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It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKß) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKß-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKß phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKß activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKß-mediated hepatic inflammation in glucose homeostasis.
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Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Glucose/metabolismo , Quinase I-kappa B/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Linhagem Celular Tumoral , Homeostase , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Fosforilação , Estabilidade ProteicaRESUMO
Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity.
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Fármacos Antiobesidade/administração & dosagem , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/metabolismo , Metabolismo Energético , Perfilação da Expressão Gênica , Glucose/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Camundongos , Triterpenos Pentacíclicos , Extratos Vegetais/administração & dosagem , Tripterygium/química , Triterpenos/administração & dosagemRESUMO
Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
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Proteínas Reguladoras de Apoptose/metabolismo , Benzilaminas/farmacologia , Endopeptidases/metabolismo , Quinazolinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Autofagia , Proteína Beclina-1 , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Camundongos , Proteases Específicas de Ubiquitina , UbiquitinaçãoRESUMO
Agent-based models have gained traction in exploring the intricate processes governing the spread of infectious diseases, particularly due to their proficiency in capturing nonlinear interaction dynamics. The fidelity of agent-based models in replicating real-world epidemic scenarios hinges on the accurate portrayal of both population-wide and individual-level interactions. In situations where comprehensive population data are lacking, synthetic populations serve as a vital input to agent-based models, approximating real-world demographic structures. While some current population synthesizers consider the structural relationships among agents from the same household, there remains room for refinement in this domain, which could potentially introduce biases in subsequent disease transmission simulations. In response, this study unveils a novel methodology for generating synthetic populations tailored for infectious disease transmission simulations. By integrating insights from microsample-derived household structures, we employ a heuristic combinatorial optimizer to recalibrate these structures, subsequently yielding synthetic populations that faithfully represent agent structural relationships. Implementing this technique, we successfully generated a spatially-explicit synthetic population encompassing over 17 million agents for Shenzhen, China. The findings affirm the method's efficacy in delineating the inherent statistical structural relationship patterns, aligning well with demographic benchmarks at both city and subzone tiers. Moreover, when assessed against a stochastic agent-based Susceptible-Exposed-Infectious-Recovered model, our results pinpointed that variations in population synthesizers can notably alter epidemic projections, influencing both the peak incidence rate and its onset.
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Doenças Transmissíveis , Epidemias , Humanos , Doenças Transmissíveis/epidemiologia , Dinâmica não Linear , China/epidemiologiaRESUMO
The lack of highly efficient and inexpensive catalysts severely hinders the large-scale application of Zn-air batteries (ZABs). High-entropy oxides (HEOs) exhibit unique structures and attractive properties; thus, they are promising to be used in ZABs. However, conventional high-temperature synthesis methods tend to obtain microscale HEOs with a lower exposure rate of active sites. Here, we report a facile solvothermal strategy for preparing two-dimensional (2D) HEO sub-1 nm nanosheets (SNSs) induced by polyoxometalate (POM) clusters. Taking advantage of the special 2D sub-1 nm structure and precise element regulation, these 2D HEOs-POM SNSs exhibit enhanced bifunctional oxygen evolution and oxygen reduction reaction activity under light irradiation. Further applying these 2D HEOs-POM SNSs to ZABs as cathode catalysts, the CoFeNiMnCuZnOx-phosphomolybdic acid SNSs-based ZABs deliver a low charge/discharge voltage gap of 0.25 V at 2 mA cm-2 under light irradiation. Meanwhile, it could maintain an ultralong-term stability for 1600 h at 2 mA cm-2 and 930 h at 10 mA cm-2. The 2D sub-1 nm structure and fine element control in HEOs provide opportunities to solve the problems of low intrinsic activity, limited active sites, and instability of air cathodes in ZABs.
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BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, nâ =â 32; AG, nâ =â 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; Pâ =â .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; Pâ <â .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; Pâ =â .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).
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Antibiotic resistant genes (ARGs) present significant risks to environments and public health. In particular, there is increasing awareness of the role of soil nitrogen in ARG dissemination. Here, we investigated the connections between antibiotic resistome and nitrogen-cycling microbes in paddy soil by performing five-year field experiments with the treatments of no nitrogen fertilization (CK), reduced chemical nitrogen fertilization (LN), conventional chemical nitrogen fertilization (CN) and plant-derived organic nitrogen fertilization (ON). Compared with CK treatment, CN and ON treatments significantly increased soil NH4+ and TN concentrations by 25.4%-56.5% and 10.4%-20.1%, respectively. Redundancy analysis revealed significantly positive correlation of NH4+ with most ARGs, including tetA, macB and barA. Correspondingly, CN and ON treatments enhanced ARG abundances by 21.9%-23.2%. Moreover, CN and ON treatments promoted nitrate/nitrite-reducing bacteria and linked the corresponding N-cycling functional genes (narG, narH, nirK and nrfA) with most ARGs. Metagenomic binning was performed and identified Gemmatimonadaceae, Caulobacteraceae, Ilumatobacteraceae and Anaerolineaceae as hosts for both ARGs and nitrate/nitrite reduction genes that were enriched by CN and ON treatments. Soil resistome risk score analysis indicated that, although there was increased relation of ARG to nitrogen-cycling microorganisms with nitrogen fertilizer application, the environmental risk of ARGs was not increased due to the lower distribution of ARGs in pathogens. This study contributed to a deeper understanding of the role of soil nitrogen in shaping ARG profiles and controlling soil resistome risk.
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Antibacterianos , Solo , Solo/química , Antibacterianos/farmacologia , Antibacterianos/análise , Fertilizantes/análise , Nitratos/análise , Nitritos/análise , Esterco/análise , Esterco/microbiologia , Bactérias/genética , Nitrogênio/análise , Microbiologia do Solo , Genes BacterianosRESUMO
Arbuscular mycorrhizal (AM) fungi are well known for enhancing phosphorus uptake in plants; however, their regulating roles in cation transporting gene family, such as natural resistance-associated macrophage protein (NRAMP), are still limited. Here, we performed bioinformatics analysis and quantitative expression assays of tomato SlNRAMP 1 to 5 genes under nutrient deficiency and cadmium (Cd) stress in response to AM symbiosis. These five SlNRAMP members are mainly located in the plasma or vacuolar membrane and can be divided into two subfamilies. Cis-element analysis revealed several motifs involved in phytohormonal and abiotic regulation in their promoters. SlNRAMP2 was downregulated by iron deficiency, while SlNRAMP1, SlNRAMP3, SlNRAMP4, and SlNRAMP5 responded positively to copper-, zinc-, and manganese-deficient conditions. AM colonization reduced Cd accumulation and expression of SlNRAMP3 but enhanced SlNRAMP1, SlNRAMP2, and SlNRMAP4 in plants under Cd stress. These findings provide valuable genetic information for improving tomato resilience to nutrient deficiency and heavy metal stress by developing AM symbiosis.
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Cádmio , Regulação da Expressão Gênica de Plantas , Micorrizas , Proteínas de Plantas , Solanum lycopersicum , Estresse Fisiológico , Simbiose , Micorrizas/fisiologia , Solanum lycopersicum/microbiologia , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Simbiose/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismoRESUMO
As one of the common and serious chronic complications of diabetes mellitus (DM), the related mechanism of diabetic retinopathy (DR) has not been fully understood. Müller cell reactive gliosis is one of the early pathophysiological features of DR. Therefore, exploring the manner to reduce diabetes-induced Müller cell damage is essential to delay DR. Thioredoxin 1 (Trx1), one of the ubiquitous redox enzymes, plays a vital role in redox homeostasis via protein-protein interactions, including apoptosis signal-regulating kinase 1 (ASK1). Previous studies have shown that upregulation of Trx by some drugs can attenuate endoplasmic reticulum stress (ERS) in DR, but the related mechanism was unclear. In this study, we used DM mouse and high glucose (HG)-cultured human Müller cells as models to clarify the effect of Trx1 on ERS and the underlying mechanism. The data showed that the diabetes-induced Müller cell damage was increased significantly. Moreover, the expression of ERS and reactive gliosis was also upregulated in diabetes in vivo and in vitro. However, it was reversed after Trx1 overexpression. Besides, ERS-related protein expression, reactive gliosis, and apoptosis were decreased after transfection with ASK1 small-interfering RNA in stable Trx1 overexpression Müller cells after HG treatment. Taken together, Trx1 could protect Müller cells from diabetes-induced damage, and the underlying mechanism was related to inhibited ERS via ASK1.
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Diabetes Mellitus , Retinopatia Diabética , Camundongos , Humanos , Animais , Células Ependimogliais/metabolismo , Gliose , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/farmacologia , Retinopatia Diabética/genética , Apoptose , Inflamação , Estresse do Retículo EndoplasmáticoRESUMO
Intraspecific recurrent selection in V. vinifera is an effective method for grape breeding with high quality and disease resistance. The core theory of this method is the substitution accumulation of multi-genes with low disease resistance. The discovery of multi-genes for disease resistance in V. vinifera may provide a molecular basis for breeding for disease resistance in V. vinifera. In this study, resistance to downy mildew was identified, and genetic analysis was carried out in the intraspecific crossing population of V. vinifera (Ecolly × Dunkelfelder) to screen immune, highly resistant and disease-resistant plant samples; transcriptome sequencing and differential expression analysis were performed using high-throughput sequencing. The results showed that there were 546 differential genes (194 up-regulated and 352 down-regulated) in the immune group compared to the highly resistant group, and 199 differential genes (50 up-regulated and 149 down-regulated) in the highly resistant group compared to the resistant group, there were 103 differential genes (54 up-regulated and 49 down-regulated) in the immune group compared to the resistant group. KEGG analysis of differentially expressed genes in the immune versus high-resistance group. The pathway is mainly concentrated in phenylpropanoid biosynthesis, starch and sucrose metabolism, MAPK signaling pathway-plant, carotenoid biosyn-thesis and isoquinoline alkaloid biosynthesis. The differential gene functions of immune and resistant, high-resistant and resistant combinations were mainly enriched in plant-pathogen interaction pathway. Through the analysis of disease resistance-related genes in each pathway, the potential minor resistance genes in V. vinifera were mined, and the accumulation of minor resistance genes was analyzed from the molecular level.
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Oomicetos , Vitis , Resistência à Doença/genética , Transcriptoma , Vitis/metabolismo , Melhoramento Vegetal , Oomicetos/genética , Doenças das Plantas/genética , Regulação da Expressão Gênica de Plantas , Perfilação da Expressão GênicaRESUMO
Cadmium (Cd) contamination in rice grains is posing a significant threat to global food security. To restrict the transport of Cd in the soil-rice system, an efficient way is to use the ionomics strategy. Since calcium (Ca) and Cd have similar ionic radii, their uptake and translocation may be linked in multiple aspects in rice. However, the underlying antagonistic mechanisms are still not fully understood. Therefore, we first summarized the current knowledge on the physiological and molecular footprints of Cd translocation in plants and then explored the potential antagonistic points between Ca and Cd in rice, including exchange adsorption on roots, plant cell-wall composition, co-transporter gene expression, and transpiration inhibition. This review provides suggestions for Ca/Cd interaction studies on rice and introduces ionomics research as a means of better controlling the accumulation of Cd in plants.
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Oryza , Poluentes do Solo , Cádmio/metabolismo , Cálcio/metabolismo , Oryza/genética , Oryza/metabolismo , Transporte Biológico , Solo , Cálcio da Dieta/metabolismo , Poluentes do Solo/metabolismo , Raízes de Plantas/metabolismoRESUMO
BACKGROUND: Mycotoxins are secondary metabolites produced by fungi, which have serious effects on humans and animals. In this study, we selected the monodispersed polystyrene fluorescent microspheres with good luminescence performance and strong stability as markers to conjugate with four mycotoxins antibodies for preparing fluorescent probes. We have developed a fluorescent microsphere based immunochromatographic assay (FMICA) to detect sensitively and quickly zearalenone (ZEN), aflatoxin B1 (AFB1 ), fumonisin B1 (FB1 ), and ochratoxin A (OTA) in cereal. RESULTS: Under optimal experimental conditions, the procedure of this method can be completed within 10 min. The limit of detection (LOD) of FMICA for ZEN, AFB1 , FB1 , and OTA is 0.072, 0.093, 0.32, and 0.19 µg L-1 , respectively. And FMICA has good specificity and no cross-reactivity with other mycotoxins. Four mycotoxins in naturally contaminated cereal samples (corn, rice, and oat) are detected by this method, and the results are highly consistent with that of ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). CONCLUSION: The developed FMICA has good accuracy, high sensitivity, simplicity, convenience, rapidity, and low cost, and it could be employed for sensitive and quantitative detecting of mycotoxins in cereal on-site. © 2022 Society of Chemical Industry.
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Micotoxinas , Zearalenona , Humanos , Animais , Micotoxinas/análise , Grão Comestível/química , Microesferas , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Zearalenona/análise , Imunoensaio/métodos , Contaminação de Alimentos/análiseRESUMO
Transition metal oxide (TMO) anode materials in lithium-ion batteries (LIBs) usually suffer from serious volume expansion leading to the pulverization of structures, further giving rise to lower specific capacity and worse cycling stability. Herein, by introducing polyoxometalate (POM) clusters into TMOs and precisely controlling the amount of POMs, the MnZnCuOx -phosphomolybdic acid hybrid sub-1â nm nanosheets (MZC-PMA HSNSs) anode is successfully fabricated, where the special electron rich structure of POMs is conducive to accelerating the migration of lithium ions on the anode to obtain higher specific capacity, and the non-covalent interactions between POMs and TMOs make the HSNSs possess excellent structural and chemical stability, thus exhibiting outstanding electrochemical performance in LIBs, achieving a high reversible capacity (1157â mAh g-1 at 100â mA g-1 ) and an admirable long-term cycling stability at low and high current densities.
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High entropy oxides (HEOs) with fascinating physical and chemical properties have exhibited unprecedented application potential in many fields. However, it remains a huge challenge to realize the precise control of the dimension and morphology at the sub-1 nm scale. Herein, with the aid of polyoxometalate (POM) clusters, we first develop a versatile strategy to realize the controllable incorporation of multiple immiscible metal oxides into sub-1 nm nanowires (SNWs) under 140 °C to obtain a wide range of HEO-POM SNWs with highly ordered structures, where the species of metal oxides and POMs could be regulated flexibly. Meanwhile, these obtained HEO materials are first to be used as anodes in Na-ion batteries. Benefiting from the effect of entropy modulation, these HEO-POM SNWs show better electrochemical properties in Na-ion batteries with the increase of metal oxide species stepwise. A long cycle life with a capacity retention of â¼92% even after 5000 cycles at 10C further confirms the good stability under fast discharging/charging. This method opens a new insight for designing and preparing HEOs at the sub-1 nm scale under facile conditions.
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Crotonaldehyde (CRA)-one of the major environmental pollutants from tobacco smoke and industrial pollution-is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, ß-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA.
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Clear cell renal cell carcinoma (ccRCC) is one frequent form of urologic malignancy characterized by deregulated hypoxia-inducible factor signaling, genetic and epigenetic alterations. Metastasis is the leading cause of mortality from ccRCC, and understanding the underlying mechanism of this event will provide better strategies for its management. Here, we identify tripartite motif containing 7 (TRIM7) as a tumor suppressor in ccRCC cells, which negatively regulates hypoxia-inducible factor 1α (HIF-1α) signaling through targeting the proto-oncogene Src. We observed the downregulated expression of TRIM7 in clinical ccRCC tissues and its correlation with the poor prognosis. In Caki-1 cells, depletion of TRIM7 increased cell migration and invasion under normoxic and hypoxic conditions. TRIM7 markedly reduced the abundance of Src protein via the ubiquitin-proteasome pathway. Further study showed that TRIM7 affected HIF-1α accumulation through targeting either the Src-triggered PI3K/AKT/mTOR signaling pathway or reactive oxygen species production. Overall, our findings highlight a novel mechanism for negative regulation of HIF-1 signaling pathway by TRIM7 and define a promising therapeutic strategy for ccRCC by modulating TRIM7.
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Carcinoma de Células Renais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune paraneoplastic encephalitis, and is primarily associated with ovarian teratomas. Here, we report the first case of a patient diagnosed with chronic myelogenous leukemia (CML) during the recovery phase of anti-NMDAR encephalitis. CASE PRESENTATION: The patient was admitted with fever, headache, and seizures. Brain MRI revealed a cerebrospinal fluid (CSF)-containing arachnoid cyst in the left temporal lobe with no other abnormal signals. EEG showed diffuse background slowing in the delta-theta range. The patient tested positive for anti-NMDAR antibodies in both the serum and CSF. One year after the onset of encephalitis, the patient was referred to the Department of Hematology for extreme leukocytosis. Karyotype analysis showed the presence of Philadelphia chromosome t(9;22)(q34;q11). Quantitative reverse transcriptase PCR analysis further identified BCR/ABL1 fusion transcripts; thus, CML was diagnosed. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-NMDAR encephalitis associated with CML. This report should alert clinicians to consider CML as a malignancy that is possibly associated with limbic encephalitis.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Leucemia Mielogênica Crônica BCR-ABL Positiva , Encefalite Límbica , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite , Doença de Hashimoto , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Receptores de N-Metil-D-AspartatoRESUMO
Progressive loss and dysfunction of islet ß-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet ß-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of ß-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced ß-cell death and promotes ß-cell regeneration. rReg3α could serve as a potential drug for ß-cell maintenance in anti-diabetic treatment.
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Células Secretoras de Insulina , Insulinas , Ilhotas Pancreáticas , Pancreatite , Doença Aguda , Animais , Apoptose , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Aglutininas do Germe de Trigo/farmacologiaRESUMO
Two-dimensional (2D) zinc oxides have attracted more and more research interests due to their unique properties. Yet, it remains a great challenge to limit the thickness to the sub-1 nm scale and further combine with other components to obtain 2D hybrid zinc oxide (ZnO)-based sub-1 nm materials. Herein, a versatile strategy was successfully developed to realize the controllable preparation of ZnO-polyoxometalate (POM)-based 2D hybrid sub-1 nm nanosheet (HSNS) superstructures by incorporating three kinds of molybdenum-based POM clusters into the zinc oxide system. Molecular dynamics simulation results demonstrated that POM clusters interact with ZnO/Zn(OH)2 molecules and coassembled into stable 2D HSNSs. Significantly, theses materials as robust catalysts showed excellent catalytic activity, selectivity, and stability in the oxidation of thioethers at room temperature, which partly can be attributed to the special 2D sub-1 nm nanostructures with large specific areas leading to the full exposure of active sites. Meanwhile, the synergetic effect of multiple components also played an important role during the catalytic process. Thus, this work would pave the way for the precise synthesis of multicomponent 2D hybrid sub-1 nm materials for widespread applications.
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BACKGROUND: Cervical cancer seriously threatens both the health and life of women. We aimed to investigate whether RNA interference of long non-coding RNA (lncRNA) DCST1-AS1 could promote miR-874-3p expression to affect the proliferation, migration and invasion of cervical cancer cells. METHODS: DCST1-AS1 expression levels in cervical cancer cells and transfection effects were detected by quantitative reverse transcriptase-polymerase chain reaction analysis. Proliferation, invasion and migration of cells were separately shown by cell-counting kit-8, wound healing and transwell assays, and relative protein expression was determined by western blot analysis. Dual-luciferase reporter and RNA immunoprecipitation assays verified the interaction of DCST1-AS1 and miR-874-3p. RESULTS: DCST1-AS1 expression was increased in cervical cancer tissues and cells. The DCST1-AS1 expression in Hela and SiHa cells was the highest, and so the cells were selected for the next experiment. Inhibition of DCST1-AS1 suppressed the proliferation, invasion and migration of cervical cancer cells and decreased the expression of KI67, proliferating cell nuclear antigen, matrix metalloproteinase (MMP)-2 and MMP-9. miR-874-3p expression was increased when cells were transfected with miR-874-3p mimic or shRNA-DCST1-AS1-1, and DCST1-AS1 expression was down-regulated when cells were transfected with miR-874-3p mimic. DCST1-AS1 can directly target miR-874-3p. Furthermore, inhibition of miR-874-3p could effectively alleviate the effect of inhibition of DCST1-AS1 with respect to the proliferation, invasion and migration of cervical cancer cells. CONCLUSIONS: Inhibition of DCST1-AS1 suppressed the proliferation, migration and invasion of cervical cancer cells by increasing miR-874-3p expression, which could be alleviated by the inhibition of miR-874-3p.