RESUMEN
Cambial development in the stems of perennial woody species is rigorously regulated by phytohormones. Auxin and gibberellin (GA) play crucial roles in stimulating cambial activity in poplar (Populus spp.). In this study, we show that the DELLA protein REPRESSOR of ga1-3 Like 1 (RGL1), AUXIN RESPONSE FACTOR 7 (ARF7), and Aux/INDOLE-3-ACETIC ACID 9 (IAA9) form a ternary complex that mediates crosstalk between the auxin and GA signaling pathways in poplar stems during cambial development. Biochemical analysis revealed that ARF7 physically interacts with RGL1 and IAA9 through distinct domains. The arf7 loss-of-function mutant showed markedly attenuated responses to auxin and GA, whereas transgenic poplar plants overexpressing ARF7 displayed strongly improved cambial activity. ARF7 directly binds to the promoter region of the cambial stem cell regulator WOX4 to modulate its expression, thus integrating auxin and GA signaling to regulate cambial activity. Furthermore, the direct activation of PIN-FORMED 1 expression by ARF7 in the RGL1-ARF7-IAA9 module increased GA-dependent cambial activity via polar auxin transport. Collectively, these findings reveal that the crosstalk between auxin and GA signaling mediated by the RGL1-ARF7-IAA9 module is crucial for the precise regulation of cambial development in poplar.
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Proteínas de Arabidopsis , Populus , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Giberelinas/metabolismo , Ácidos Indolacéticos/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismoRESUMEN
BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/metabolismo , Células Asesinas Naturales/patología , Inmunoterapia , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Ligandos , PronósticoRESUMEN
The clinical application of oncology therapy is hampered by high glutathione concentrations, hypoxia, and inefficient activation of cell death mechanisms in cancer cells. In this study, Fe and Mo bimetallic sulfide nanomaterial (FeS2@MoS2) based on metal-organic framework structure is rationally prepared with peroxidase (POD)-, catalase (CAT)-, superoxide dismutase (SOD)-like activities and glutathione depletion ability, which can confer versatility for treating tumors and mending wounds. In the lesion area, FeS2@MoS2 with SOD-like activity can facilitate the transformation of superoxide anions (O2 -) to hydrogen peroxide (H2O2), and then the resulting H2O2 serves as a substrate for the Fenton reaction with FMS to produce highly toxic hydroxyl radicals (âOH). Simultaneously, FeS2@MoS2 has an ability to deplete glutathione (GSH) and catalyze the decomposition of nicotinamide adenine dinucleotide phosphate (NADPH) to curb the regeneration of GSH from the source. Thus it can realize effective tumor elimination through synergistic apoptosis-ferroptosis strategy. Based on the alteration of the H2O2 system, free radical production, glutathione depletion and the alleviation of hypoxia in the tumor microenvironment, FeS2@MoS2 NPS can not only significantly inhibit tumors in vivo and in vitro, but also inhibit multidrug-resistant bacteria and hasten wound healing. It may open the door to the development of cascade nanoplatforms for effective tumor treatment and overcoming wound infection.
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Antineoplásicos , Estructuras Metalorgánicas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Animales , Antiinfecciosos/farmacología , Antiinfecciosos/química , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/química , Línea Celular Tumoral , Ratones , Glutatión/metabolismo , Hierro/química , Hierro/metabolismo , Apoptosis/efectos de los fármacos , Molibdeno/química , Molibdeno/farmacología , Nanoestructuras/química , Ferroptosis/efectos de los fármacosRESUMEN
BACKGROUND: Fried food has increased in popularity worldwide. However, deep frying can increase the production of peroxidative toxins in food, which might be harmful to fetal development. The antioxidative effect of vitamin D3 (VD3) has been reported previously. OBJECTIVES: This study aimed to explore how maternal VD3 supplementation in an oxidized-oil diet during gestation affects fetal antioxidative ability and development. METHODS: Pregnant mice were randomly assigned into 3 groups: Control group (diet with fresh soybean oil), OSO group [diet with oxidized soybean oil (OSO)], and OSOV group (diet with OSO and 10,000 IU/Kg VD3). Mice were fed with the corresponding diet during gestation. On day 16.5 of gestation, the placenta and fetus were harvested to analyze antioxidative status. RESULTS: Maternal oxidized-oil diet during gestation significantly reduced placental vessel abundance, labyrinth zone area, and fetal body weight. However, dietary VD3 supplementation prevented these negative effects of oxidized-oil diet. Maternal intake of oxidized-oil diet increased serum concentrations of malondialdehyde, total-nitric oxide synthase, and inducible nitric oxide synthase, whereas VD3 supplementation showed a protection effect on it. Additionally, maternal VD3 supplementation increased the levels of antioxidative enzymes and the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby protecting placenta and fetus from apoptosis and oxidative stress caused by an oxidized-oil diet. The gene expression and protein levels of a fatty acid transporter solute carrier family 27 member 1 in the fetal liver were increased by maternal VD3 supplementation under oxidized-oil diet. Notably, NRF2 could be co-immunoprecipitated with the VD receptor in the placenta. CONCLUSIONS: Maternal VD3 supplementation could protect fetus from oxidized-oil diet induced developmental impairment by alleviating oxidative stress in the placenta and fetus through the VD receptor/NRF2 pathway, at least partially. Thus, ensuring adequate levels of VD3 through supplementation is often critical during pregnancy.
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Nonalcoholic fatty liver disease (NAFLD), which leads to insulin resistance, steatosis, and even hepatocellular carcinoma, is the most common chronic liver disease worldwide, however, effective treatment is still lacking. This study determined the role of liver FGF21 and the mechanisms underlying the protective effects of time-restricted feeding (TRF) in NAFLD. FGF21 liver knockout (FGF21 LKO) mice and C57BL/6 wild-type (WT) mice were fed either a normal or a high-fat diet (HFD) for 16 weeks. Mice with diet-induced obesity (DIO) were also used. The mice were fed either ad libitum or in a time-restricted manner. Serum FGF21 levels were significantly increased after 16 weeks of TRF. TRF prevented body weight gain, improved glucose homeostasis, and protected against high-fat diet-induced hepatosteatosis and liver damage. The expression of genes related to liver lipogenesis and inflammation was reduced in TRF mice, but the expression of genes involved in fatty acid ß-oxidation was increased. However, those beneficial effects of TRF were blunted in the FGF21 LKO mice. Moreover, TRF promoted improvements in insulin sensitivity and liver damage in DIO mice. Our data show that liver FGF21 signaling was involved in the effect of TRF on high-fat diet-induced fatty liver.
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Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Dieta Alta en Grasa , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND AND AIM: Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux. METHODS AND RESULTS: We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane. CONCLUSION: These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.
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Lesión Pulmonar Aguda , Histonas , Macrófagos Alveolares , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Potasio , Sepsis , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/inmunología , Potasio/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/inmunología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Histonas/metabolismo , Masculino , Ratones , Líquido del Lavado Bronquioalveolar , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Línea Celular , Canales de Potasio/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Inflamasomas/metabolismo , LipopolisacáridosRESUMEN
Alpha-foetoprotein (AFP) is taken as a diagnostic tumor marker for the screening and diagnosis of cancer. Nucleic acid-based isothermal amplification strategies are emerging as a potential technology in early screening and clinical diagnosis of AFP. The leakages between hairpins dramatically increase the background and reduce the sensitivity. Thus, it is necessary to develop some strategies to reduce the leakage for isothermal amplification strategies. A DNAzyme-locked leakless enzyme-free amplification system was developed for AFP detection in liver cancer and breast cancer. AFP could open the apt-hairpin and initiate the catalytic hairpin assembly (CHA) reaction to produce a Y-shaped duplex. Two tails of a Y-shaped duplex cleaved the two kinds of leakless hairpins. Then, the third tail of the Y-shaped duplex catalyzed the second CHA between the cleaved leakless hairpins to recover the fluorescent intensity. The limit of detection reached 5 fg/mL by the two levels of signal amplifications. Importantly, the leakless hairpin design effectively reduced leakage between hairpins and weakened the background. In addition, it also showed a great promising potential for AFP detection in early screening and clinical diagnosis.
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Neoplasias de la Mama , ADN Catalítico , Límite de Detección , Neoplasias Hepáticas , Técnicas de Amplificación de Ácido Nucleico , alfa-Fetoproteínas , ADN Catalítico/química , ADN Catalítico/metabolismo , alfa-Fetoproteínas/análisis , Humanos , Técnicas de Amplificación de Ácido Nucleico/métodos , Neoplasias de la Mama/diagnóstico , Neoplasias Hepáticas/diagnóstico , Femenino , Biomarcadores de Tumor/sangre , Técnicas Biosensibles/métodosRESUMEN
BACKGROUND: More than 30% of reproductive-age women are obese or overweight. Obesity and exposure to a high-fat diet (HFD) detrimentally affect endometrial development and embryo implantation. We previously reported that time-restricted feeding (TRF) improved ovarian follicular development, but whether and how TRF modulates embryo implantation are poorly understood. OBJECTIVE: We investigated the effect of TRF on embryo implantation. METHODS: In TRF group, mice had 10 h of food free access from 9 pm to 7 am, and fed a normal diet or a HFD. Tail vein injection of Chicago blue dye was used to examine embryo implantation sites at day 5.5 (D5.5) of pregnancy. Serum collected at D0.5 and D4.5 of pregnancy was used to examine the level of estradiol (E2) and progesterone. Uterine estrogen receptor (ER) and progesterone receptor levels and their targeted aquaporins (AQPs) were measured. LC-MS was used to analyze bile acid (BA) composition, and primary hepatocytes were used to test the effects of BA on the expression level of SULT1E1, a key enzyme in estrogen inactivation and elimination. RESULTS: We found that TRF prevented HFD-induced embryo loss and alleviated the defect in luminal closure on D4.5 of pregnancy. The cyclic changes of E2 level were lost in mice fed ad libitum but not in TRF mice on the HFD. The HFD increased ER-α expression and transcriptional activity, which induced AQP3 and AQP5 expression on D4.5 of pregnancy. TRF prevented the negative effect of the HFD on uterine luminal closure. Furthermore, in vitro and in vivo results showed that BA suppressed estrogen degradation by activating liver SULT1E1 expression. CONCLUSIONS: Our findings demonstrated that TRF prevented HFD-induced defects in luminal closure, thereby improving embryonic implantation, and provide novel insights into the effects of dietary intervention on obesity and associated infertility.
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Dieta Alta en Grasa , Receptor alfa de Estrógeno , Embarazo , Ratones , Femenino , Animales , Receptor alfa de Estrógeno/genética , Obesidad , Implantación del Embrión/fisiología , Estrógenos , Ratones Endogámicos C57BLRESUMEN
PURPOSE: To investigate the prognosis value of a combined model based on 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) baseline and interim parameters in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We retrospectively analyzed the PET metabolic parameters and clinical data of 154 DLBCL patients between December 2015 and October 2020. All of these patients underwent 18F-FDG PET/CT scan before treatment and after three or four courses of chemotherapy. The optimal cut-off values for quantitative variables were determined by the receiver operating characteristic (ROC) curve. The baseline and interim PET/CT parameters, which respectively included maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax) and total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), and clinical characteristics were analyzed by chi-squared test, Kaplan-Meier survival curve, and Cox regression analysis. RESULTS: Of 154 patients, 35 exhibited disease progression or recurrence. ROC analysis revealed that baseline 18F-FDG PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax), along with interim 18F-FDG PET/CT metabolic parameters such as total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), were predictive of relapse or progression in DLBCL patients (P < 0.05). The chi-squared test showed that TMTV0, STMTV0, Dmax, SUVmax1, TMTV1, TTLG1, %ΔSUVmax, Deauville score, IPI, Ann Arbor stage, and LDH were associated with patient prognosis (P < 0.05). Multivariate Cox regression analysis showed that Dmax (P = 0.021) and %ΔSUVmax (P = 0.030) were independent predictors of prognosis in DLBCL patients. There were statistically significant differences in PFS among the three groups with high, intermediate, and low risk according to the combination model (P < 0.001). The combination model presented higher predictive efficacy than single indicators. CONCLUSION: The combined model of baseline parameter Dmax and intermediate parameter %ΔSUVmax of 18F-FDG PET/CT improved the predictive efficacy of PFS and contributed to the risk stratification of patients, providing a reference for clinical individualization and precision treatment.
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Linfoma de Células B Grandes Difuso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Fluorodesoxiglucosa F18 , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Tomografía de Emisión de Positrones , Pronóstico , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológicoRESUMEN
Drug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK phosphatase 3 (MKP-3) is a positive regulator for gluconeogenesis. Thus, this study was conducted to investigate the role of MKP-3 in the suppression of gluconeogenesis by acute ER stress, as well as the regulatory role of acute ER stress on the expression of MKP-3. Results showed that acute ER stress induced by tunicamycin significantly suppressed gluconeogenesis in both hepatocytes and mouse liver, reduced glucose production level in hepatocytes, and decreased fasting blood glucose level in mice. Additionally, the protein level of MKP-3 was reduced by acute ER stress in both hepatocytes and mouse liver. Mkp-3 deficiency eliminated the inhibitory effect of acute ER stress on gluconeogenesis in hepatocytes. Moreover, the reduction effect of acute ER stress on blood glucose level and hepatic glucose 6-phosphatase (G6pc) expression was not observed in the liver-specific Mkp-3 knockout mice. Furthermore, activation of protein kinase R-like ER kinase (PERK) decreased the MKP-3 protein level, while inactivation of PERK abolished the reduction effect of acute ER stress on the MKP-3 protein level in hepatocytes. Taken together, our study suggested that acute ER stress could suppress hepatic gluconeogenesis by stimulating MKP-3 degradation via PERK, at least partially. Thus, MKP-3 might be a therapeutic target for DILI-related hypoglycemia.
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Fosfatasa 6 de Especificidad Dual , Gluconeogénesis , Hipoglucemia , Animales , Ratones , Glucemia/metabolismo , Estrés del Retículo Endoplásmico , Hepatocitos/metabolismo , Hipoglucemia/metabolismo , Hígado/metabolismo , Ratones Noqueados , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Fosfatasa 6 de Especificidad Dual/metabolismoRESUMEN
The analysis of chiral α-amino acids is of great significance in asymmetric synthesis, nutrition, food science, and microbiology. However, the ability of chiral recognition is difficult to achieve. Due to the demand for expensive equipment and skilled operators, traditional methods such as high-performance liquid chromatography are limited. The previously reported methods based on chemical sensor arrays usually cannot carry out the chiral analysis. Here, we developed a novel biosensor array based on the interaction between a suite of host-based luminescent bacteria and amino acids and used linear discriminant analysis to reflect their luminescence response patterns. This biosensor array could effectively discriminate chiral amino acids, including 19 L-amino acids, their corresponding D-enantiomers, and the achiral glycine. In addition, the determination of enantiomeric purity and quantitative ability has been proved. The successful identification of a complex system containing multiple chiral amino acids further demonstrates the superiority of the bioluminescent sensor array. Moreover, this sensor array could efficiently monitor the dynamic composition of free amino acids in the process of milk fermentation. Finally, the bioluminescence response mechanism of the luminescent bacteria for the recognition of chirality was clarified. This approach possessed the advantages of facile construction, high throughput, easy operation, high accuracy and fast response.
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Aminoácidos , Luminiscencia , Aminas , Aminoácidos/química , Fermentación , Glicina , Estereoisomerismo , Yogur/análisisRESUMEN
Accumulating evidence have demonstrated that circular RNAs (circRNAs) exert important roles in tumor initiation and progression. Nevertheless, the role and mechanism of circRNA ceramide synthase 6 (circCERS6) in epithelial ovarian cancer (EOC) remain to be clarified. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay, we measured RNA and protein expression. We analyzed the effects of circCERS6/microRNA-630 (miR-630)/Ras-association domain family member 8 (RASSF8) axis in cell proliferation, migration, and invasion by 5-Ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, scratch test, and transwell assay. Using RNA-pull down assay and dual-luciferase reporter assay, the interaction between miR-630 and circCERS6 or RASSF8 was verified. The in vivo role of circCERS6 in tumor growth was analyzed using xenograft mice model. CircCERS6 expression was markedly reduced in EOC tissues and cell lines. CircCERS6 overexpression hampered the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of EOC cells. CircCERS6 directly interacted with miR-630. miR-630 expression was up-regulated in EOC tissues and cell lines. CircCERS6 overexpression-induced anti-tumor effects in EOC were largely reversed by the overexpression of miR-630. RASSF8 was a direct target of miR-630. RASSF8 level was decreased in EOC tissues and cell lines. CircCERS6 up-regulated RASSF8 expression by acting as a molecular sponge for miR-630 in EOC cells. CircCERS6 overexpression-mediated suppressive effects in EOC cells were largely overturned by the silence of RASSF8. CircCERS6 overexpression blocked tumor growth in vivo. CircCERS6 overexpression hampered the proliferation, migration, invasion, and EMT of EOC cells by up-regulating RASSF8 via sponging miR-630.
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Carcinoma Epitelial de Ovario , MicroARNs , Neoplasias Ováricas , ARN Circular , Proteínas Supresoras de Tumor , Animales , Femenino , Humanos , Ratones , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas Supresoras de Tumor/genética , ARN Circular/genéticaRESUMEN
To investigate the effects of dietary fibre on follicular atresia in pigs fed a high-fat diet, we fed thirty-two prepubescent gilts a basal diet (CON) or a CON diet supplemented with 300 g/d dietary fibre (fibre), 240 g/d soya oil (SO) or both (fibre + SO). At the 19th day of the 4th oestrus cycle, gilts fed the SO diet showed 112 % more atretic follicles and greater expression of the apoptotic markers, Bax and caspase-3, and these effects were reversed by the fibre diet. The abundance of SCFA-producing microbes was decreased by the SO diet, but this effect was reversed by fibre treatment. Concentrations of serotonin and melatonin in the serum and follicular fluid were increased by the fibre diet. Overall, dietary fibre protected against high fat feeding-induced follicular atresia at least partly via gut microbiota-related serotonin-melatonin synthesis. These results provide insight into preventing negative effects on fertility in humans consuming a high-energy diet.
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Fibras de la Dieta/farmacología , Suplementos Dietéticos , Atresia Folicular/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Alimentación Animal/análisis , Animales , Dieta Alta en Grasa/veterinaria , Femenino , Líquido Folicular/metabolismo , Melatonina/metabolismo , Modelos Animales , Ovario/metabolismo , Serotonina/metabolismo , Sus scrofa , PorcinosRESUMEN
BACKGROUND: Excision repair cross-complementation group 6-like (ERCC6L) is overexpressed in some malignancies; however, its role in hepatocellular carcinoma (HCC) remains to be further investigated. AIMS: In the present study, we explored the expression and function of ERCC6L in HCC. METHODS AND RESULTS: We investigated the expression of ERCC6L by microarray analysis, using the Cancer Genome Atlas database, and by HCC tissue microarray. The results showed that ERCC6L expression was upregulated in tumor specimens and HCC cell lines. High ERCC6L expression in tumor tissues was significantly correlated with poor prognosis and could serve as an independent prognostic indicator for HCC patients. Results of in vitro and in vivo assays revealed that ERCC6L substantially promoted cell proliferation, and our flow cytometry analysis revealed that this was accomplished by acceleration of the G1/S transition. Finally, gene set enrichment analysis and western blotting results indicated that ERCC6L might regulate HCC proliferation by activating p53 signaling. CONCLUSIONS: Our study suggests that ERCC6L plays an important role in HCC proliferation and that it might serve as a promising therapeutic target in HCC.
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Carcinoma Hepatocelular , Proliferación Celular/fisiología , ADN Helicasas , Neoplasias Hepáticas , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , ADN Helicasas/genética , ADN Helicasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Pronóstico , Transducción de Señal , Regulación hacia ArribaRESUMEN
OBJECTIVES: Inflammation is associated with the occurrence and prognosis of ischemic stroke. The aim of this study was to evaluate the association between inflammatory biomarkers and the short-term clinical outcomes of acute ischemic stroke (AIS) patients after intravenous thrombolysis (IVT). MATERIALS AND METHODS: A total of 208 AIS patients treated with IVT were enrolled in this retrospective study. Blood tests of inflammatory biomarkers, including the leukocyte count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio and high-sensitivity C-reactive protein level, were conducted within 24 h after IVT. The primary outcome was decent functional recovery (DFR) [modified Rankin Scale score (mRS) of 0-2] at 3 months. The secondary outcomes included symptomatic intracranial hemorrhage and 3-month mortality. A multivariate analysis was performed to evaluate the associations between inflammatory biomarkers and 3-month clinical outcomes. RESULTS: At 3 months follow-up, 113 (62.2%) patients achieved DFR. As compared to patients with DFR, patients without DFR had higher leukocyte counts (8.5 ± 2.4â¯×â¯109/L versus 6.9 ± 1.7â¯×â¯109/L, P=0.000), neutrophil counts (6.1 ± 2.3â¯×â¯109/L versus 4.6±1.7â¯×â¯109/L, P=0.000) and neutrophil-to-lymphocyte ratio (4.6 ± 2.4 versus 3.3 ± 1.9, P=0.000). After adjusting for the stroke subtype, severity of stroke, and medical history, the leukocyte count and neutrophil count remained significantly correlated with non-DFR (adjusted odds ratio [OR] 1.488; 95% confidence interval [CI], 1.247-1.776; P=0.000 and adjusted OR 1.522; 95% CI, 1.269-1.826; P=0.000, respectively). CONCLUSIONS: This study demonstrates that increased levels of inflammatory biomarkers are independently associated with poor outcomes at 3 months in AIS patients treated with IVT.
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Proteína C-Reactiva/análisis , Fibrinolíticos/administración & dosificación , Mediadores de Inflamación/sangre , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Terapia Trombolítica , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Evaluación de la Discapacidad , Femenino , Fibrinolíticos/efectos adversos , Estado Funcional , Humanos , Infusiones Intravenosas , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/diagnóstico , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Estudios Retrospectivos , Factores de Riesgo , Terapia Trombolítica/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Liver fibrosis and cirrhosis resulting from chronic liver injury represent a major healthcare burden worldwide. Growth differentiation factor (GDF) 11 has been recently investigated for its role in rejuvenation of ageing organs, but its role in chronic liver diseases has remained unknown. Here, we investigated the expression and function of GDF11 in liver fibrosis, a common feature of most chronic liver diseases. DESIGN: We analysed the expression of GDF11 in patients with liver fibrosis, in a mouse model of liver fibrosis and in hepatic stellate cells (HSCs) as well as in other liver cell types. The functional relevance of GDF11 in toxin-induced and cholestasis-induced mouse models of liver fibrosis was examined by in vivo modulation of Gdf11 expression using adeno-associated virus (AAV) vectors. The effect of GDF11 on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)+ liver progenitor cells was studied in mouse and human liver organoid culture. Furthermore, in vivo depletion of LGR5+ cells was induced by injecting AAV vectors expressing diptheria toxin A under the transcriptional control of Lgr5 promoter. RESULTS: We showed that the expression of GDF11 is upregulated in patients with liver fibrosis and in experimentally induced murine liver fibrosis models. Furthermore, we found that therapeutic application of GDF11 mounts a protective response against fibrosis by increasing the number of LGR5+ progenitor cells in the liver. CONCLUSION: Collectively, our findings uncover a protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.
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Proteínas Morfogenéticas Óseas/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Células Madre/metabolismo , Animales , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Flujo Génico , Humanos , Hibridación in Situ , Hígado/citología , Masculino , Ratones , Ratones Endogámicos BALB C , Regulación hacia ArribaRESUMEN
BACKGROUND: Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is a group of isoforms produced by alternative splicing and is overexpressed in human malignancies including hepatocellular carcinoma (HCC). However, the prognostic value and biological functions of its major protein isoforms, named CABYR-a/b (combined CABYR-a and CABYR-b), in HCC remain to be established. METHODS: CABYR-a/b expression was detected in HCC tissues and cell lines by quantitative real-time polymerase chain reaction and Western blot analysis. The correlation of CABYR-a/b expression with clinical characteristics and its prognosis impact were determined by statistical analysis. Finally, the biological functions and molecular mechanism of CABYR-a/b were also investigated using molecular biology approaches. RESULTS: The present research found that CABYR-a/b was markedly elevated in HCC specimens and cell lines. Upregulated CABYR-a/b level had positive association with tumor size and differentiation in patients. Moreover, cases with elevated CABYR-a/b level had poorer overall survival (OS) and disease-free survival (DFS) than those with reduced CABYR-a/b level. Multivariate analysis and prognostic nomograms demonstrated that CABYR-a/b overexpression was an independent predictive indicator for OS and DFS. The calibration curve for the odds of OS and DFS demonstrated that the prediction by nomograms was in excellent accordance with actual situation. CABYR-a/b downregulation suppressed cell proliferation and induced G1-phase arrest via decreasing cyclin D1 and cyclin dependent kinase 4, while promoted apoptosis by reducing B-cell lymphoma 2 (Bcl-2) and increasing Bcl-2-associated death promoter. CONCLUSION: Our research indicates that CABYR-a/b exerts an oncogenic effect on HCC development and may become a new prognostic indicator for patients with HCC.
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Apoptosis , Proteínas de Unión al Calcio , Calcio/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Tirosina/química , Anciano , Empalme Alternativo , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/metabolismo , Carcinoma Hepatocelular/diagnóstico , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Unión Proteica , Isoformas de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/metabolismo , Resultado del TratamientoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19) has spread worldwide. Whether antibodies are important for the adaptive immune responses against SARS-CoV-2 infection needs to be determined. Here, 26 cases of COVID-19 in Jinan, China, were examined and shown to be mild or with common clinical symptoms, and no case of severe symptoms was found among these patients. Strikingly, a subset of these patients had SARS-CoV-2 and virus-specific IgG coexist for an unexpectedly long time, with two cases for up to 50 days. One COVID-19 patient who did not produce any SARS-CoV-2-bound IgG successfully cleared SARS-CoV-2 after 46 days of illness, revealing that without antibody-mediated adaptive immunity, innate immunity alone may still be powerful enough to eliminate SARS-CoV-2. This report may provide a basis for further analysis of both innate and adaptive immunity in SARS-CoV-2 clearance, especially in nonsevere cases.
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Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Interacciones Huésped-Patógeno/inmunología , SARS-CoV-2/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Biomarcadores , COVID-19/sangre , Niño , Preescolar , Femenino , Humanos , Inmunidad Innata , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Carga Viral , Adulto JovenRESUMEN
The ongoing outbreak of a new coronavirus (2019-nCoV, or severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) has caused an epidemic of the acute respiratory syndrome known as coronavirus disease (COVID-19) in humans. SARS-CoV-2 rapidly spread to multiple regions of China and multiple other countries, posing a serious threat to public health. The spike (S) proteins of SARS-CoV-1 and SARS-CoV-2 may use the same host cellular receptor, angiotensin-converting enzyme 2 (ACE2), for entering host cells. The affinity between ACE2 and the SARS-CoV-2 S protein is much higher than that of ACE2 binding to the SARS-CoV S protein, explaining why SARS-CoV-2 seems to be more readily transmitted from human to human. Here, we report that ACE2 can be significantly upregulated after infection of various viruses, including SARS-CoV-1 and SARS-CoV-2, or by the stimulation with inflammatory cytokines such as interferons. We propose that SARS-CoV-2 may positively induce its cellular entry receptor, ACE2, to accelerate its replication and spread; high inflammatory cytokine levels increase ACE2 expression and act as high-risk factors for developing COVID-19, and the infection of other viruses may increase the risk of SARS-CoV-2 infection. Therefore, drugs targeting ACE2 may be developed for the future emerging infectious diseases caused by this cluster of coronaviruses.
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Enzima Convertidora de Angiotensina 2/genética , COVID-19/inmunología , Receptores Virales/genética , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/genética , Enzima Convertidora de Angiotensina 2/inmunología , COVID-19/virología , Expresión Génica , Células HEK293 , Humanos , Interferones/farmacología , Análisis por Micromatrices , Unión Proteica , Receptores Virales/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Regulación hacia ArribaRESUMEN
Although luminescent bacteria-based bioluminescence inhibition assay has been widely used in the toxicity assessment of environmental pollutants, the response of a luminescent bacterium usually lacks specificity to a target analyte. Recently, some specific analyte inductive promoters were fused to the lux genes for the purpose of selective bioluminescent sensing, and suits of specific promoters were fused to lux genes to compose a bioluminescent array sensor for simultaneous identification of multiple analytes. However, specific promoter-based methods still suffer from drawbacks including limited selectivity, slow responding time, expensive to construct different promoters involved plasmids, and laborious to find new promoters. Herein, we proposed a novel strategy to construct a lux reporter array sensor by directly transforming the natural lux genes in different bacterial hosts without the involvement of any specific promoters. Due to the distinct pathways of signal production, the responding time of the current different bacterial host (DBH)-based lux reporter array has nearly an order of magnitude faster than with specific promoter-based methods. The DBH-based lux reporter array was successfully used for simultaneous identification, quantification, and toxicity/bioactivity assessment of multiple metal ions. Obviously, all the chemical synthetic material-based metal ion sensing methods cannot simultaneously achieve analysis and toxicity evaluation. This approach possessed additional advantages of facile construction, easy operation, high selectivity, fast response, and strong adaptability to other analytes. A different bacterial host-based lux reporter array was established for simultaneous analysis and toxicity assessment of multiple metal ions.