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Objective: Triple-negative breast cancer (TNBC) poses a significant challenge for treatment efficacy. CD8+ T cells, which are pivotal immune cells, can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology. By leveraging these genes, our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy. Methods: Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases. In the initial stage, we identified 67 differentially expressed genes associated with immune response in CD8+ T cells. Subsequently, we narrowed our focus to three key genes, namely CXCL13, GBP2, and GZMB, which were used to construct a prognostic model. The accuracy of the model was assessed using the validation set data and receiver operating characteristic (ROC) curves. Furthermore, we employed various methods, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, immune infiltration, and correlation analyses with CD274 (PD-L1) to explore the model's predictive efficacy in immunotherapeutic responses. Additionally, we investigated the potential underlying biological pathways that contribute to divergent treatment responses. Results: We successfully developed a model capable of predicting the prognosis of patients with TNBC. The areas under the curve (AUC) values for the 1-, 3-, and 5-year survival predictions were 0.618, 0.652, and 0.826, respectively. Employing this risk model, we stratified the samples into high- and low-risk groups. Through KEGG enrichment analysis, we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism, whereas the low-risk group demonstrated significant enrichment in cytokine pathways. Furthermore, immune landscape analysis revealed noteworthy variations between (PD-L1) expression and risk scores, indicating that our model effectively predicted the response of patients to immune-based treatments. Conclusion: Our study demonstrates the potential of CXCL13, GBP2, and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC. These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.
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Linfocitos T CD8-positivos , Inmunoterapia , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Humanos , Linfocitos T CD8-positivos/inmunología , Pronóstico , FemeninoRESUMEN
This study aims to discern the possible molecular mechanism of the effect of ubiquitin-specific peptidase 18 (USP18) on the resistance to BRAF inhibitor vemurafenib in BRAF V600E mutant melanoma by regulating cyclic GMP-AMP synthase (cGAS). The cancer tissues of BRAF V600E mutant melanoma patients before and after vemurafenib treatment were collected, in which the protein expression of USP18 and cGAS was determined. A BRAF V600E mutant human melanoma cell line (A2058R) resistant to vemurafenib was constructed with its viability, apoptosis, and autophagy detected following overexpression and depletion assays of USP18 and cGAS. Xenografted tumors were transplanted into nude mice for in vivo validation. Bioinformatics analysis showed that the expression of cGAS was positively correlated with USP18 in melanoma, and USP18 was highly expressed in melanoma. The expression of cGAS and USP18 was up-regulated in cancer tissues of vemurafenib-resistant patients with BRAF V600E mutant melanoma. Knockdown of cGAS inhibited the resistance to vemurafenib in A2058R cells and the protective autophagy induced by vemurafenib in vitro. USP18 could deubiquitinate cGAS to promote its protein stability. In vivo experimentations confirmed that USP18 promoted vemurafenib-induced protective autophagy by stabilizing cGAS protein, which promoted resistance to vemurafenib in BRAF V600E mutant melanoma cells. Collectively, USP18 stabilizes cGAS protein expression through deubiquitination and induces autophagy of melanoma cells, thereby promoting the resistance to vemurafenib in BRAF V600E mutant melanoma.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Animales , Ratones , Humanos , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Ratones Desnudos , Indoles/farmacología , Indoles/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Resistencia a Antineoplásicos/genética , Mutación , Línea Celular Tumoral , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Autofagia/genética , Nucleotidiltransferasas/genética , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/farmacologíaRESUMEN
Background: Although the overall global incidence of gastric cancer has been declining, the number of new cases in people under the age of 50 is increasing, which is related to metastasis, late pathological stages, and poor prognosis. There is a scarcity of large-scale studies to evaluate and predict distant metastasis in patients with early-onset gastric cancer. Methods: From January 2010 to December 2019, data on early-onset GC patients undergoing surgery were gathered from the Surveillance, Epidemiology, and End Results (SEER) database. We investigated the independent risk factors for distant metastasis in patients with early-onset gastric cancer. Based on these risk factors, we developed a nomogram to predict distant metastasis. The model underwent internal validation on the test set and external validation on 205 patients from the First Affiliated Hospital of Sun Yat-sen University and the seventh Affiliated Hospital of Sun Yat-sen University. The novel nomogram model was then evaluated using the receiver operating characteristic (ROC) curve, calibration, the area under the curve (AUC), and decision curve analysis (DCA). The training set nomogram score was used to classify the different risk clusters of distant metastasis. Results: Our study enrolled 2217 patients after establishing the inclusion and exclusion criteria, with 1873 having no distant metastasis and 344 having distant metastasis. The tumor size, total lymph nodes, whether or not receiving radiotherapy and chemotherapy, T stage, and N stage were significant predictors of advanced distant metastasis (p < 0.05). The AUC of the ROC analysis demonstrated our model's high accuracy. Simultaneously, the prediction model shows high stability and clinical practicability in the calibration curve and DCA analysis. Conclusions: We developed an innovative nomogram containing clinical and pathological characteristics to predict distant metastasis in patients younger than 50 years old with gastric cancer. The tool can alert clinicians about distant metastasis and help them develop more effective clinical treatment plans.
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OBJECTIVE: We conducted an in-depth study of the immune system and ferroptosis to identify prognostic biomarkers and therapeutic targets for renal clear cell carcinoma. METHODS: Immune ferroptosis-related differentially expressed genes (IFR-DEGs) were selected from The Cancer Genome Atlas (TCGA). A lasso-Cox risk scoring model was established; its prognostic value was determined using prognostic analysis and single multivariate Cox analysis. Model genes were subjected to subcellular fluorescence localization, mRNA and protein expression analyses, and single-cell RNA sequencing localization analysis. Risk score was analyzed using the immune score, immune infiltrating cell correlation, immune checkpoint, TIDE, and drug sensitivity. RESULTS: A total of 103 IFR-DEGs were identified; a risk model comprising ACADSB, CHAC1, LURAP1L, and PLA2G6 was established. The survival curve, single multivariate Cox regression, and receiver operating characteristic (ROC) curve analysis showed that the model had good predictive ability (p < 0.05). It was also validated using the validation set and total cohort. Subcellular fluorescence localization revealed that ACADSB, CHAC1, and PLA2G6 were distributed in the cytoplasm and LURAP1L in the nucleus. The mRNA and protein expression trends were consistent. Single-cell RNA sequencing mapping revealed that ACADSB was enriched in distal tubule cell clusters. In the Kidney renal clear cell carcinoma (KIRC) mutation correlation analysis, 1.56% of the patients were found to have genetic alterations; The Spearman correlation analysis of model gene mutations showed that ACADSB was positively correlated with LURAP1L, which may have a synergistic effect; it was negatively correlated with CHAC1 and PLA2G6, and CHAC1 was negatively correlated with LURAP1L, which may have an antagonistic effect. Model and immune correlation analyses found that high-risk patients had significantly higher levels of CD8+ T cells, regulatory T cells (Tregs), immune checkpoints, immune scores, and immune escape than those in low-risk patients. High-risk patients had a higher susceptibility to small-molecule drugs. CONCLUSION: A novel prognostic model of immune ferroptosis-related genes (ACADSB, CHAC1, LURAP1L, and PLA2G6), which plays an important role in immune infiltration, microenvironment, and immune escape, was constructed. It effectively predicts the survival of patients with KIRC.
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MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.
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The design of artificial photocatalytic devices that simulates the ingenious and efficient photosynthetic systems in nature is promising. Herein, a metal-organic cage [Pd6(NPyCzPF)12]12+ (MOC-PC6) integrating 12 organic ligands NPyCzBP and 6 Pd2+ catalytic centers is designed, which is well defined to include organic dye fluorescein (FL) for constructing a supramolecular photochemical molecular device (SPMD) FL@MOC-PC6. Photoinduced electron transfer (PET) between MOC-PC6 and the encapsulated FL has been observed by steady-state and time-resolved emission spectroscopy. FL@MOC-PC6 is successfully heterogenized with TiO2 by a facile sol-gel method to achieve a robust heterogeneous FL@MOC-PC6-TiO2. The close proximity between the Pd2+ catalytic site and FL included in the cage enables PET from the photoexcited FL to Pd2+ sites through a powerful intramolecular pathway. The photocatalytic hydrogen production assessments of the optimized 4 wt % FL@MOC-PC6-TiO2 demonstrate an initial H2 production rate of 2402 µmol g-1 h-1 and a turnover number of 4356 within 40 h, enhanced by 15-fold over that of a homogeneous FL@MOC-PC6. The effect of the MOC content on photocatalytic H2 evolution (PHE) is investigated and the inefficient comparison systems, such as MOC-PC6, MOC-PC6-TiO2, FL-sensitized MOC-PC6/FL-TiO2, and analogue FL/MOC-PC6-TiO2 with free FL, are evaluated. This study provides a creative and distinctive approach for the design and preparation of novel heterogeneous SPMD catalysts based on MOCs.
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BACKGROUND: Dysfunction of cerebral autoregulation is one of the pathophysiological mechanisms that causes delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Pressure reactivity index (PRx) have been confirmed to reflect the level of cerebral autoregulation and used to derive optimal cerebral perfusion pressure (CPPopt). The goal of this study is to explore the associations between autoregulation, CPPopt, PRx, and DCI. METHODS: Continuous intracranial pressure (ICP), arterial blood pressure (ABP), and cerebral perfusion pressure (CPP) signals acquired from 61 aSAH patients were retrospectively analyzed. PRx was calculated and collected by Pneumatic computer system. The CPP at the lowest PRx was determined as the CPPopt. The duration of a hypoperfusion event (dHP) was defined as the cumulative time that the PRx was > 0.3 and the CPP was
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Long nanopore reads are advantageous in de novo genome assembly. However, nanopore reads usually have broad error distribution and high-error-rate subsequences. Existing error correction tools cannot correct nanopore reads efficiently and effectively. Most methods trim high-error-rate subsequences during error correction, which reduces both the length of the reads and contiguity of the final assembly. Here, we develop an error correction, and de novo assembly tool designed to overcome complex errors in nanopore reads. We propose an adaptive read selection and two-step progressive method to quickly correct nanopore reads to high accuracy. We introduce a two-stage assembler to utilize the full length of nanopore reads. Our tool achieves superior performance in both error correction and de novo assembling nanopore reads. It requires only 8122 hours to assemble a 35X coverage human genome and achieves a 2.47-fold improvement in NG50. Furthermore, our assembly of the human WERI cell line shows an NG50 of 22 Mbp. The high-quality assembly of nanopore reads can significantly reduce false positives in structure variation detection.
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Nanoporos , Análisis de Secuencia de ADN , Línea Celular , Cromosomas Humanos/genética , Genoma Humano , Humanos , Retinoblastoma/genética , Programas InformáticosRESUMEN
Kasabach-Merritt phenomenon (KMP) is a rare disease that is characterized by severe thrombocytopenia and consumptive coagulation dysfunction caused by kaposiform hemangioendothelioma or tufted hemangioma. This condition primarily occurs in infants and young children, usually with acute onset and rapid progression. This review article introduced standardized recommendations for the pathogenesis, clinical manifestation, diagnostic methods and treatment process of KMP in China, which can be used as a reference for clinical practice.
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Síndrome de Kasabach-Merritt/diagnóstico , Síndrome de Kasabach-Merritt/terapia , Niño , China/epidemiología , Diagnóstico Diferencial , Humanos , Síndrome de Kasabach-Merritt/epidemiología , Nivel de AtenciónRESUMEN
Emerging evidence indicates that pentraxin 3 is an acute-phase protein that is linked with the immune response to inflammation. It is also a newly discovered marker of anti-inflammatory A2 reactive astrocytes, and potentially has multiple protective effects in stroke; however, its role in the adult brain after traumatic brain injury is unknown. In the present study, a moderate model of traumatic brain injury in mice was established using controlled cortical impact. The models were intraventricularly injected with recombinant pentraxin 3 (the recombinant pentraxin 3 group) or an equal volume of vehicle (the control group). The sham-operated mice underwent craniotomy, but did not undergo the controlled cortical impact. The potential neuroprotective and neuroregenerative roles of pentraxin 3 were investigated on days 14 and 21 after traumatic brain injury. Western blot assay showed that the expression of endogenous pentraxin 3 was increased after traumatic brain injury in mice. Furthermore, the neurological severity test and wire grip test revealed that recombinant pentraxin 3 treatment reduced the neurological severity score and increased the wire grip score, suggesting an improved recovery of sensory-motor functions. The Morris water maze results demonstrated that recombinant pentraxin 3 treatment reduced the latency to the platform, increased the time spent in the correct quadrant, and increased the number of times traveled across the platform, thus suggesting an improved recovery of cognitive function. In addition, to investigate the effects of pentraxin 3 on astrocytes, specific markers of A2 astrocytes were detected in primary astrocyte cultures in vitro using western blot assay. The results demonstrated that pentraxin 3 administration activates A2 astrocytes. To explore the protective mechanisms of pentraxin 3, immunofluorescence staining was used. Intraventricular injection of recombinant pentraxin 3 increased neuronal maintenance in the peri-injured cortex and ipsilateral hippocampus, increased the number of doublecortin-positive neural progenitor cells in the subventricular and subgranular zones, and increased the number of bromodeoxyuridine (proliferation) and neuronal nuclear antigen (mature neuron) double-labeled cells in the hippocampus and peri-injured cortex. Pentraxin 3 administration also increased the number of neurospheres and the number of bromodeoxyuridine and doublecortin double-labeled cells in neurospheres, and enhanced the proliferation of neural progenitor cells in primary neural progenitor cell cultures in vitro. In conclusion, recombinant pentraxin 3 administration activated A2 astrocytes, and consequently improved the recovery of neural function by increasing neuronal survival and enhancing neurogenesis. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China on March 1, 2016.
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INTRODUCTION: Axonal injury results in long-term neurological deficits in traumatic brain injury (TBI) patients. Apolipoprotein E (ApoE) has been reported to activate intracellular adaptor protein Disabled-1 (Dab1) phosphorylation via its interaction with ApoE receptors. The Dab1 pathway acts as a regulator of axonal outgrowth and growth cone formation in the brain. AIMS: We hypothesized that ApoE may alleviate axonal injury and regulate axonal regeneration via the Dab1 pathway after TBI. RESULTS: In this study, we established a model of controlled cortical impact (CCI) to mimic TBI in vivo. Using diffusion tensor imaging to detect white matter integrity, we demonstrated that APOE-deficient mice exhibited lower fractional anisotropy (FA) values than APOE+/+ mice at 28 days after injury. The expression levels of axonal regeneration and synapse plasticity biomarkers, including growth-associated protein 43 (GAP43), postsynaptic density protein 95 (PSD-95), and synaptophysin, were also lower in APOE-deficient mice. In contrast, APOE deficiency exerted no effects on the levels of myelin basic protein (MBP) expression, oligodendrocyte number, or oligodendrocyte precursor cell number. Neurological severity score (NSS) and behavioral measurements in the rotarod, Morris water maze, and Y maze tests revealed that APOE deficiency caused worse neurological deficits in CCI mice. Furthermore, Dab1 activation downregulation by the ApoE receptor inhibitor receptor-associated protein (RAP) or Dab1 shRNA lentivirus attenuated the beneficial effects of ApoE on FA values, GAP43, PSD-95, and synaptophysin expression, and neurological function tests. Additionally, the effects of ApoE on axonal regeneration were further validated in vitro. In a mechanical scratch injury model of primary cultured neurons, recombinant ApoE protein treatment enhanced axonal outgrowth and growth cone formation in injured neurons; however, these effects were attenuated by Dab1 shRNA, consistent with the in vivo results. CONCLUSION: Collectively, these data suggest that ApoE promotes axonal regeneration partially through the Dab1 pathway, thereby contributing to functional recovery following TBI.
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Apolipoproteínas E/administración & dosificación , Lesiones Traumáticas del Encéfalo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal/fisiología , Sustancia Blanca/metabolismo , Animales , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Células Cultivadas , Imagen de Difusión Tensora/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/efectos de los fármacosRESUMEN
Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
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Antiparkinsonianos/farmacología , Autofagia/efectos de los fármacos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Encéfalo/efectos de los fármacos , Curcumina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Naftiridinas/farmacología , Estrés Oxidativo/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Ácido Ascórbico , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Curcumina/análogos & derivados , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Ratones Endogámicos C57BL , Mitofagia/efectos de los fármacos , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitum alkaloids are responsible for its pharmacological activity and toxicity. Although a large number of studies on Fuzi have been reported, no comprehensive review on its pharmacokinetics has yet been published. PURPOSE: This paper seeks to present a comprehensive review regarding the phytochemistry, pharmacokinetic features and toxicity of Fuzi. The regulation of drug-metabolizing enzymes (DMEs) and efflux transporters (ETs) by Fuzi is also concluded. Additionally, the use of Fuzi as a personalized medicine based on the bioavailability barrier (BB), which mainly comprises DMEs and ETs, is discussed. METHODS: All available information on Fuzi was collected by searching for key words in PubMed, ScienceDirect, CNKI, Google Scholar, Baidu Scholar, and Web of Science. RESULTS: Aconitum alkaloids, which mainly include diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and unesterified-diterpene alkaloids (UDAs), could be detected after Fuzi ingestion in vivo. The Aconitum alkaloids are rapidly absorbed in the intestine and extensively distributed in the body. DMEs, especially CYP3A4/5, are responsible for various types of metabolic reactions of the Aconitum alkaloids. ETs, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), are involved in the efflux of the DDAs and MDAs. The kidney is the most important organ involved in the excretion of the Aconitum alkaloids. DDAs are the main toxic compounds present in Fuzi, and their acute toxicity is mainly due to their effects on the voltage-dependent sodium channels. Furthermore, Fuzi can substantially regulate DMEs and ETs. CONCLUSIONS: The toxicity of DDAs is acute. However, further investigations are necessary to determine the exact toxicological mechanisms. The significant impact of Fuzi on DMEs and ETs suggests that the co-administration of Fuzi with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions (HDIs). The BB network controlled exposure to the Aconitum alkaloids in vivo. Polymorphisms of DMEs and ETs in different individuals contribute to the differences in the efficacy and toxicity of Fuzi ingestion. In the future, the use of Fuzi as personalized medicine based on the BB network is necessary and practical to achieve ideal therapeutic efficacy with minimal toxicity.
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Diterpenos/química , Diterpenos/farmacocinética , Aconitum/química , Alcaloides/química , Alcaloides/farmacocinética , Alcaloides/farmacología , Animales , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Diterpenos/toxicidad , Medicamentos Herbarios Chinos , Interacciones de Hierba-Droga , Humanos , Inactivación Metabólica/efectos de los fármacos , Fitoterapia/métodos , Extractos Vegetales/química , Medicina de Precisión , Distribución TisularRESUMEN
PURPOSE: To identify potential biomarkers and to uncover the mechanisms underlying asthma based on Gibbs sampling. METHODS: The molecular functions (MFs) with genes greater than 5 were determined using AnnotationMFGO of BAGS package, and the obtained MFs were then transformed to Markov chain (MC). Gibbs sampling was conducted to obtain a new MC. Meanwhile, the average probabilities of MFs were computed via MC Monte Carlo (MCMC) algorithm, followed by identification of differentially expressed MFs based on the probabilities of MF more than 0.6. Moreover, the differentially expressed genes (DEGs) and their correlated genes were screened and merged, called as co-expressed genes. Pathways enrichment analysis was implemented for the co-expressed genes. RESULTS: Based on the gene set more than 5, overall 396 MFs were determined. After Gibbs sampling, 5 differentially expressed MF were acquired according to alfa.pi>0.6. Moreover, the genes in these 5 differentially expressed MF were merged, and 110 DEGs were identified. Subsequently, 338 co-expressed genes were gained. Based on the P value<0.01, the co-expressed genes were significantly enriched in 6 pathways. Among these, ubiquitin mediated proteolysis contained the maximum numbers of 35 co-expressed genes, and cell cycle were enriched by the second largest number of 11 co-expressed genes, respectively. CONCLUSIONS: The identified pathways such as ubiquitin mediated proteolysis and cell cycle might play important roles in the development of asthma and may be useful for developing the credible therapeutic approaches for diagnosis and treatment of asthma in future.
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Asma/genética , Marcadores Genéticos , Método de Montecarlo , Ciclo Celular/genética , Perfilación de la Expresión Génica , Redes y Vías Metabólicas/genética , ProteolisisRESUMEN
Two different culture media were used to cultivate fungus Aspergillus ruber 1017 and resulted in the isolation of one new compound (1) and 23 known compounds (2-24). Alkaloids were the major metabolite in soybean medium instead of anthraquinone from rice medium. The structures of these compounds were elucidated according to spectroscopic analysis and comparison with reported data. Antibacterial activities of compounds 1-12 against 12 aquatic bacteria were evaluated.
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Aspergillus/metabolismo , Medios de Cultivo/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/metabolismo , Antraquinonas/metabolismo , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Aspergillus/química , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oryza/metabolismo , Glycine max/metabolismo , Análisis EspectralRESUMEN
OBJECTIVE: To study the effects of postnatal growth retardation on early neurodevelopment in premature infants with intrauterine growth retardation (IUGR). METHODS: A retrospective analysis was performed on the clinical data of 171 premature infants who were born between May 2008 and May 2012 and were followed up until a corrected gestational age of 6 months. These infants were classified into two groups: IUGR group (n=40) and appropriate for gestational age (AGA) group (n=131). The growth retardation rates at the corrected gestational ages of 40 weeks, 3 months, and 6 months, as well as the neurodevelopmental outcome (evaluated by Gesell Developmental Scale) at corrected gestational ages of 3 and 6 months, were compared between the two groups. RESULTS: The growth retardation rate in the IUGR group was significantly higher than in the AGA group at the corrected gestational ages of 40 weeks, 3 months, and 6 months. All five developmental quotients evaluated by Gesell Developmental Scale (gross motor, fine motor, language, adaptability and individuality) in the IUGR group were significantly lower than in the AGA group at the corrected gestational ages of 3 months. At the corrected gestational age of 6 months, the developmental quotients of fine motor and language in the IUGR group were significantly lower than in the AGA group, however, there were no significant differences in the developmental quotients of gross motor, adaptability and individuality between the two groups. All five developmental quotients in IUGR infants with catch-up lag in weight were significantly lower than in IUGR and AGA infants who had caught up well. CONCLUSIONS: Growth retardation at early postnatal stages may adversely affect the early neurodevelopment in infants with IUGR.
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Desarrollo Infantil , Retardo del Crecimiento Fetal/fisiopatología , Estatura , Peso Corporal , Femenino , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Inteligencia , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: To study the incidence and risk factors for extrauterine growth retardation (EUGR) at discharge in premature infants. METHODS: A retrospective analysis was performed on 596 premature infants who were admitted to the neonatal intensive care unit between 2006 and 2010. These subjects were classified into EUGR (n=217) and non-EUGR groups (n=379) based on the body weight at discharge. The risk factors for the occurrence of EUGR were studied by multivariate logistic regression analysis. RESULTS: Based on the body weight, length, and head circumference, the incidence of EUGR at discharge was 36.4% (217 cases), 42.0% (250 cases), and 22.8% (136 cases), respectively. Low gestational age, low birth weight, intrauterine growth retardation (IUGR), delayed enteral feeding and complications of the respiratory system were identified as risk factors for EUGR (OR=6.508, 14.522, 5.101, 1.366, and 1.501, respectively). CONCLUSIONS: The incidence of EUGR might be greatly decreased by strengthening the perinatal care, reducing the incidence of premature delivery and IUGR, undertaking early enteral feeding, and actively preventing postnatal complications.
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Retardo del Crecimiento Fetal/etiología , Femenino , Retardo del Crecimiento Fetal/epidemiología , Humanos , Recién Nacido , Recien Nacido Prematuro , Modelos Logísticos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: Human neonates are highly susceptible to a wide range of infections, which has been attributed to deficiencies in their innate and adaptive immunity. In contrast to the well-documented immaturity in neonatal adaptive immunity, deficiencies in their innate immunity are less defined. This study examined the inflammatory response of neonatal monocytes to bacterial lipopolysaccharide (LPS) and peptidoglycan (PGN) stimulation and discriminated the underlying Toll-like receptor (TLR)-mediated signal transduction pathways. METHODS: Cord blood from 30 healthy newborns of full-term elective cesarean sections and peripheral blood from 25 healthy adult volunteers were collected. Ex vivo production of inflammatory cytokines was assessed by cytometric bead array, and expression of CD14, TLR4, TLR2, phosphorylated NF-κB p65 and p38 on monocytes were detected by FACScan analysis. RESULTS: Neonatal whole blood showed significantly decreased ex vivo TNF-α and IL-1ß production in response to stimulation with the TLR4 agonist LPS, but not the TLR2 agonist PGN, when compared with adult whole blood. Consistent with the diminished inflammatory cytokine response to LPS stimulation, neonatal monocytes exhibited substantially impaired TLR-mediated signal transduction pathways characterized by down-regulated expression of CD14 and TLR4, and suppressed phosphorylation of NF-κB p65 at Ser536 and p38 following LPS stimulation. In addition, neonates had a significantly lower percentage of TLR4(+)/CD14(+) monocytes than adults. CONCLUSIONS: These results indicate that in contrast to the adult, human neonates display deficiencies in innate immunity-associated inflammatory cytokine responses due to their defective TLR signaling pathways, which may render them more susceptible to microbial infection.
Asunto(s)
Citocinas/metabolismo , Bacterias Gramnegativas/inmunología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Transducción de Señal , Receptores Toll-Like/metabolismo , Adulto , Citocinas/sangre , Femenino , Humanos , Inmunidad Innata , Inmunofenotipificación , Recién Nacido , Mediadores de Inflamación/sangre , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , FN-kappa B/metabolismo , Fenotipo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVE: To evaluate the clinical effects of the early use of recombinant human erythropoietin (rhEPO) on the neurointelligence development in very low birth weight infants (VLBWI). METHODS: Seventy-eight VLBWI were divided into rhEPO treatment group (n=35) and control group (n=43) according to the choice of their parents. Neonatal behavioral neurological assessment (NBNA) was performed at 40 weeks of corrected gestational age. The Gesell Developmental Schedules were used for neurodevelopmental evaluation at 3, 6, and 12 months of corrected age. The abnormal rates of auditory brainstem response (ABR) and cranial ultrasound were evaluated at 6 months of corrected age. RESULTS: The rhEPO treatment group had significantly higher NBNA scores at 40 weeks of corrected gestational age than the control group (P<0.05). The adaptability at 3 months of corrected age, the gross motor, adaptability, and sociability at 6 months, and the gross motor, adaptability, fine motor, sociability, and language at 12 months were significantly better in the rhEPO treatment group than in the control group (P<0.05). The abnormal rates of ABR and cranial ultrasound in the rhEPO treatment group were significantly lower than in the control group at 6 months of corrected age (P<0.05). CONCLUSIONS: Early use of rhEPO can promote the early recovery of neurological symptoms and improve the cognitive, motor, and language abilities in VLBWI due to its protective effects on the nervous system.
Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Eritropoyetina/farmacología , Recién Nacido de muy Bajo Peso/crecimiento & desarrollo , Inteligencia/efectos de los fármacos , Sistema Nervioso/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Humanos , Recién Nacido , Masculino , Sistema Nervioso/crecimiento & desarrollo , Proteínas Recombinantes/farmacologíaRESUMEN
OBJECTIVE: To study the effects of post-discharge formula (PDF) for preterm infants, breast milk (BM) and term infant formula (TF) on increase rates of body weight, length and head circumference in preterm and low-birth-weight infants (PLBWIs) from discharge to 3 months after birth, and to provide a reference for the choice of feeding pattern for PLBWIs. METHODS: A total of 407 PLBWIs discharged from the newborn departments of ten hospitals in Guangzhou City and Foshan City in Guangdong Province, China were chosen for this study. According to feeding pattern, they were assigned to three groups: PDF-fed (n=258), BM-fed (n=58) and TF-fed (n=91). Their body weight, length and head circumference were measured at 3 months after birth, and the increase rates of growth indices relative to baseline values (at birth) were calculated and compared. RESULTS: At 3 months after birth, the PDF-fed group had significantly greater body weight, length and head circumference than the BM-fed and TF-fed groups (P<0.05). The increase rates of body weight and length were significantly higher in the PDF-fed group than in the BM-fed and TF-fed groups (P<0.05). CONCLUSIONS: Compared with those fed with BM and TF after discharge, the PDF-fed PLBWIs have higher increase rates of body weight and length and show greater body weight and length at 3 months after birth. However, further study is needed to investigate the long-term effects.