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N6-methyladenosine (m6A) modification is deemed to be co-transcriptionally installed on pre-mRNAs, thereby influencing various downstream RNA metabolism events. However, the causal relationship between m6A modification and RNA processing is often unclear, resulting in premature or even misleading generalizations on the function of m6A modification. Here, we develop 4sU-coupled m6A-level and isoform-characterization sequencing (4sU-m6A-LAIC-seq) and 4sU-GLORI to quantify the m6A levels for both newly synthesized and steady-state RNAs at transcript and single-base-resolution levels, respectively, which enable dissecting the relationship between m6A modification and alternative RNA polyadenylation. Unexpectedly, our results show that many m6A addition events occur post-transcriptionally, especially on transcripts with high m6A levels. Importantly, we find higher m6A levels on shorter 3' UTR isoforms, which likely result from sequential polyadenylation of longer 3' UTR isoforms with prolonged nuclear dwelling time. Therefore, m6A modification can also take place post-transcriptionally to intimately couple with other key RNA metabolism processes to establish and dynamically regulate epi-transcriptomics in mammalian cells.
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Excessive peroxynitrite (ONOO-) is closely related to the occurrence and progression of inflammation. Therefore, the development of an efficacious ONOO- activatable probe holds great potential for the early diagnosis of pathological inflammation, and the direct evaluation of the therapeutic efficacy of active protectants. In this work, a new ONOO--activated fluorescent probe (SZP) which greatly improved the specificity and sensitivity (LOD = 8.03 nM) with large Stokes shift (150 nm) through introducing two reaction triggers (diphenyl phosphinate moiety, CC unsaturated bond) was rationally designed for rapid detecting ONOO- (within 2 min). The excellent properties of probe SZP enable it to realize the fluorescence-guided diagnosis of inflammation. More importantly, probe SZP has also been utilized to assess the anti-inflammatory efficacy of traditional Chinese medicines (TCMs) active ingredients for the remediation of inflammation by monitoring ONOO- fluctuation for the first time.
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Colorantes Fluorescentes , Inflamación , Ácido Peroxinitroso , Ácido Peroxinitroso/análisis , Ácido Peroxinitroso/antagonistas & inhibidores , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Inflamación/tratamiento farmacológico , Animales , Estructura Molecular , Ratones , Humanos , Células RAW 264.7 , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Antiinflamatorios/uso terapéutico , Imagen Óptica , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis química , MasculinoRESUMEN
INTRODUCTION: PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. METHODS: The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. RESULTS: A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. CONCLUSION: The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.
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Antiinflamatorios no Esteroideos , Flurbiprofeno , Geles , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Administración Cutánea , Administración Tópica , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Relación Dosis-Respuesta a Droga , Flurbiprofeno/farmacocinética , Flurbiprofeno/administración & dosificación , Voluntarios Sanos , Piel/metabolismo , Absorción Cutánea , Pueblos del Este de AsiaRESUMEN
In this paper, we investigate the optical nondegenerate solitons in a birefringent fiber with a 35 degree elliptical angle. We derive the nondegenerate bright one- and two-soliton solutions by solving the coupled Schrödinger equation. The formation of nondegenerate solitons is related to the wave numbers of the solitons, and we further demonstrate that it is caused by the incoherent addition of different components. We note that the interaction between two degenerate solitons or a nondegenerate soliton and a degenerate soliton is usually inelastic. This is led to the incoherent interaction between solitons of different components and the coherent interaction between solitons of the same component. Through the asymptotic analysis, we find that the two degenerate solitons are elastic interactions under certain conditions, and analyzed the influence of the Kerr nonlinear intensity coefficient γ and the second-order group velocity dispersion ß2 in this system on solitons: the velocity and amplitude of the solitons are proportional to |ß2|, while the amplitude of the solitons is inversely proportional to γ. Two nondegenerate solitons are elastic interactions, but the phase of the soliton can be adjusted to make it inelastic. Furthermore, regardless of the situation mentioned above, total intensities of the solitons before the interaction are equal to that after the soliton interaction.
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Background: Asthma is characterized by airway hyperresponsiveness, reversible airway obstruction, and chronic airway inflammation. It is the most common chronic disease in childhood. However, the diagnosis of childhood asthma remains challenging, and there is an urgent need to develop new diagnostic methods. Methods: To identify biomarkers of asthma in children, we adopted the Orbitrap-based data-independent acquisition (DIA) mass spectrometry proteomics method to analyze the serum proteomic signatures of children with acute asthma and convalescent children. Results: We identified 747 proteins in 46 serum samples and 50 differentially expressed proteins (DEPs) that distinguished between asthmatic and healthy children. Next, functional enrichment analysis of the DEPs was conducted, it was indicated that the DEPs were significantly enriched in immune-related and function terms and pathways. Furthermore, we performed statistical analysis and identified MMP14, ABHD12B, PCYOX1, LTBP1, CFHR4, APOA1, IGHG4, ANG and IGFALS proteins as the diagnostic biomarker candidates. Ultimately, a promising asthma diagnostic model for preschool children based on IGFALS was built and evaluated. The area under the curve (AUC) of the IGFALS model was 0.959. Conclusions: In this study, the DIA proteome strategy was used and the largest number of proteins of asthmatic children serum proteomics was identified. The proteomics results showed that the DEPs play the central role of the inflammation-immune mechanism in asthma pathogenesis, suggesting that these proteins may be used in asthma diagnosis, prognosis, or therapy, and suggested biomarkers for asthma of preschool children. In conclusion, our results provide insight into the pathophysiology of asthma. We believe that the diagnostic model will facilitate clinical decision-making regarding asthma in preschool children.
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We talk to authors Yu Zhou, Ting Shan, and Feiyan Liu about their paper "m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3" (in this issue of Molecular Cell), their passion for RNA biology, and what it's like leading a "wet and dry" lab.
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TolnaftatoRESUMEN
In the cytoplasm, mRNAs are dynamically partitioned into translating and non-translating pools, but the mechanism for this regulation has largely remained elusive. Here, we report that m6A regulates mRNA partitioning between polysome and P-body where a pool of non-translating mRNAs resides. By quantifying the m6A level of polysomal and cytoplasmic mRNAs with m6A-LAIC-seq and m6A-LC-MS/MS in HeLa cells, we observed that polysome-associated mRNAs are hypo-m6A-methylated, whereas those enriched in P-body are hyper-m6A-methylated. Downregulation of the m6A writer METTL14 enhances translation by switching originally hyper-m6A-modified mRNAs from P-body to polysome. Conversely, by proteomic analysis, we identify a specific m6A reader IGF2BP3 enriched in P-body, and via knockdown and molecular tethering assays, we demonstrate that IGF2BP3 is both necessary and sufficient to switch target mRNAs from polysome to P-body. These findings suggest a model for the dynamic regulation of mRNA partitioning between the translating and non-translating pools in an m6A-dependent manner.
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Adenina , Cuerpos de Procesamiento , Biosíntesis de Proteínas , Proteínas de Unión al ARN , Humanos , Cromatografía Liquida , Células HeLa , Polirribosomas/genética , Proteómica , ARN Mensajero/genética , Espectrometría de Masas en Tándem , Adenina/análogos & derivados , Adenina/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Colorantes Fluorescentes , Humanos , Línea Celular , Células Hep G2 , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , gamma-Glutamiltransferasa , GlutatiónRESUMEN
BACKGROUND AND OBJECTIVES: Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. METHODS: A physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios. RESULTS: Inflammation showed opposite effects on drug exposure for drugs eliminated via the liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4 substrates, the relative increase in AUC could exceed 50% for low-ER drugs. Finally, the impact of inflammation-induced changes in drug clearance is smaller for drugs with a larger unbound fraction. CONCLUSION: This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes.
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Citocromo P-450 CYP3A , Interleucina-6 , Humanos , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Tasa de Filtración Glomerular , Interleucina-6/metabolismo , Riñón/metabolismo , InflamaciónRESUMEN
INTRODUCTION: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be an effective apoptosis inducer due to its selectivity for tumor cells. However, many cancer cells, especially metastatic cancer cells, often exhibit resistance to TRAIL because their apoptotic pathway is impaired or their pro-survival pathway is overactivated. TRAIL resistance is the main obstacle to current TRAIL therapy. Nowadays, ceramide analogs represent a new class of potential anticancer agents. Therefore, we hypothesized that disrupting pro-survival signaling with ceramide analogs would increase TRAIL-mediated apoptosis. METHODS: MTT assay and flow cytometry were conducted to evaluate the synergistic effect of ceramide analog 5cc on TRAIL in metastatic colon cancer cells. Western blot was used to detect signaling proteins affected by 5cc. RNA interference was performed to analyze the effects of specific gene on 5cc-enhanced apoptosis. RESULTS: Ceramide analog 5cc markedly enhanced TRAIL-induced apoptosis evidenced by increased propidium iodide/annexin V double-positive cells and PARP cleavage in SW620 and LS411N cells. At the molecular level, 5cc significantly reduced the expression of anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP) through the activation of the c-Jun n-terminal kinase (JNK) pathway which is critically involved in sensitizing tumor cells to TRAIL/5cc combination. JNK-silenced cells exhibited a significant reversal of TRAIL/5cc-mediated apoptosis. CONCLUSION: Our data demonstrated that ceramide analog 5cc overcomes TRAIL resistance by enhancing JNK activation and repressing XIAP expression in metastatic colon cancer cells.
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Neoplasias del Colon , Proteína Inhibidora de la Apoptosis Ligada a X , Humanos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/farmacología , Ceramidas/farmacología , Ligandos , Línea Celular Tumoral , Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
One of the most important features of innate immunity is the presence of a special group of pattern recognition receptors (PRRs) called toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), resulting in a quick and effective immune response to them. Glomerulonephritis (GN) is one of the most important categories of renal disorders characterized by destructive responses of the immune system to the glomerulus. To date, the association of TLRs as important innate immune system members with GN has been one of the topics that attracted the attention of researchers in this field. However, the exact role of these receptors in the immunopathogenesis of GN has not yet been fully discussed. Therefore, this study aims to overview the role of TLRs in GN and the possibility of using them as a potential therapeutic target.
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Despite the high mutation frequencies of KRAS, NRAS, and BRAF in colorectal cancer (CRC), there are no effective and reliable inhibitors for these biomarkers. Protocadherin-7 (PCDH7) is regarded as a potentially targetable surface molecule in cancer cells and plays an important role in their proliferation, metastasis, and drug resistance. However, the roles and underlying mechanisms of PCDH7 in CRC remain unclear. In the current study, we found that different colorectal cancer cells expressed PCDH7 over a wide range. The levels of PCDH7 expression were positively associated with cell proliferation and drug resistance in CRC cells but negatively correlated with the potential for cell migration and invasion. Our data indicated that PCDH7 mediated the resistance of CRC cells to ABT-263 (a small-molecule Bcl-2 inhibitor that induces apoptosis) by inhibiting cell apoptosis, which was supported by the downregulation of caspase-3, caspase-9, and PARP cleavage. We found that PCDH7 effectively promoted Mcl-1 expression at both mRNA and protein levels. Furthermore, PCDH7 activated the Wnt signaling pathway, which was confirmed by the increase in ß-catenin and c-Myc expression. Finally, and notably, S63845, a novel Mcl-1 inhibitor, not only effectively attenuated the inhibitory effect of PCDH7 on cell apoptosis induced by ABT-263 in vitro but also sensitized PCDH7-overexpressed CRC cell-derived xenografts to ABT-263 in vivo. Taken together, although PCDH7 inhibited the migration and invasion of CRC cells, it could facilitate the development of drug resistance in colorectal cancer cells by positively modulating Mcl-1 expression. The application of the Mcl-1 inhibitor S63845 could be a potential strategy for CRC chemotherapy, especially in CRC with high levels of PCDH7.
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Objective: To evaluate the impact of the integrated care in Luohu, China on the hypertension management. Methods: Hypertensive patients aged 35-74 years were recruited by the cluster-randomized sampling method from Luohu district which adopted integrated care and another district that remained original routine care during October 2018~January 2020, with 1353 and 583 patients from integrated and routine care communities, respectively. Health information, knowledge, attitude, and practice (KAP) towards cardiovascular diseases, pharmaceutical expenditure on hypertension and its comorbidities, and healthcare-related satisfaction were collected by questionnaires, with the expenditure additionally verified by hospitals' billing records database. Continuous and categorical variables were compared by Wilcoxon test and Chi-square test, respectively. The age-standardized hypertension control rate was calculated by direct standardization. Results: The standardized hypertension management rate in the integrated care communities (45.75%) was significantly higher than that in routine care communities (14.07%) (P < 0.0001), while the age-standardized hypertension control rates were similar (integrated care: 50.3%, routine care: 52.65%, P = 0.518). The pharmaceutical expenditure on hypertension and its comorbidities in the integrated care communities was Ò°264.23 ± 357.38/month/person, lower than that in the routine care communities (Ò°354.56 ± 430.59/month/person). Patients in the integrated care had higher KAP scores (73.48 ± 11.54), compared with routine care (68.89 ± 15.51) (P < 0.0001). Moreover, the integrated care communities had higher satisfaction rates towards the convenience of dual referral (90.15% vs. 77.99%) and service quality (95.18% vs. 87.81%) than routine care communities (P < 0.0001). Conclusion: The practice of the integrated care in Luohu has substantially improved the hypertension management and the healthcare-related satisfaction while with relatively low pharmaceutical expenditure. The investigation of long-term impact of the integrated care on hypertension control and management is warranted.
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Hexavalent chromium (Cr6+) owns hypertoxicity, non-biodegradability, and carcinogenicity, thus the detection of Cr6+ is of paramount significance for environmental monitoring and human health maintenance. Herein, a simple, rapid, and feasible fluorescent method based on gold nanoclusters (AuNCs) was established for determination of Cr6+. The AuNCs was coated by a simple and fast one-pot method using d-histidine (d-His) and polylysine (P-Lys) as stabilizers and reductants, which could be quenched by the addition of Cr6+ owing to the aggregation of AuNCs and fluorescence resonance energy transfer (FRET) between AuNCs and Cr6+. Under the optimal conditions, the fluorescent sensor exhibited good linearity within 10-10000 µg/L with limit of detection of 7.2 µg/L. The developed sensor possessed favorable sensitivity and selectivity. Additionally, the proposed method also had favorable recovery with good precision and accuracy within the actual sample, including celery cabbage, rice, capsule shell, and river water.
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Oro , Nanopartículas del Metal , Humanos , Histidina , Sustancias Reductoras , Polilisina , Colorantes Fluorescentes , Agua , Espectrometría de Fluorescencia/métodosRESUMEN
The present study aimed to compare the therapeutic effect of sodium/glucose cotransporter 2 (SGLT2) inhibitor and benazepril on diabetic nephropathy (DN) rats and provide a potential novel agent for the clinical treatment of DN. The DN model was established on rats. Animals were dosed orally with SGLT2 and benazepril daily for 4 weeks. The pathological state of renal tissues were evaluated using hematoxylin and eosin, Masson and periodic acid-Schiff staining. The change in the morphology of renal tissues was observed through transmission electron microscopy. Western blotting was utilized to determine the expression level of TGF-ß, N-terminal fragment of the B-type natriuretic peptide precursor (NT-proBNP) and matrix metalloproteinase-9 (MMP-9). The expression level of endothelin 1 (ET-1), von Willebrand factor (vWF), collagen (col)-I and α smooth muscle actin (α-SMA) in renal tissues was visualized using immunohistochemical assay. Significant pathological changes in the glomerular basement membrane, mesangial membrane, renal tubules, lumen, renal interstitial region and renal tubular epithelial cells were observed in DN rats, accompanied by increased collagen fibers. SGLT2 inhibitor treatment demonstrated more alleviatory effects on the pathological changes of renal tissues compared with benazepril. Compared with control, TGF-ß and NT-proBNP were upregulated in DN rats, accompanied by the downregulation of MMP-9, ET-1, vWF, col-I and α-SMA, which were markedly reversed by treatment with SGLT2 inhibitor and benazepril. Compared with benazepril, the effects of SGLT2 inhibitor on the expression level of TGF-ß, NT-proBNP, MMP-9, ET-1, vWF, col-I and α-SMA were more significant. Overall, SGLT2 inhibitor demonstrated an increased therapeutic effect against DN rats compared with benazepril by regulating cytokines, renal fibrosis and extracellular matrix degradation.
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The environmental Kuznets curve (EKC) is often used to analyze the relationship between environmental pollution health indicators and economic development level in different regions. In developed countries, the blood lead levels (BLLs) of children have been declining fitting the EKC since the 1970s. However, such figures in China have remained at relatively high levels, without any obvious decline, since 2010. We explored spatial variations and graded countermeasures using reported data on BLLs including the lead poisoning rates (LPRs) of children. We found that there were prefectures where either the mean BLLs of the children had reached 100.00 µg/L or the LPRs of more than 40% of the children had reached 100 µg/L. When we reduced the average BLLs to 50 µg/L or lowered the proportion of children with a lead poisoning rate (LPR) above 100 µg/L to 10.00%, the EKC trend decreased, and the linear slope after 2010 became -0.202. If the areas where children's BLLs exceeded 50.00 µg/L or the proportion of children with an LPR above 100 µg/L was more than 10.00% will be controlled, the linear slope of the EKC decrease trend after 2010 will became -0.989, and the national average of children's BLLs would decline by 22.17%. The study concluded that children's BLLs in different regions of China are situated at different EKC stages, and urgent prevention and control strategies must be put in place for undeveloped areas.
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Sepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network of regulatory relationships was developed for key immune components associated with sepsis pathogenesis after TLR4 activation. Perturbation analyses were conducted to identify therapeutic targets associated with organ dysfunction or antibacterial activity. The developed model consisted of 42 nodes and 183 interactions. Perturbation analyses suggest that over-expression of tumour necrosis factor alpha (TNF-α) or inhibition of soluble receptor sTNF-R, tissue factor, and inflammatory cytokines (IFN-γ, IL-12) may lead to a reduced activation of organ dysfunction related endpoints. Over-expression of complement factor C3b and C5b led to an increase in the bacterial clearance related endpoint. We identified that combinatory blockade of IFN-γ and IL-10 may reduce the risk of organ dysfunction. Finally, we found that combining antibiotic treatment with IL-1ß targeted therapy may have the potential to decrease thrombosis. In summary, we demonstrate how existing biological knowledge can be effectively integrated using Boolean network analysis for hypothesis generation of potential treatment strategies and characterization of biomarker responses associated with the early inflammatory response in sepsis.
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Sepsis , Receptor Toll-Like 4 , Humanos , Citocinas/metabolismo , Lipopolisacáridos/farmacología , Insuficiencia Multiorgánica/tratamiento farmacológico , Insuficiencia Multiorgánica/complicaciones , Sepsis/tratamiento farmacológico , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Farmacología en RedRESUMEN
Hexavalent chromium (Cr(VI)) determination is of great importance to the public health because of its extensive sources and high toxicity. However, interference from non-target ions and complex matrix remains challenges for Cr(VI) detection. In this work, we constructed a novel sensing system for high selectivity detection of Cr(VI), which is composed of strong emitting carbon dots (CE-CDs) and a specific masking agent. The detection conditions, anti-interference capability and the sensing and masking mechanisms of CE-CDs-based sensing method were systematically investigated. The results revealed that the optimal detection conditions included pH 4-10, reaction time 180 s and CE-CDs concentration 18 mg/L. Under optimal conditions, the linear range of the method was up to 500 µm, and the detection limit was as low as 23 nM. In addition, the interference of Hg(II) can be accurately eliminated by using DMPS, an effective masking agent. During the sensing process, inner filter effect and ion-molecular interaction between Cr(VI) and CE-CDs accounted for the fluorescence quenching mechanism, while the efficient masking was attributed to the strong coordination interaction between Hg(II) and DMPS. Most notably, this method had broad applicability, even for the trace detection of Cr(VI) in colored leather with complex matrix. These findings indicate that this approach is expected to open up new avenues for Cr(VI) detection.
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Mercurio , Puntos Cuánticos , Carbono/química , Cromo/química , Puntos Cuánticos/química , Espectrometría de Fluorescencia/métodosRESUMEN
Clinical studies in healthy volunteers challenged with lipopolysaccharide (LPS), a constituent of the cell wall of Gram-negative bacteria, represent a key model to characterize the Toll-like receptor 4 (TLR4)-mediated inflammatory response. Here, we developed a mathematical modelling framework to quantitatively characterize the dynamics and inter-individual variability of multiple inflammatory biomarkers in healthy volunteer LPS challenge studies. Data from previously reported LPS challenge studies were used, which included individual-level time-course data for tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP). A one-compartment model with first-order elimination was used to capture the LPS kinetics. The relationships between LPS and inflammatory markers was characterized using indirect response (IDR) models. Delay differential equations were applied to quantify the delays in biomarker response profiles. For LPS kinetics, our estimates of clearance and volume of distribution were 35.7 L h-1 and 6.35 L, respectively. Our model adequately captured the dynamics of multiple inflammatory biomarkers. The time delay for the secretion of TNF-α, IL-6 and IL-8 were estimated to be 0.924, 1.46 and 1.48 h, respectively. A second IDR model was used to describe the induced changes of CRP in relation to IL-6, with a delayed time of 4.2 h. The quantitative models developed in this study can be used to inform design of clinical LPS challenge studies and may help to translate preclinical LPS challenge studies to humans.
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Interleucina-8 , Lipopolisacáridos , Humanos , Interleucina-6 , Factor de Necrosis Tumoral alfa , Inflamación/inducido químicamente , Inflamación/patología , Biomarcadores , Proteína C-ReactivaRESUMEN
Colorimetric and fluorescent sensors were developed for the detection of profenofos. The colorimetric assay relied on the aggregation of cysteine modified gold nanoparticles (Au-cys) composite caused by the hydrogen bond and Au-S bond between profenofos and Au-cys. The further addition of S, N-doped carbon quantum dots (CDs) (fluorescence quantum yield up to 98%) into the Au-cys system depended on the change of fluorescence intensity of Au-cys-CDs owing to the inner filter effect between Au-cys and CDs. Under the optimal conditions, the sensor exhibits good linearity within 0.2-1.2 mg L-1 and 20-320 µg L-1, and limit of detection of 21.7 µg L-1 and 5.5 µg L-1 in colorimetry and fluorescence mode, respectively. The developed sensor did not only possess favorable selectivity and sensitivity, but also feasibility of usage in the actual detection of profenofos in farmland system samples.