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1.
Int J Antimicrob Agents ; 63(5): 107122, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38431108

RESUMO

BACKGROUND: With increasing antibiotic resistance and regulation, the issue of antibiotic combination has been emphasised. However, antibiotic combination prescribing lacks a rapid identification of feasibility, while its risk of drug interactions is unclear. METHODS: We conducted statistical descriptions on 16 101 antibiotic coprescriptions for inpatients with bacterial infections from 2015 to 2023. By integrating the frequency and effectiveness of prescriptions, we formulated recommendations for the feasibility of antibiotic combinations. Initially, a machine learning algorithm was utilised to optimise grading thresholds and habits for antibiotic combinations. A feedforward neural network (FNN) algorithm was employed to develop antibiotic combination recommendation model (ACRM). To enhance interpretability, we combined sequential methods and DrugBank to explore the correlation between antibiotic combinations and drug interactions. RESULTS: A total of 55 antibiotics, covering 657 empirical clinical antibiotic combinations were used for ACRM construction. Model performance on the test dataset showed AUROCs of 0.589-0.895 for various antibiotic recommendation classes. The ACRM showed satisfactory clinical relevance with 61.54-73.33% prediction accuracy in a new independent retrospective cohort. Antibiotic interaction detection showed that the risk of drug interactions was 29.2% for strongly recommended and 43.5% for not recommended. A positive correlation was identified between the level of clinical recommendation and the risk of drug interactions. CONCLUSIONS: Machine learning modelling of retrospective antibiotic prescriptions habits has the potential to predict antibiotic combination recommendations. The ACRM plays a supporting role in reducing the incidence of drug interactions. Clinicians are encouraged to adopt such systems to improve the management of antibiotic usage and medication safety.


Assuntos
Antibacterianos , Infecções Bacterianas , Interações Medicamentosas , Aprendizado de Máquina , Humanos , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Estudos Retrospectivos , Quimioterapia Combinada , Algoritmos
2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(1): 98-101, 2024 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-38404282

RESUMO

Sepsis is caused by infection, which can ultimately lead to multiple organ dysfunction and even life-threatening. Early recognition and early treatment can significantly improve the prognosis of sepsis patients. However, the effect of using a single biomarker for early diagnosis of sepsis is still not ideal. In recent years, researchers have turned their attention to artificial intelligence technology for early diagnosis of sepsis. This paper briefly introduces the advantages and disadvantages of sepsis related inflammatory indicators, biomarkers, and scoring systems of disease severity for early identification of sepsis, and focuses on the research progress and limitations of artificial intelligence technology for early diagnosis of sepsis, aiming to seek new methods and ideas for early diagnosis of sepsis.


Assuntos
Inteligência Artificial , Sepse , Humanos , Prognóstico , Biomarcadores , Sepse/diagnóstico , Sepse/terapia , Diagnóstico Precoce
3.
Sci Rep ; 14(1): 284, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38168639

RESUMO

We examined the effects of climatic factors and Demodex infestations on meibomian gland dysfunction (MGD)-associated dry eye disease (DED) in a cross-sectional study. This study included 123 patients from Tianjin and Chengdu regions, and climate factors and the Air Quality Index (AQI) were recorded for one year. Ocular surface parameters and Demodex infestations were evaluated using various tests. Significant differences in all climatic factors and AQI were observed between Tianjin and Chengdu (P < 0.01), and ocular surface parameters also differed significantly between the two regions (P < 0.05). Temperature, relative humidity, and precipitation positively correlated with tear break-up time (BUT), meibum gland expressibility, and lid margin irregularity but negatively correlated with lissamine green staining scores (P < 0.05). Wind speed and atmospheric pressure positively correlated with corneal fluorescein staining and lissamine green staining but negatively correlated with BUT and lid margin irregularity (P < 0.05). AQI positively correlated with DED symptoms and corneal findings but negatively correlated with tear film stability and meibomian gland characteristics (P < 0.05). Demodex infestation was only positively correlated with meibum quality scores (P < 0.05). Our findings suggest that geographic climates influence ocular surface characteristics in MGD-associated DED, with daily precipitation potentially playing a significant role, and Demodex infestation contributes to meibum gland degeneration.


Assuntos
Síndromes do Olho Seco , Disfunção da Glândula Tarsal , Humanos , Estudos Transversais , Glândulas Tarsais , Síndromes do Olho Seco/diagnóstico , Lágrimas
4.
Nat Commun ; 14(1): 7464, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38016946

RESUMO

Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.


Assuntos
Proteínas de Homeodomínio , Leucemia , Feminino , Camundongos , Animais , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Leucemia/genética , Proteínas de Neoplasias/metabolismo , Regulação para Cima , Cromatina , Regulação Leucêmica da Expressão Gênica
5.
Toxicol Sci ; 196(2): 170-186, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37707797

RESUMO

The aryl hydrocarbon receptor (AhR) is an inducible transcription factor whose ligands include the potent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Ligand-activated AhR binds to DNA at dioxin response elements (DREs) containing the core motif 5'-GCGTG-3'. However, AhR binding is highly tissue specific. Most DREs in accessible chromatin are not bound by TCDD-activated AhR, and DREs accessible in multiple tissues can be bound in some and unbound in others. As such, AhR functions similarly to many nuclear receptors. Given that AhR possesses a strong core motif, it is suited for a motif-centered analysis of its binding. We developed interpretable machine learning models predicting the AhR binding status of DREs in MCF-7, GM17212, and HepG2 cells, as well as primary human hepatocytes. Cross-tissue models predicting transcription factor (TF)-DNA binding generally perform poorly. However, reasons for the low performance remain unexplored. By interpreting the results of individual within-tissue models and by examining the features leading to low cross-tissue performance, we identified sequence and chromatin context patterns correlated with AhR binding. We conclude that AhR binding is driven by a complex interplay of tissue-agnostic DRE flanking DNA sequence and tissue-specific local chromatin context. Additionally, we demonstrate that interpretable machine learning models can provide novel and experimentally testable mechanistic insights into DNA binding by inducible TFs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Aprendizado de Máquina , Receptores de Hidrocarboneto Arílico , Humanos , Genoma Humano , Especificidade de Órgãos , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
6.
Shock ; 60(1): 42-50, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37267265

RESUMO

ABSTRACT: Background: Pulmonary sepsis and abdominal sepsis have pathophysiologically distinct phenotypes. This study aimed to compare their clinical characteristics and predictors of mortality. Methods: In this multicenter retrospective trial, 1,359 adult patients who fulfilled the Sepsis-3 criteria were enrolled and classified into the pulmonary sepsis or abdominal sepsis groups. Plasma presepsin was measured, and the scores of Acute Physiology and Chronic Health Evaluation (APACHE) II, Mortality in Emergency Department Sepsis (MEDS), and Simplified Acute Physiology Score (SAPS) II were calculated at enrollment. Data on 28-day mortality were collected for all patients. Results: Compared with patients with abdominal sepsis (n = 464), patients with pulmonary sepsis (n = 895) had higher 28-day mortality rate, illness severity scores, incidence of shock and acute kidney injury, and hospitalization costs. Lactate level and APACHE II and MEDS scores were independently associated with 28-day mortality in both sepsis types. Independent predictors of 28-day mortality included Pa o2 /F io2 ratio (hazard ratio [HR], 0.998; P < 0.001) and acute kidney injury (HR, 1.312; P = 0.039) in pulmonary sepsis, and SAPS II (HR, 1.037; P = 0.017) in abdominal sepsis. A model that combined APACHE II score, lactate, and MEDS score or SAPS II score had the best area under the receiver operating characteristic curve in predicting mortality in patients with pulmonary sepsis or abdominal sepsis, respectively. Interaction term analysis confirmed the association between 28-day mortality and lactate, APACHE II score, MEDS score, SAPS II score, and shock according to the sepsis subgroups. The mortality of patients with pulmonary sepsis was higher than that of patients with abdominal sepsis among patients without shock (32.9% vs. 8.8%; P < 0.001) but not among patients with shock (63.7 vs. 48.4%; P = 0.118). Conclusions: Patients with pulmonary sepsis had higher 28-day mortality than patients with abdominal sepsis. The study identified sepsis subgroup-specific mortality predictors. Shock had a larger effect on mortality in patients with abdominal sepsis than in those with pulmonary sepsis.


Assuntos
Injúria Renal Aguda , Infecções Intra-Abdominais , Sepse , Adulto , Humanos , Estudos Retrospectivos , Prognóstico , Curva ROC , Ácido Láctico , Fragmentos de Peptídeos , Receptores de Lipopolissacarídeos
7.
J Immunol Res ; 2023: 4835710, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37124548

RESUMO

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with significant morbidity, progressive deterioration of lung function till death, and lack of effective treatment options. This study aims to explore the global research trends in IPF and immune response to predict the research hotspot in the future. Materials and methods. All related publications on IPF and immune response since the establishment of diagnostic criteria for IPF were retrieved using the Web of Science (WOS) database. VOSviewer, GraphPad Prism 6, CiteSpace version 5.6. R5 64-bit, and a bibliometrics online platform were used to extract and analyze the trends in relevant fields. Results: From March 1, 2000, to September 30, 2022, a total of 658 articles with 25,126 citations met the inclusion criteria. The United States ranked first in number of publications (n = 217), number of citations (n = 14,745), and H-index (62). China ranked second in publications (n = 124) and seventh and fifth for citation frequency and H-index, respectively. The American Journal of Respiratory and Critical Care Medicine (impact factor = 30.528) published the most articles in the field. The author Kaminski N. from the United States was the most influential author with 26 publications and an H-index of 24. Among the 52 keywords that co-occurred at least 20 times, the main keywords were concentrated in "Inflammation related" and "Biomarker related" clusters. "biomarker" (AAY 2018.64, 25 times) was a newly emerged keyword. Conclusions: The United States has an unequivocal advantage in IPF and immunization, but China shows a faster developing trend. The American Journal of Respiratory and Critical Care Medicine should be prioritized for leading articles. This study indicates that exploration of ideal immune-related biomarkers to provide evidence for the clinical work of IPF might be a hotspot in the near future.


Assuntos
Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Inflamação , Imunização , Bibliometria , Imunidade
8.
J Immunol Res ; 2023: 4452414, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36741234

RESUMO

Sepsis is defined as a dysregulated immune response to infection that leads to multiple organ dysfunction. To date, though a growing body of knowledge has gained insight into the clinical risk factors, pathobiology, treatment response, and recovery methods, sepsis remains a significant concern and clinical burden. Therefore, further study is urgently needed to alleviate the acute and chronic outcomes. Berberine (BBR), a traditional Chinese medicine with multiple actions and mechanisms, has been investigated in cellular and rodent animal models of sepsis mainly based on its anti-inflammatory effect. However, the practical application of BBR in sepsis is still lacking, and it is imperative to systematically summarize the study of BBR in sepsis. This review summarized its pharmacological activities and mechanisms in septic-related organ injuries and the potential BBR-based therapeutic strategies for sepsis, which will provide comprehensive references for scientific research and clinical application.


Assuntos
Berberina , Sepse , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Medicina Tradicional Chinesa , Sepse/tratamento farmacológico
9.
Endocrinology ; 163(10)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35933634

RESUMO

In women, excess androgen causes polycystic ovary syndrome (PCOS), a common fertility disorder with comorbid metabolic dysfunctions including diabetes, obesity, and nonalcoholic fatty liver disease. Using a PCOS mouse model, this study shows that chronic high androgen levels cause hepatic steatosis while hepatocyte-specific androgen receptor (AR)-knockout rescues this phenotype. Moreover, through RNA-sequencing and metabolomic studies, we have identified key metabolic genes and pathways affected by hyperandrogenism. Our studies reveal that a large number of metabolic genes are directly regulated by androgens through AR binding to androgen response element sequences on the promoter region of these genes. Interestingly, a number of circadian genes are also differentially regulated by androgens. In vivo and in vitro studies using a circadian reporter [Period2::Luciferase (Per2::LUC)] mouse model demonstrate that androgens can directly disrupt the hepatic timing system, which is a key regulator of liver metabolism. Consequently, studies show that androgens decrease H3K27me3, a gene silencing mark on the promoter of core clock genes, by inhibiting the expression of histone methyltransferase, Ezh2, while inducing the expression of the histone demethylase, JMJD3, which is responsible for adding and removing the H3K27me3 mark, respectively. Finally, we report that under hyperandrogenic conditions, some of the same circadian/metabolic genes that are upregulated in the mouse liver are also elevated in nonhuman primate livers. In summary, these studies not only provide an overall understanding of how hyperandrogenism associated with PCOS affects liver gene expression and metabolism but also offer insight into the underlying mechanisms leading to hepatic steatosis in PCOS.


Assuntos
Hiperandrogenismo , Hepatopatia Gordurosa não Alcoólica , Síndrome do Ovário Policístico , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Modelos Animais de Doenças , Epigênese Genética , Feminino , Histonas/metabolismo , Humanos , Hiperandrogenismo/complicações , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Síndrome do Ovário Policístico/metabolismo
10.
Front Cardiovasc Med ; 9: 915533, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35837606

RESUMO

Aims: To perform a systematic review assessing the clinical manifestations and outcomes of cardiorenal syndrome or the presence of both cardiac and renal complications in the 2019 coronavirus disease (COVID-19) patients. Methods: All relevant studies about cardiorenal syndrome or both cardiac and renal complications in COVID-19 patients were retrieved on PUBMED, MEDLINE, and EMBASE from December 1, 2019 to February 20, 2022. Results: Our search identified 15 studies including 637 patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications followingSARS-CoV-2 infection. They were male predominant (66.2%, 422/637), with a mean age of 58 years old. Cardiac complications included myocardial injury (13 studies), heart failure (7 studies), arrhythmias (5 studies), or myocarditis and cardiomyopathy (2 studies). Renal complications manifested as acute kidney injury with or without oliguria. Patients with cardiorenal injury were often associated with significantly elevated levels of inflammatory markers (CRP, PCT, IL-6). Patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications had more severe disease and poorer prognosis (9 studies). Conclusion: The presence of either cardiorenal syndrome or concurrent cardiac and renal complications had a significant impact on the severity of the disease and the mortality rate among patients with COVID-19 infection. Therefore, careful assessment and management of potential cardiac and renal complications in patients with COVID-19 infection are important to improve their outcomes.

11.
Microsyst Nanoeng ; 8: 80, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846174

RESUMO

A new electrochemical angular microaccelerometer with integrated sensitive electrodes perpendicular to flow channels was developed in this paper. Based on a liquid inertial mass, an incoming angular acceleration was translated into varied concentrations of reactive ions around sensitive microelectrodes, generating a detection current. Key structural parameters of the sensitive microelectrodes were designed and compared based on theoretical analysis and numerical simulations. An angular microaccelerometer incorporating sensitive microelectrodes was then fabricated, assembled and characterized, producing a sensitivity of 338 V/(rad/s2), a -3 dB bandwidth of 0.01-10 Hz and a noise level of 4.67 × 10-8 (rad/s2)/Hz1/2 @ 1 Hz. These performances were better than their commercial counterparts based on traditional electrodes and previously reported microaccelerometers based on microsensitive electrodes in parallel with flow channels, which can be applied to measure rotational accelerations in earthquakes and buildings.

12.
Biol Reprod ; 107(3): 813-822, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-35657015

RESUMO

The anti-Müllerian hormone (AMH) produced by the granulosa cells of growing follicles is critical for folliculogenesis and is clinically used as a diagnostic and prognostic marker of female fertility. Previous studies report that AMH-pretreatment in mice creates a pool of quiescent follicles that are released following superovulation, resulting in an increased number of ovulated oocytes. However, the quality and developmental competency of oocytes derived from AMH-induced accumulated follicles as well as the effect of AMH treatment on live birth are not known. This study reports that AMH priming positively affects oocyte maturation and early embryonic development culminating in higher number of live births. Our results show that AMH treatment results in good-quality oocytes with greater developmental competence that enhances embryonic development resulting in blastocysts with higher gene expression. The transcriptomic analysis of oocytes from AMH-primed mice compared with those of control mice reveal that AMH upregulates a large number of genes and pathways associated with oocyte quality and embryonic development. Mitochondrial function is the most affected pathway by AMH priming, which is supported by more abundant active mitochondria, mitochondrial DNA content and adenosine triphosphate levels in oocytes and embryos isolated from AMH-primed animals compared with control animals. These studies for the first time provide an insight into the overall impact of AMH on female fertility and highlight the critical knowledge necessary to develop AMH as a therapeutic option to improve female fertility.


Assuntos
Hormônio Antimülleriano , Coeficiente de Natalidade , Animais , Hormônio Antimülleriano/genética , Hormônio Antimülleriano/metabolismo , Desenvolvimento Embrionário , Feminino , Nascido Vivo , Camundongos , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Gravidez
13.
Shock ; 57(1): 63-71, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34618727

RESUMO

INTRODUCTION: Long-term use of antibiotics for septic patients leads to bacterial resistance, increased mortality, and hospital stay. In this study, we investigated an emerging biomarker presepsin-guided strategy, which can be used to evaluate the shortening of antibiotic treatment in patients with sepsis without risking a worse outcome. METHODS: In this multicenter prospective cohort trial, patients were assigned to the presepsin or control groups. In the presepsin group, antibiotics were ceased based on predefined cut-off ranges of presepsin concentrations. The control group stopped antibiotics according to international guidelines. The primary endpoints were the number of days without antibiotics within 28 days and mortality at 28 and 90 days. Secondary endpoints were the percentage of patients with a recurrent infection, length of stay in ICU and hospital, hospitalization costs, days of first episode of antibiotic treatment, percentage of antibiotic administration and multidrug-resistant bacteria, and SOFA score. RESULTS: Overall, 656 out of an initial 708 patients were eligible and assigned to the presepsin group (n = 327) or the control group (n = 329). Patients in the presepsin group had significantly more days without antibiotics than those in the control group (14.54 days [SD 9.01] vs. 11.01 days [SD 7.73]; P < 0.001). Mortality in the presepsin group showed no difference to that in the control group at days 28 (17.7% vs. 18.2%; P = 0.868) and 90 (19.9% vs. 19.5%; P = 0.891). Patients in the presepsin group had a significantly shorter mean length of stay in the hospital and lower hospitalization costs than control subjects. There were no differences in the rate of recurrent infection and multidrug-resistant bacteria and the SOFA score tendency between the two groups. CONCLUSIONS: Presepsin guidance has potential to shorten the duration of antibiotic treatment in patients with sepsis without risking worse outcomes of death, recurrent infection, and aggravation of organ failure. TRIAL REGISTRATION: ChiCTR, ChiCTR1900024391. Registered 9 July 2019-Retrospectively registered, http://www.chictr.org.cn.


Assuntos
Antibacterianos/administração & dosagem , Receptores de Lipopolissacarídeos/sangue , Fragmentos de Peptídeos/sangue , Sepse/tratamento farmacológico , Idoso , Biomarcadores/sangue , Estudos de Coortes , Esquema de Medicação , Feminino , Custos Hospitalares , Humanos , Tempo de Internação , Masculino , Sepse/sangue , Sepse/mortalidade
15.
Micromachines (Basel) ; 12(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34683207

RESUMO

This paper presents a micro-electromechanical systems (MEMS)-based integrated triaxial electrochemical seismometer, which can detect three-dimensional vibration. By integrating three axes, the integrated triaxial electrochemical seismometer is characterized by small volume and high symmetry. The numerical simulation results inferred that the integrated triaxial electrochemical seismometer had excellent independence among three axes. Based on the experimental results, the integrated triaxial electrochemical seismometer had the advantage of small axial crosstalk and could detect vibration in arbitrary directions. Furthermore, compared with the uniaxial electrochemical seismometer, the integrated triaxial electrochemical seismometer had similar sensitivity curves ranging from 0.01 to 100 Hz. In terms of random ground motion response, high consistencies between the developed integrated triaxial electrochemical seismometer and the uniaxial electrochemical seismometer could be easily observed, which indicated that the developed integrated triaxial electrochemical seismometer produced comparable noise levels to those of the uniaxial electrochemical seismometer. These results validated the performance of the integrated triaxial electrochemical seismometer, which has a good prospect in the field of deep geophysical exploration and submarine seismic monitoring.

16.
Micromachines (Basel) ; 12(6)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203906

RESUMO

This paper presents a new process to fabricate a sensing unit of electrochemical seismometers using only one silicon-glass-silicon bonded wafer. By integrating four electrodes on one silicon-glass-silicon bonded wafer, the consistency of the developed sensing unit was greatly improved, benefiting from the high alignment accuracy. Parameter designs and simulations were carried out based on this sensing unit, which indicated that the sensitivities of the developed electrochemical seismometer decreased with the decrease in the number of flow holes in the sensing unit, and the initial stabilization time decreased gradually with the decrease in the thickness of the glass layer. Based on experimental results of four devices, the peak sensitivity was quantified as 5345.45 ± 43.78 V/(m/s) at 2 Hz, which proved high consistency of the fabricated electrochemical seismometer. In terms of the responses to random ground motions, high consistencies between the developed electrochemical seismometer and the commercial counterpart of CME6011 (R-sensors, Moscow, Russia) were found, where the developed electrochemical seismometer produced comparable noise levels to those of CME6011. These results validated the performance of the device and it may function as an effective tool for a variety of applications.

17.
Eur J Pharmacol ; 903: 174135, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940030

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease resulting in respiratory failure with no efficient treatment options. We investigated the protective effect of RS4651 on pulmonary fibrosis in mice and the mechanism. METHODS: Intratracheal injection of bleomycin (BLM) was used to induce pulmonary fibrosis in mice. RS4561 was administered intraperitoneally at different doses. Histopathological changes were observed. The level of alpha-smooth muscle actin (α-SMA) were also tested. In vitro, the proliferation and migratory effects of RS4651 treatment on MRC-5 cells pre-treated with transforming growth factor (TGF-ß1) were examined. RNA-sequencing was used to detect differentially expressed target genes. Then, the expression of α-SMA, pSMAD2 and SMAD7 were analysed during RS4651 treatment of MRC-5 cells with or without silencing by SMAD7 siRNA. RESULTS: Histopathological staining results showed decreased collagen deposition in RS4651 administered mice. Additionally, a lower level of α-SMA was also observed compared to the BLM group. The results of in vitro studies confirmed that RS4651 can inhibit the proliferation and migration, as well as α-SMA and pSMAD2 expression in MRC-5 cells treated with TGF-ß1. RNA-sequencing data identified the target gene SMAD7. We found that RS4651 could upregulate SMAD7 expression and inhibit the proliferation and migration of MRC-5 cells via SMAD7, and RS4651 inhibition of α-SMA and pSMAD2 expression was blocked in SMAD7-siRNA MRC-5 cells. In vivo studies further confirmed that RS4651 could upregulate SMAD7 expression in BLM-induced lung fibrosis in mice. CONCLUSIONS: Our data suggest that RS4651 alleviates BLM-induced pulmonary fibrosis in mice by inhibiting the TGF-ß1/SMAD signalling pathway.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Bleomicina/toxicidade , Linhagem Celular , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Proteína Smad7/antagonistas & inibidores , Proteína Smad7/genética , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/toxicidade , Regulação para Cima/efeitos dos fármacos
18.
Biosensors (Basel) ; 11(5)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924783

RESUMO

In recent years, Synthetic Biology has emerged as a new discipline where functions that were traditionally performed by electronic devices are replaced by "cellular devices"; genetically encoded circuits constructed of DNA that are built from biological parts (aka bio-parts). The cellular devices can be used for sensing and responding to natural and artificial signals. However, a major challenge in the field is that the crosstalk between many cellular signaling pathways use the same signaling endogenous molecules that can result in undesired activation. To overcome this problem, we utilized a specific promoter that can activate genes with a natural, non-toxic ligand at a highly-induced transcription level with low background or undesirable off-target expression. Here we used the orphan aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that upon activation binds to specific AHR response elements (AHRE) of the Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) promoter. Flavonoids have been identified as AHR ligands. Data presented here show the successful creation of a synthetic gene "off" switch that can be monitored directly using an optical reporter gene. This is the first step towards bioengineering of a synthetic, nanoscale bio-part for constructing a sensor for molecular events.


Assuntos
Apigenina/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Técnicas Biossensoriais , Receptores de Hidrocarboneto Arílico/química , Bioengenharia , Citocromo P-450 CYP1A1 , Flavonoides , Humanos , Ligantes , Ligação Proteica , Transdução de Sinais
19.
Micromachines (Basel) ; 12(4)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918243

RESUMO

Electrochemical seismic sensors that employ liquid as their inertial masses have the advantages of high performances in the low-frequency domain and a large working inclination. However, the surrounding temperature changes have serious impacts on the sensitivities of the sensors, which makes them unable to work as expected. This paper studied the temperature characteristics of electrochemical seismic sensors based on MEMS (micro-electro-mechanical systems), and analyzed the influences of the temperature effects on the open-loop and closed-loop amplitude-frequency curves. Most importantly, the temperature compensation circuits based on thermistors were developed, which effectively adjusted pole frequencies and sensitivity coefficients, and finally realized the real-time temperature compensation for both open-loop and closed-loop measurements for the first time. The results showed that in the temperature range of -10 °C ~ +40 °C, and with the 3 dB bandwidth range of 0.01 Hz ~ 40 Hz, the change of the maximum sensitivity was reduced from about 25 dB before temperature compensation to less than 2 dB after temperature compensation.

20.
Sensors (Basel) ; 21(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530375

RESUMO

This study developed a MEMS-based electrochemical seismometer relying on a cathode-anode-cathode (CAC) integrated three-electrode structure where two cathodes were positioned on two surfaces of a silicon wafer, while one anode was positioned on the sidewalls of the through holes of the silicon wafer. Device design and numerical simulations were conducted to model the functionality of the three-electrode structure in detecting vibration signals with the key geometrical parameters optimized. The CAC integrated three-electrode structure was then manufactured by microfabrication, which demonstrated a simplified fabrication process in comparison with conventional four-electrode structures. Device characterization shows that the sensitivity of the CAC microseismometer was an order of magnitude higher than that of the CME6011 (a commercially available four-electrode electrochemical seismometer), while the noise level was comparable. Furthermore, in response to random vibrations, a high correlation coefficient between the CAC and the CME6011 (0.985) was located, validating the performance of the developed seismometer. Thus, the developed electrochemical microseismometer based on an integrated three-electrode structure may provide a new perspective in seismic observations and resource explorations.

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