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Studying the spatial and temporal changes of grassland soil organic carbon (SOC) is helpful in promote the management of regional ecosystem carbon sinks. Grazing is one of the main ways of rational utilization of grassland. Different grazing intensities will affect the change of SOC density. Under different grazing intensity and management measures in Zhangye grassland, this study uses the parameter localized CENTURY model to simulate the temporal and spatial variations of SOC density from 1970 to 2022. The results showed that long-term light grazing reduced the average SOC by 195.114 g·m-2 and 1.91%. Moderate and severe grazing, respectively, for a long time made the total SOC density loss of 5.21% and 17.69%. In a short period, mild and moderate grazing reduced total SOC first and then increased it. Under light grazing, total SOC density appeared higher relative changes in the southeast, and lower in the northwest and central. There was no significant difference in the relative changes of total SOC between steppe and desert grasslands under light grazing. The decrease range of steppe was gradually greater than that in desert grassland. Since different management measures were implemented in some sampling sites in 2017, we divided the study period into two periods, 1970-2016 and 2017-2022. The implementation of degraded grassland improvement, fallow grazing, and rotational grazing would increase the total SOC density and mild SOC density, rotational grazing > degraded grassland improvement > rest grazing. Rotational grazing and the improvement of degraded grassland increased the density of active and inert SOC, while resting grazing decreased the density of SOC.
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Diagnosis of tuberculosis remains a challenge when microbiological tests are negative. Immune cell atlas of patients with tuberculosis and healthy controls were established by single-cell transcriptome. Through integrated analysis of scRNA-seq with microarray and bulk RNA sequencing data, a ferroptosis-related gene signature containing ACSL4, CTSB, and TLR4 genes that were associated with tuberculosis disease was identified. Four gene expression datasets from blood samples of patients with tuberculosis, latent tuberculosis infection, and healthy controls were used to assess the diagnostic value of the gene signature. The areas under the ROC curve for the combined gene signature were 1.000, 0.866, 0.912, and 0.786, respectively, in differentiating active tuberculosis from latent infection. During anti-tuberculosis treatment, the expression of the gene signature decreased significantly in cured patients with tuberculosis. In conclusion, the ferroptosis-related gene signature was associated with tuberculosis treatment efficacy and was a promising biomarker for differentiating active tuberculosis from latent infection.
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Principal Component Analysis (PCA) aims to acquire the principal component space containing the essential structure of data, instead of being used for mining and extracting the essential structure of data. In other words, the principal component space contains not only information related to the essential structure of data but also some unrelated information. This frequently occurs when the intrinsic dimensionality of data is unknown or when it has complex distribution characteristics such as multi-modalities, manifolds, etc. Therefore, it is unreasonable to identify noise and useful information based solely on reconstruction error. For this reason, PCA is unsuitable as a preprocessing technique for most applications, especially in noisy environment. To solve this problem, this paper proposes robust PCA based on fuzzy local information reservation (FLIPCA). By analyzing the impact of reconstruction error on sample discriminability, FLIPCA provides a theoretical basis for noise identification and processing. This not only greatly improves its robustness but also extends its applicability and effectiveness as a data preprocessing technique. Meanwhile, FLIPCA maintains consistent mathematical descriptions with traditional PCA while having few adjustable hyperparameters and low algorithmic complexity. Finally, we conducted comprehensive experiments on synthetic and real-world datasets, which substantiated the superiority of our proposed algorithm.
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Long non-coding RNAs are considered to be key regulatory factors of oncogenesis and tumor progression. It is reported that LINC00460 plays the role of oncogene in some tumors. However, LINC00460's role and mechanism of action in pancreatic cancer have not yet been fully elucidated. We identified LINC00460 by analyzing data from the Gene Expression Omnibus database. The role of LINC00460 in proliferation and metastasis was examined using CCK8, colony formation, wound healing, and transwell assays. The potential mechanisms of LINC00460 in regulating mRNA levels were elucidated by RNA pull-down, RNA immunoprecipitation, Chromatin immunoprecipitation, Co-immunoprecipitation, and Immunofluorescence assays. The results showed that LINC00460 was upregulated in pancreatic cancer cells and tissues. Highly expressed LINC00460 is significantly related to short survival of pancreatic cancer patients. Inhibition of LINC00460 attenuated pancreatic cancer cell proliferation and metastasis, whereas its overexpression reversed this effect. Mechanically, LINC00460 is induced by hypoxia, through binding of the hypoxia-inducible factor 1-α in the promoter region of LINC00460. Furthermore, LINC00460 functioned as an miR-4689 sponge to regulate the downstream target gene UBE2V1, enhancing the stability of mutant p53 in pancreatic cancer cells. LINC00460 also further promotes pancreatic cancer development by sequestering USP10, a cytoplasmic ubiquitin-specific protease that deubiquitinates p53 and enhances its stability. Collectively, our study demonstrated that LINC00460 is a hypoxia-induced lncRNA that plays the role of oncogene in pancreatic cancer by modulating the miR-4689/UBE2V1 axis, sequestering USP10, and ultimately enhancing the stability of mutant p53.
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MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Pancreáticas/genética , Proliferación Celular/genética , Hipoxia , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Factores de Transcripción/genética , Enzimas Ubiquitina-Conjugadoras/genética , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Bisphenol A (BPA), a typical environmental endocrine disruptor, is an "obesogen" that can induce lipid accumulation in the liver. Highly similar in structure to BPA, bisphenol F (BPF) is becoming the dominant BPA substitute on the market, which attracts more and more attention due to its potential adverse effects. Recently, BPF exposure is found to cause non-alcoholic fatty liver disease (NAFLD)-like changes; however, the underlying toxic effects remain poorly understood. Therefore, in the current study, we focused on BPF-mediated lipid homeostasis, especially the alterations of lipid components and metabolism. In human serum, the BPF levels in healthy controls and NAFLD patients were assessed by ELISA, and BPF-induced disturbance of lipid metabolism was evaluated in mouse model via non-targeted lipomic methods with ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. It suggested that BPF exposure was positively correlated with NAFLD severity and triglyceride level in patients. Based on the relationships, lipid metabolites were assessed in mouse livers between control and BPF-treated group, and it revealed that twenty-six lipid metabolites (including phospholipids, sphingolipids, and glycerides) were significantly changed in mouse livers. Phosphatidylcholine, phosphatidylethanolamine, and diglyceryl ester levels were lower than those in the control mice; hexose ceramide content in sphingolipids markedly increased in BPF-treated mouse livers. Noteworthily, the glycerophospholipid metabolic pathway was found to be the most pronounced in BPF-induced disturbance of lipid metabolism. Therefore, the current study, for the first time, is deciphering the BPF-induced lipid metabolic disturbance, which may provide novel intervention strategies for BPF-induced NAFLD-like changes.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipidómica , Modelos Animales de Enfermedad , Hígado , Compuestos de Bencidrilo/metabolismo , Lípidos , Esfingolípidos/metabolismo , Esfingolípidos/farmacologíaRESUMEN
Under the background of carbon peak and carbon neutrality, grassland carbon sinks are a key pathway to carbon neutrality. Based on the Coupled Model Intercomparison Project Phase 6 (CMIP6) climate scenario data, the Daycent model was used to simulate the carbon budget of Gansu grasslands from 2015 to 2100, and the trend analysis was used to study the spatial and temporal changes in grassland carbon budget in the next 78 years. The results revealed that, under the future climate scenario of SSP245, the net ecosystem productivity (NEP) indicated a non-significant fluctuating downward trend with a rate of -0.20 g·(m2·a)-1(in C, the same below), and the grassland carbon sink was in a declining state. Under the future climate scenario of SSP585, the grassland NEP indicated a significant fluctuating increase trend with a growth rate of 1.36 g·(m2·a)-1, and the grassland carbon sink gradually increased under this scenario; the spatial distribution of grassland carbon budget increased from northwest to southeast. The increase in temperature and precipitation under the SSP585 climate scenario was higher than that under the SSP245 climate scenario, and the grassland carbon budget strongly correlated positively with precipitation. However, a negative correlation was observed between grassland carbon budget and temperature. We identified the carbon sink intensity in Gansu grasslands under different climate conditions, which provides a reference for and contribution to effective carbon sequestration.
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Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8+ T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.
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Ascitis , Neoplasias Ováricas , Femenino , Humanos , Ascitis/patología , Linfocitos T CD8-positivos/patología , Ecosistema , Análisis de la Célula IndividualRESUMEN
BACKGROUND: circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown. METHODS: Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified. RESULTS: CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1. CONCLUSIONS: We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.
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Exosomas , MicroARNs , Neoplasias Pancreáticas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Proliferación Celular , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Hipoxia/genética , Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/genética , Neoplasias Pancreáticas/patología , ARN Circular/genética , Proteínas Supresoras de Tumor/genética , Enzimas Ubiquitina-Conjugadoras , Neoplasias PancreáticasRESUMEN
Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD), which represents the third leading cause of death worldwide. CS induces reactive oxygen species (ROS) production, leading to pulmonary inflammation and remodeling. NADPH oxidases (NOXs) represent essential sources of ROS production in the cardiovascular system. Whether and how NOX isoforms are activated in COPD patients and in response to acute cigarette smoke (ACS) remains incompletely understood. In the present study, the expression of NOX isoforms was examined in the lungs of end-stage COPD patients. In addition, mice silenced of NOX1 or NOX4 expression using in vivo RNA interference (RNAi), and NOX2-deficient (NOX2-/y) mice, were exposed to ACS for 1 h using a standard TE-10B smoking machine. In lung sections isolated from COPD patients undergoing lung transplantation, protein expression of NOX1, NOX2, NOX4, or NOX5 was markedly upregulated compared to non-smoking donor controls. Likewise, ACS upregulated protein expression of NOX1, NOX2, and NOX4, production of ROS, inflammatory cell infiltration, and mRNA expression of proinflammatory cytokines TNF-α and KC in the mouse lung. In vivo RNAi knockdown of NOX1 or NOX4 decreased ACS induced ROS production, inflammatory cell influx, and the expression of TNF-α and KC, which were accompanied by inhibition of the NF-κB-COX-2 axis. Although ACS induced ROS production was reduced in the lungs of NOX2-/y mice, inflammatory cell influx and expression of NF-κB/COX-2 were increased. Taken together, our results demonstrate for the first time that NOX isoforms 1, 2, 4 and 5 all remain activated in end-stage COPD patients, while NOX1 and NOX4 mediate oxidative stress and inflammatory responses in response to acute cigarette smoke. Therefore, targeting different isoforms of NOX might be necessary to treat COPD at different stages of the disease, which represents novel mechanistic insights enabling improved management of the devastating disease.
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The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Carcinoma Ductal Pancreático/metabolismo , Endopeptidasa Clp/metabolismo , Homeostasis , Humanos , Ratones , Neoplasias Pancreáticas/metabolismo , Péptido Hidrolasas/metabolismo , Proteoma/metabolismo , Neoplasias PancreáticasRESUMEN
In the present study, we investigated effects of Puerarin on the early oxidative and inflammatory responses in the lung triggered by acute cigarette smoking (ACS). C57BL/6 mice were exposed to ACS for 1 hr in the presence or absence of Puerarin and harvested at 2, 6, and 24 hours. ACS induced significant increases in superoxide production in mouse lungs at 2 and 6 hours; and superoxide production was also elevated in a time and concentration dependent manner in cigarette smoke extract (CSE) stimulated human small airway epithelial cells (HSAECs), which was dose-dependently abrogated by Puerarin. ACS exposure upregulated NOX1, NOX2, and NOX4 protein expression in mouse lungs. Likewise, NOX1 and NOX4 were upregulated in CSE-stimulated HSAECs. These responses were significantly or completely attenuated by Puerarin. ACS induced significant infiltrations of neutrophils and macrophages in mouse lung parenchyma and BAL fluid, which were completely or significantly abrogated by Puerarin, so was the activation of the NF-кB pathway and the upregulation in inflammatory mediators including TNF-α, KC (murine homolog of IL-8), COX-2, IL-6 and MCP-1. Nuclear translocation of p65, IL-8 secretion, and upregulation of COX-2 in CSE stimulated HSAECs were also markedly attenuated by Puerarin. Moreover, ACS or CSE stimulated upregulation in reactive oxygen species (ROS) production and expression of inflammatory mediators were alleviated by ROS scavenger TEMPO in vivo and vitro, with no synergy combining with Puerarin, indicating that the effects of Puerarin are redox-sensitive following activation of NOX. In summary, our data for the first time demonstrate that Puerarin robustly attenuates NOX isoform-dependent ROS production and inflammatory activation in ACS exposed mice and CSE treated HSAECs, indicating that Puerarin might be used as a robust therapeutic agent for early or early stage COPD.
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NADPH Oxidasas , Enfermedad Pulmonar Obstructiva Crónica , Animales , Ciclooxigenasa 2/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-8/metabolismo , Isoflavonas , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Superóxidos/farmacología , NicotianaRESUMEN
BACKGROUND: Prognosis for patients recurred rapidly after resection of pancreatic ductal adenocarcinoma (PDAC) was extremely poor. We proposed the concept of postoperative hyper-progression disease (PO-HPD) to define recurrence within 2 months after surgery, explored the role of surgery for postoperative HPD patients and determined the predictive preoperative risk factors and genomic features of PO-HPD. METHODS: 976 patients undergoing curative resection of PDAC were enrolled. Survival data of 1733 stage IV patients from the US Surveillance, Epidemiology and End Results database was also collected. Patients relapsed were grouped into 3 groups regarding of the recurrence time (within 2 months were PO-HPD, within 2 to 12 months were early recurrence (ER) and within > 12 months were late recurrence (LR)). Risk factors for PO-HPD were explored with logistic regression models. Genomic features of 113 patients were investigated using next-generation sequencing-based gene panel testing. RESULTS: 718 of 976 cases relapsed, 101were PO-HPD, 418 were ER and 199 were LR. Total survival of PO-HPD was 12.5 months, shorter than that of ER (16.7 months) and LR (35.1 months), and verged on that of stage IV patients (10.6 months). Preoperative risk factors for PO-HPD included red blood cell count < 3.94*10^12/L, CA19-9 ≥ 288.6 U/mL, CA125 ≥ 22.3 U/mL and tumor size≥3.45 cm. Mutations of CEBPA, ATR and JAK1 were only identified in PO-HPD and they owned lower level of CN gain compared to others. CONCLUSIONS: Prognosis of PO-HPD was extremely poor and the role of surgery for PO-HPD should be prudently assessed.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirugía , Humanos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/genética , Pancreatectomía/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
BACKGROUND: Increased postoperative serum amylase has been recently reported to be associated with increased postoperative morbidity, but studies on postoperative serum lipase are limited. The aim of this study was to evaluate the value of postoperative serum lipase in predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). METHOD: A retrospective analysis was performed on 212 patients who underwent PD from September 2018 and March 2021, focusing on the association between postoperative day (POD) 1 serum lipase and CR-POPF. RESULTS: Overall, 108 (50.9%) patients had elevated serum lipase levels (>68 U/L) on POD 1. Patients with elevated serum lipase exhibited a significantly higher incidence of CR-POPF (37.0% vs. 6.7%, p < 0.001). Receiver operating characteristic (ROC) analyses showed improved diagnostic accuracy for POD 1 serum lipase compared with POD 1 serum amylase in predicting CR-POPF (AUC: 0.801 vs. 0.745, p = 0.029). Elevated serum lipase on POD 1 and elevated serum CRP on POD 3 were identified as independent predictors of CR-POPF. A simple early postoperative model, consisting of POD 1 serum lipase levels and POD 3 serum CRP levels, showed good discrimination (AUC 0.76, 95% CI 0.69-0.83) to identify the onset of CR-POPF. CONCLUSION: Serum lipase on POD 1 outperformed serum amylase on POD 1 in predicting CR-POPF after PD. The combination of POD 1 serum lipase and POD 3 serum CRP provides a reliable predicting model for CR-POPF.
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Fístula Pancreática , Pancreaticoduodenectomía , Amilasas , Drenaje/efectos adversos , Humanos , Lipasa , Fístula Pancreática/diagnóstico , Fístula Pancreática/epidemiología , Fístula Pancreática/etiología , Pancreaticoduodenectomía/efectos adversos , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The metabolic processes of cities and their embedded regions have received great attention, but it is still unclear how the metabolic processes change at the scale from cities to urban agglomerations. In view of the lack of multi-scale research in the field of urban metabolism, this study took Beijing-Tianjin-Hebei region, one of the urban agglomerations with largest economic scales in China, as a case to construct metabolic network models at two scales of city and urban agglomeration. The material transfers between nodes were calculated, and the connection degree index was put forward in the ecological network analysis to quantify the influence of a single node on the network when multi-level transfers were considered. On this basis, the similarities and differences of metabolic nodes at the two scales were analyzed. The results showed that nearly 97% of the volume of material transfers in the urban agglomeration was concentrated within the cities, among which the transfer volumes of Tangshan, Handan, and Shijiazhuang were more than 600 Mt. Manufacturing and environment were the major contributors to material transfers. The connection degrees of nodes had both commonness and differences at the two scales. In general, the connection degrees at the urban scale were relatively homogeneous, while their difference was large at the urban agglomeration scale. The connection degrees of nodes in Langfang were prominent at the urban agglomeration scale. The connection degrees of environment and manufacturing ranked top 3 at both scales. Meanwhile, the connection degree of energy conversion at the urban scale was relatively high, while its influence was replaced by mining sector at the urban agglomeration scale. The analysis of material metabolic nodes in Beijing-Tianjin-Hebei region can provide theoretical supports to position the key points in the process of material utilization in the cities or the urban agglomeration, and help to identify the breakthrough points for subsequent regulatory.
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Ambiente , Remodelación Urbana , Beijing , China , CiudadesRESUMEN
BACKGROUND: Stanniocalcin 1 (STC1) plays an integral role in ovarian cancer (OC). However, the functional role of STC1 in metastasis, lipid metabolism and cisplatin (DDP) chemoresistance in OC is not fully understood. METHODS: Single-cell sequencing and IHC analysis were performed to reveal STC1 expression profiles in patient tissues. Metastasis, lipid metabolism and DDP chemoresistance were subsequently assessed. Cell-based in vitro and in vivo assays were subsequently conducted to gain insight into the underlying mechanism of STC1 in OC. RESULTS: Single-cell sequencing assays and IHC analysis verified that STC1 expression was significantly enhanced in OC tissues compared with para-carcinoma tissues, and it was further up-regulated in peritoneal metastasis tissues compared with OC tissues. In vitro and in vivo experiments demonstrated that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance in OC. Simultaneously, STC1 promoted lipid metabolism by up-regulating lipid-related genes such as UCP1, TOM20 and perilipin1. Mechanistically, STC1 directly bound to integrin ß6 (ITGB6) to activate the PI3K signaling pathway. Moreover, STC1 was directly regulated by Forkhead box C2 (FOXC2) in OC. Notably, targeting STC1 and the FOXC2/ITGB6 signaling axis was related to DDP chemoresistance in vitro. CONCLUSIONS: Overall, these findings revealed that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance via the FOXC2/ITGB6 signaling axis in OC. Thus, STC1 may be used as a prognostic indicator in patients with metastatic OC. Meanwhile, STC1 could be a therapeutic target in OC patients, especially those who have developed chemoresistance to DDP.
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Cisplatino , Glicoproteínas , Neoplasias Ováricas , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/metabolismo , Humanos , Cadenas beta de Integrinas/metabolismo , Metabolismo de los Lípidos , Metástasis de la Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de SeñalRESUMEN
Apple polyphenol extract (APE) has been reported to possess protective effects against hepatic steatosis. To explore whether APE-induced alleviation of hepatic steatosis is SIRT1-dependent, the present study was carried out using wild-type and hepatic SIRT1 heterozygous mutant (Sirt1+/-) C57BL/6 mice. On consideration of the sex disparity related to hepatic steatosis morbidity, both male and female mice were included in the study. Six to eight week old mice were fed a high-fat diet (HFD) and randomly assigned to one of the following groups: (1) wild-type mice (wt+HFD), (2) Sirt1+/- mice (Sirt1+/-+HFD), and (3) Sirt1+/- mice with 500 mg/(kg·bw·d) APE intragastric administration (Sirt1+/-+HAP). HFD-induced weight gain and triglyceride accumulation was more prominent in Sirt1+/- mice in comparison to wild-type mice. Following APE treatment, these effects were significantly reduced along with the alleviation of hepatic steatosis via upregulated expression of SIRT1 at the protein and mRNA levels in both male and female mice. However, APE differentially regulated the genes related to lipid metabolism (Lkb1, Ampk, Hsl, Srebp-1c, Abcg1, and Cd36) in a sex-specific manner. Moreover, APE treatment altered gut microbiota composition, with an increased relative abundance of Akkermansia and a decreased Firmicutes/Bacterodetes ratio. Thus, our study provided new evidence supporting our hypothesis that APE-induced alleviation of hepatic steatosis is SIRT1-dependent.
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Hígado Graso , Enfermedad del Hígado Graso no Alcohólico , Animales , Ácido Clorogénico , Dieta Alta en Grasa/efectos adversos , Hígado Graso/etiología , Hígado Graso/genética , Femenino , Flavonoides , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Sirtuina 1/genética , Sirtuina 1/metabolismo , TaninosRESUMEN
KRASâPDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (K D = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRASâPDEδ interaction.
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OBJECTIVE: Latent tuberculosis infection (LTBI) may be a risk of developing tuberculosis (TB) and thus a health hazard. The aim of this meta-analysis is to explore the association between vitamin D and LTBI. METHODS: Databases including PubMed, Embase, Scopus, and ProQuest were electronically searched to identify observational or interventional studies that reported the association between vitamin D and LTBI. The retrieval time is limited from inception to 30 September 2021. Two reviewers independently screened literature, extracted data, and assessed risk bias of included studies. Meta-analysis was performed by using STATA 12.0 software. RESULTS: A total of 5 studies involving 2 case-control studies and 3 cohort studies were included. The meta-analysis result showed that the risk of LTBI among individuals was not associated with high vitamin D level (OR 0.51, 95% CI 0.05-5.65, P = 0.58). The result from cohort studies also suggested that relatively high vitamin D level was not a protective factor for LTBI (RR = 0.56, 95%CI 0.19-1.67, P = 0.300). CONCLUSIONS: Our meta-analysis suggested that serum vitamin D levels were not associated with incidence of LTBI, and relatively high serum vitamin D level was not a protective factor for LTBI. Further RCTs are needed to verify whether sufficient vitamin D levels and vitamin D supplementation reduces the risk of LTBI.