadena Simple , Desmetilación del ADN , Reparación del ADN , Elementos de Facilitación Genéticos , Células Madre Pluripotentes Inducidas , Neuronas , Timina ADN Glicosilasa , Diferenciación Celular , Neuronas/enzimología , 5-Metilcitosina/metabolismo , Humanos , Transdiferenciación Celular
7.
Mol Cell ; 82(21): 4018-4032.e9, 2022 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-36332605

RESUMEN

Kinetochore assembly on centromeres is central for chromosome segregation, and defects in this process cause mitotic errors and aneuploidy. Besides the well-established protein network, emerging evidence suggests the involvement of regulatory RNA in kinetochore assembly; however, it has remained elusive about the identity of such RNA, let alone its mechanism of action in this critical process. Here, we report CCTT, a previously uncharacterized long non-coding RNA (lncRNA) transcribed from the arm of human chromosome 17, which plays a vital role in kinetochore assembly. We show that CCTT highly localizes to all centromeres via the formation of RNA-DNA triplex and specifically interacts with CENP-C to help engage this blueprint protein in centromeres, and consequently, CCTT loss triggers extensive mitotic errors and aneuploidy. These findings uncover a non-centromere-derived lncRNA that recruits CENP-C to centromeres and shed critical lights on the function of centromeric DNA sequences as anchor points for kinetochore assembly.


Asunto(s)
ARN Largo no Codificante , Humanos , Aneuploidia , Proteína A Centromérica/metabolismo , ADN , Cinetocoros/metabolismo , ARN Largo no Codificante/genética , Centrómero
8.
Anal Chem ; 94(28): 10118-10126, 2022 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-35729862

RESUMEN

The abnormal activation of the epidermal growth factor receptor (EGFR) is strongly associated with cancer invasion and metastasis. Tools and methods are required to study and visualize EGFR activation under (patho)physiological conditions. Here, we report the development of a two-step photoaffinity probe (HX101) by incorporation of a diazirine as a photoreactive group and an alkyne as a ligation handle to quantitively study EGFR kinase activity in native cellular contexts and human tissue slices. HX101 is a multifunctional probe based on the pharmacophore of the EGFR tyrosine kinase inhibitor (EGFR-TKI) and can covalently target the EGFR upon photoactivation. The incorporated alkyne serves as a versatile ligation handle and enables HX101 to introduce distinct reporter groups (e.g., fluorophore and biotin) via click chemistry. With variable reporter tags, HX101 enables visualization and target engagement studies of the active EGFR in a panel of cancer cells using flow cytometry, confocal microscopy, and mass spectrometry. Furthermore, as a proof of concept study, we applied HX101 in stochastic optical reconstruction microscopy super-resolution imaging to study EGFR activation in live cells. Importantly, HX101 was also applied to visualize EGFR mutant activity in tumor tissues from lung cancer patients for prediction of EGFR-TKI sensitivity. Altogether, our results demonstrate the wide application of a selective photoaffinity probe in multi-modal assessment/visualization of EGFR activity in both live cells and tissue slices. We anticipate that these diverse applications can facilitate the translation of a strategically functionalized probe into medical use.


Asunto(s)
Neoplasias Pulmonares , Tirosina , Alquinos/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología
9.
Cell Rep ; 38(8): 110398, 2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35196493

RESUMEN

CaMKII has long been known to be a key effector for synaptic plasticity. Recent studies have shown that a variety of modulators interact with the subunits of CaMKII to regulate the long-term potentiation (LTP) of hippocampal neurons. However, whether long non-coding RNAs modulate the activity of CaMKII and affect synaptic plasticity is still elusive. Here, we identify a previously uncharacterized long non-coding RNA Carip that functions as a scaffold, specifically interacts with CaMKIIß, and regulates the phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor subunits in the hippocampus. The absence of Carip causes dysfunction of synaptic transmission and attenuates LTP in hippocampal CA3-CA1 synapses, which further leads to impairment of spatial learning and memory. In summary, our findings demonstrate that Carip modulates long-term synaptic plasticity by changing AMPA receptor and NMDA receptor activities, thereby affecting spatial learning and memory in mice.


Asunto(s)
ARN Largo no Codificante , Aprendizaje Espacial , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Ratones , Plasticidad Neuronal/fisiología , ARN Largo no Codificante/genética , Receptores AMPA/genética , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo
10.
Front Pharmacol ; 12: 638993, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33935728

RESUMEN

Anthraquinones are bioactive natural products, some of which are active components in medicinal medicines, especially Chinese medicines. These compounds exert actions including purgation, anti-inflammation, immunoregulation, antihyperlipidemia, and anticancer effects. This study aimed to review the pharmacokinetics (PKs) of anthraquinones, which are importantly associated with their pharmacological and toxicological effects. Anthraquinones are absorbed mainly in intestines. The absorption rates of free anthraquinones are faster than those of their conjugated glycosides because of the higher liposolubility. A fluctuation in blood concentration and two absorption peaks of anthraquinones may result from the hepato-intestinal circulation, reabsorption, and transformation. Anthraquinones are widely distributed throughout the body, mainly in blood-flow rich organs and tissues, such as blood, intestines, stomach, liver, lung, kidney, and fat. The metabolic pathways of anthraquinones are hydrolysis, glycuronidation, sulfation, methylation/demethylation, hydroxylation/dehydroxylation, oxidation/reduction (hydrogenation), acetylation and esterification by intestinal flora and liver metabolic enzymes, among which hydrolysis, glycuronidation and sulfation are dominant. Of note, anthraquinones can be transformed into each other. The main excretion routes for anthraquinones are the kidney, recta, and gallbladder. Conclusion: Some anthraquinones and their glycosides, such as aloe-emodin, chrysophanol, emodin, physcion, rhein and sennosides, have attracted the most PK research interest due to their more biological activities and/or detectability. Anthraquinones are mainly absorbed in the intestines and are mostly distributed in blood flow-rich tissues and organs. Transformation into another anthraquinone may increase the blood concentration of the latter, leading to an increased pharmacological and/or toxicological effect. Drug-drug interactions influencing PK may provide insights into drug compatibility theory to enhance or reduce pharmacological/toxicological effects in Chinese medicine formulae and deserve deep investigation.

11.
Biol Chem ; 402(7): 839-848, 2021 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-33894112

RESUMEN

Glioblastoma (GBM) is the most common and fatal type of primary malignant tumours in the central nervous system. Cytokines such as interleukins (ILs) play an important role in GBM progression. Our present study found that IL-24 is down-regulated in GBM cells. Recombinant IL-24 (rIL-24) can suppress the in vitro migration and invasion of GBM cells while increase its chemo-sensitivity to temozolomide (TMZ) treatment. rIL-24 negatively regulates the expression of Zeb1, one well known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Over expression of Zeb1 can attenuate IL-24-suppressed malignancy of GBM cells. Mechanistically, IL-24 decreases the protein stability of Zeb1 while has no effect on its mRNA stability. It is due to that IL-24 can increase the expression of FBXO45, which can destabilize Zeb1 in cancer cells. Collectively, we reveal that IL-24 can suppress the malignancy of GBM cells via decreasing the expression of Zeb1. It suggests that targeted activation of IL-24 signals might be a potential therapy approach for GBM treatment.


Asunto(s)
Neoplasias del Sistema Nervioso Central/metabolismo , Glioblastoma/metabolismo , Interleucinas/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Células Cultivadas , Neoplasias del Sistema Nervioso Central/patología , Glioblastoma/patología , Humanos , Interleucinas/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética
12.
Nature ; 593(7859): 440-444, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33767446

RESUMEN

Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons1,2. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell-type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.


Asunto(s)
Roturas del ADN de Cadena Simple , Reparación del ADN , Elementos de Facilitación Genéticos/genética , Neuronas/metabolismo , 5-Metilcitosina/metabolismo , Línea Celular , ADN/biosíntesis , Replicación del ADN , Humanos , Masculino , Metilación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Análisis de Secuencia de ADN
13.
Virol Sin ; 36(2): 231-240, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32767210

RESUMEN

During virus infection, RIG-I-like receptors (RLRs) recognize viral RNAs and recruit the adaptor protein VISA to activate downstream signaling, leading to activation of transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs). IFNs further induce expression of hundreds of IFN-stimulated genes (ISGs) that suppress viral replication and facilitate the adaptive immune response. Dysregulated production of IFNs is implicated in various immune diseases. Here we identified Signal Recognition Particle 54 (SRP54) as a negative regulator of RLRs-induced antiviral signaling. Overexpression of SRP54 inhibited RNA virus-triggered induction of IFN-ß and increased viral replication, whereas knockdown of SRP54 had opposite effects. Mechanistically, SRP54 interacted with both RIG-I and MDA5 and impaired their association with VISA. Our findings demonstrate that SRP54 acts as a negative regulator of RLRs-mediated innate immune response by disrupting the recruitment of VISA to RIG-I/MDA5.


Asunto(s)
Interferón Tipo I , Interferón beta , Antivirales , Expresión Génica , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/genética , Helicasa Inducida por Interferón IFIH1/metabolismo , Partícula de Reconocimiento de Señal
14.
Genome Res ; 30(11): 1570-1582, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33060173

RESUMEN

Retrotransposons are populated in vertebrate genomes, and when active, are thought to cause genome instability with potential benefit to genome evolution. Retrotransposon-derived RNAs are also known to give rise to small endo-siRNAs to help maintain heterochromatin at their sites of transcription; however, as not all heterochromatic regions are equally active in transcription, it remains unclear how heterochromatin is maintained across the genome. Here, we address these problems by defining the origins of repeat-derived RNAs and their specific chromatin locations in Drosophila S2 cells. We demonstrate that repeat RNAs are predominantly derived from active gypsy elements and processed by Dcr-2 into small RNAs to help maintain pericentromeric heterochromatin. We also show in cultured S2 cells that synthetic repeat-derived endo-siRNA mimics are sufficient to rescue Dcr-2-deficiency-induced defects in heterochromatin formation in interphase and chromosome segregation during mitosis, demonstrating that active retrotransposons are required for stable genetic inheritance.


Asunto(s)
División Celular/genética , Heterocromatina , Retroelementos , Animales , Centrómero , Segregación Cromosómica , Drosophila/genética , Proteínas de Drosophila/genética , Eucromatina , Secuenciación de Nucleótidos de Alto Rendimiento , ARN Helicasas/genética , ARN Interferente Pequeño , Ribonucleasa III/genética
15.
PLoS Pathog ; 16(1): e1008178, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31968013

RESUMEN

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.


Asunto(s)
Virus ADN/inmunología , Inmunidad Innata , Proteínas de la Membrana/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Animales , Enzima Desubiquitinante CYLD/metabolismo , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Estabilidad Proteica , Transducción de Señal , Ubiquitinación
16.
Cancer Genet ; 241: 25-33, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31964588

RESUMEN

Recently, a number of long noncoding RNAs (lncRNAs) have been reported to play significant roles in human tumorigenesis. However, only few gastric cancer related lncRNAs have been well characterized. Here, we identified one lncRNA HRCEG, whose expression was decreased in the gastric cancer tissues compared with adjacent normal tissues. Overexpression of HRCEG significantly promoted cell apoptosis and inhibited cell proliferation. Importantly, we demonstrated that HRCEG levels inversely correlated with EMT process and HRCEG was regulated by the histone deacetylase 1 (HDAC1) in gastric cancer. These findings suggest that HRCEG might be regulated by HDAC1 to inhibit gastric cancer progress and metastatic capability via EMT pathway.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 1/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Gastrectomía , Técnicas de Silenciamiento del Gen , Histona Desacetilasa 1/genética , Humanos , Invasividad Neoplásica/genética , ARN Largo no Codificante/genética , ARN Interferente Pequeño/metabolismo , Estómago/patología , Estómago/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía
17.
EMBO J ; 38(17): e101110, 2019 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-31334575

RESUMEN

Hepatocellular carcinoma (HCC) is the most prevalent liver cancer, characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanism underlying their self-renewal maintenance is poorly understood. Here, we identified a long noncoding RNA (lncRNA) termed HAND2-AS1 that is highly expressed in liver CSCs. Human HAND2-AS1 and its mouse ortholog lncHand2 display a high level of conservation. HAND2-AS1 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, HAND2-AS1 recruits the INO80 chromatin-remodeling complex to the promoter of BMPR1A, thereby inducing its expression and leading to the activation of BMP signaling. Importantly, interfering with expression of HAND2-AS1 by antisense oligonucleotides (ASOs) and BMPR1A by siRNAs has synergistic anti-tumorigenic effects on humanized HCC models. Moreover, knockout of lncHand2 or Bmpr1a in mouse hepatocytes impairs BMP signaling and suppresses the initiation of liver cancer. Our findings reveal that HAND2-AS1 promotes the self-renewal of liver CSCs and drives liver oncogenesis, offering a potential new target for HCC therapy.


Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Células Madre Neoplásicas/química , ARN Largo no Codificante/genética , Transducción de Señal , ATPasas Asociadas con Actividades Celulares Diversas/genética , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Proteínas Morfogenéticas Óseas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Autorrenovación de las Células , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Regulación hacia Arriba
18.
Brief Bioinform ; 19(6): 1302-1309, 2018 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-28575155

RESUMEN

Biological processes, especially developmental processes, are often dynamic. Previous BodyMap projects for human and mouse have provided researchers with portals to tissue-specific gene expression, but these efforts have not included dynamic gene expression patterns. Over the past few years, substantial progress in our understanding of the molecular mechanisms of protein-coding and long noncoding RNA (lncRNA) genes in development processes has been achieved through numerous time series RNA sequencing (RNA-seq) studies. However, none of the existing databases focuses on these time series data, thus rendering the exploration of dynamic gene expression patterns inconvenient. Here, we present Dynamic BodyMap (Dynamic-BM), a database for temporal gene expression profiles, obtained from 2203 time series of RNA-seq samples, covering >25 tissues from five species. Dynamic-BM has a user-friendly Web interface designed for browsing and searching the dynamic expression pattern of genes from different sources. It is an open resource for efficient data exploration, providing dynamic expression profiles of both protein-coding genes and lncRNAs to facilitate the generation of new hypotheses in developmental biology research. Additionally, Dynamic-BM includes a literature-based knowledgebase for lncRNAs associated with tissue development and a list of manually selected lncRNA candidates that may be involved in tissue development. Dynamic-BM is available at http://bioinfo.ibp.ac.cn/Dynamic-BM.


Asunto(s)
Bases de Datos Factuales , Análisis de Secuencia de ARN/métodos , Perfilación de la Expresión Génica , Internet , Interfaz Usuario-Computador
19.
Discov Med ; 21(116): 239-50, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-27232510

RESUMEN

Rapidly growing evidence has shown that long noncoding RNAs (lncRNAs) are playing more and more important roles in a variety of biological processes and have been involved in various types of cancer. How to better decode these noncoding transcripts and how to predict their potential roles in tumorigenesis particularly in nasopharyngeal carcinoma (NPC) are still open questions. In this study, we applied our custom-designed lncRNA+mRNA gene expression microarray, which contains probes against 38,141 lncRNA transcripts, to assaying the expression profiling of flash-frozen tumorous and non-tumorous tissue samples from nonkeratinizing carcinoma (NKC), which is the major histologic type of NPC. As a result, 481 differentially expressed (DE) lncRNAs (231 up-regulated and 250 down-regulated) were identified. Moreover, integrated bioinformatics analyses including gene ontology, lncRNA functional prediction based on coding-noncoding gene co-expression network, interactive miRNAs, and transcription factor binding motifs were all carried out to decode the potential functional roles of these newly identified DE-lncRNAs. This work hence offers new resource and insight into lncRNAs for further understanding the molecular mechanisms of tumorigenesis of NKC, and may also define new biomarkers or therapy targets for the translational studies of NKC.


Asunto(s)
Carcinoma/genética , Perfilación de la Expresión Génica/métodos , MicroARNs/genética , Neoplasias Nasofaríngeas/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Biomarcadores , Carcinogénesis/genética , Regulación hacia Abajo , Humanos , MicroARNs/aislamiento & purificación , Carcinoma Nasofaríngeo , ARN Largo no Codificante/aislamiento & purificación , ARN Mensajero/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba
20.
Biotechnol Lett ; 37(1): 9-18, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25179823

RESUMEN

Resveratrol, a major stilbene phytoalexin, is a valuable polyphenol that has been recognized for its benefits to human health. Resveratrol has antioxidant and antitumor effects and promotes longevity. It is used in medicine, health care products, cosmetics, and other industries. Therefore, a sustainable source for resveratrol production is required. This review describes the metabolic engineering of microorganisms, the biotransformation and biosynthesis of endophytes and the oxidation or degradation of resveratrol. We compare various available methods for resveratrol production, and summarize the practical challenges facing the microbial production of resveratrol. The future research direction for resveratrol is also discussed.


Asunto(s)
Escherichia coli/metabolismo , Microbiología Industrial , Ingeniería Metabólica , Saccharomyces cerevisiae/metabolismo , Estilbenos , Aciltransferasas , Biocatálisis , Biotransformación , Glucósidos/metabolismo , Redes y Vías Metabólicas , Resveratrol , Estilbenos/química , Estilbenos/metabolismo
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