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1.
Front Microbiol ; 12: 763498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880839

RESUMO

Traditional Chinese medicines (TCMs), as a unique natural medicine resource, were used to prevent and treat bacterial diseases in China with a long history. To provide a prediction model of screening antibacterial TCMs for the design and discovery of novel antibacterial agents, the literature about antibacterial TCMs in the China National Knowledge Infrastructure (CNKI) and Web of Science database was retrieved. The data were extracted and standardized. A total of 28,786 pieces of data from 904 antibacterial TCMs were collected. The data of plant medicine were the most numerous. The result of association rules mining showed a high correlation between antibacterial activity with cold nature, bitter and sour tastes, hemostatic, and purging fire efficacies. Moreover, TCMs with antibacterial activity showed a specific aggregation in the phylogenetic tree; 92% of them came from Tracheophyta, of which 74% were mainly concentrated in rosids, asterids, Liliopsida, and Ranunculales. The prediction models of anti-Escherichia coli and anti-Staphylococcus aureus activity, with AUC values (the area under the ROC curve) of 77.5 and 80.0%, respectively, were constructed by the Neural Networks (NN) algorithm after Bagged Classification and Regression Tree (Bagged CART) and Linear Discriminant Analysis (LDA) selection. The in vitro experimental results showed the prediction accuracy of these two models was 75 and 60%, respectively. Four TCMs (Cirsii Japonici Herba Carbonisata, Changii Radix, Swertiae Herba, Callicarpae Formosanae Folium) were proposed for the first time to show antibacterial activity against E. coli and/or S. aureus. The results implied that the prediction model of antibacterial activity of TCMs based on properties and families showed certain prediction ability, which was of great significance to the screening of antibacterial TCMs and can be used to discover novel antibacterial agents.

2.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21267805

RESUMO

The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 {micro}g mRNA-1273. A 50 {micro}g boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.

3.
J Bone Joint Surg Am ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34826301

RESUMO

BACKGROUND: It is hypothesized that leukocyte-poor (LP) platelet-rich plasma (PRP) is preferred over leukocyte-rich (LR) PRP for the treatment of knee osteoarthritis (OA). METHODS: The MEDLINE, Embase, and Cochrane databases were reviewed for all English-language studies comparing LP-PRP or LR-PRP with relevant controls or each other. The follow-up periods were 6 months and 12 months. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between baseline and follow-up. The secondary outcome measures were changes in the WOMAC pain subscale, visual analog scale (VAS) for pain, and International Knee Documentation Committee (IKDC) subjective score between baseline and follow-up, and the incidence of local adverse reactions. Treatment outcomes were analyzed using the mean difference between treatments for continuous outcomes and the odds ratio for binary outcomes, with 95% credibility intervals. Treatment modalities were ranked using the surface under the cumulative ranking (SUCRA) probabilities. Risk of bias was assessed using the relevant Cochrane tools, RoB 2 (version 2 of the Cochrane risk-of-bias tools) for randomized controlled trials (RCTs) and ROBINS-I (Risk of Bias in Non-Randomized Studies - of Interventions) for prospective comparative studies (PCSs). RESULTS: This network meta-analysis included 23 studies: 20 RCTs and 3 PCSs, with a total of 2,260 patients and a mean follow-up period of 9.9 months. The overall risk-of-bias assessment of the RCTs revealed that 9 studies had low risk, 7 had some concerns, and 4 had high risk. The overall risk-of-bias assessment of the PCSs revealed that 1 study had low risk and 2 had moderate risk. We found no significant (p < 0.05) difference in all outcome measures and local adverse reactions between LP-PRP and LR-PRP. SUCRA rankings revealed that, for all outcome measures, LP-PRP is preferred to LR-PRP across follow-up periods. CONCLUSIONS: Leukocyte concentration of PRP does not play a significant role in patient-reported outcome measures for knee OA. LP-PRP is preferred to LR-PRP according to SUCRA rankings, but this preference may not be important in clinical practice. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

4.
ACS Appl Mater Interfaces ; 13(48): 57489-57496, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34839656

RESUMO

Lithium (Li) metal batteries are promising future rechargeable batteries with high-energy density as the Li metal anode (LMA) possesses a high specific capacity and the lowest potential. However, the commercial application of the LMA has been hindered by a low Coulombic efficiency and dendrite growth, which are related to the unstable interphase with poor Li+ ion transport. Herein, we report novel polymer zwitterion-based artificial interphase layers (AILs) with improved Li+ ion transport and high stability for long-life LMAs. Benefitting from the unique zwitterion effect within the polymer zwitterion-based AILs, a high Li+ ion transference number (0.81) and a good ionic conductivity (0.75 × 10-4 S cm-1) can be realized simultaneously at the interface. By regulating the weight ratio of the sulfonate group and the phosphate group in polymer zwitterion-based AILs, the modified LMA enables long-term Li plating/stripping for 1400 h at 1 mA cm-2 and stable cycling in a full cell. This interfacial engineering concept could shed light on the development of safe LMAs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34758922

RESUMO

BACKGROUND: Perioperative services have been scrutinized in the context of cost containment in health care, particularly in the procurement and reprocessing of surgical instruments. Although solutions such as surgical instrument inventory optimization (IO) have been proposed, there is a paucity of literature on how to implement this change. The purpose of this project was to describe the implementation of an IO using Kotter's Change Model (KCM). METHODS: This study was conducted at a tertiary academic hospital across the four highest-volume surgical services. The IO was implemented using the steps outlined by KCM: (1) create coalition, (2) create vision for change, (3) establish urgency, (4) communicate the vision, (5) empower broad-based action, (6) generate short-term wins, (7) consolidate gains, and (8) anchor change. This process was evaluated using inventory metrics, operational efficiency metrics, and clinician satisfaction. RESULTS: Total inventory was reduced by 37.7%, with an average tray size reduction of 18.0%. This led to a total reprocessing time savings of 1,333 hours per annum and labor cost savings of $39,995 per annum. Depreciation cost savings were $64,320 per annum. Case cancellation rate due to instrument-related errors decreased from 3.9% to 0.2%. The proportion of staff completely satisfied with the inventory was 1.7% pre-IO and 80.0% post-IO. CONCLUSION: This is the first study to describe the successful implementation of KCM to facilitate change in the perioperative setting. This success contributes to the growing body of literature supporting KCM as a valuable change management tool in health care.

6.
Int Immunopharmacol ; : 108372, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34810128

RESUMO

Citrate has a prominent role as a substrate in cellular energy metabolism. Recently, citrate has been shown to drive inflammation. However, the role of citrate in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Here, we aimed to clarify whether extracellular citrate aggravated the LPS-induced ALI and the potential mechanism. Our findings demonstrated that extracellular citrate aggravated the pathological lung injury induced by LPS in mice, characterized by up-regulation of pro-inflammatory factors and over-activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in the lungs. In vitro, we found that citrate treatment significantly augmented the expression of NLRP3 and pro-IL-1ß and enhanced the translocation of NF-κB/p65 into the nucleus. Furthermore, extracellular citrate plus adenosine-triphosphate (ATP) significantly increased the production of reactive oxygen species (ROS) in primary murine macrophages. Inhibiting the production of ROS with a ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the activation of NLRP3 inflammasome. Altogether, we conclude that extracellular citrate may serve as a damage-associated molecular pattern (DAMP) and aggravates LPS-induced ALI by activating the NLRP3 inflammasome.

7.
Signal Transduct Target Ther ; 6(1): 375, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34728602

RESUMO

The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.

8.
Front Nutr ; 8: 723446, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34595199

RESUMO

Bamboo leaf extracts, with high content of flavonoids and diverse biological activities, are used in animal husbandry. Increasing evidence has suggested an association between the bovine physiology and the udder microbiome, yet whether the microbiota and the metabolites of milk affect the mammary gland health or the milk quality remains unknown. In this study, we provide a potential mechanism for the effects of bamboo leaf extracts on milk microbiota and metabolites of dairy cows. Twelve multiparous lactating Chinese Holstein dairy cows were randomly separated into two groups: basal diet as the control group (CON, n = 6) and a diet supplemented with 30 g/d bamboo leaf extract per head as antioxidants of bamboo leaf (AOB) group (AOB, n = 6) for 7 weeks (2-week adaptation, 5-week treatment). Milk samples were collected at the end of the trial (week 7) for microbiome and associated metabolic analysis by 16S ribosomal RNA (rRNA) gene sequencing and liquid chromatography-mass spectrometry (LC-MS). The results showed that the milk protein was increased (p < 0.0001) and somatic cell count (SCC) showed a tendency to decrease (p = 0.09) with AOB supplementation. The relative abundance of Firmicutes was significantly decreased (p = 0.04) while a higher relative abundance of Probacteria (p = 0.01) was seen in the group receiving AOB compared to the CON group. The AOB group had a significantly lower relative abundance of Corynebacterium_1 (p = 0.01), Aerococcus (p = 0.01), and Staphylococcus (p = 0.02). There were 64 different types of metabolites significantly upregulated, namely, glycerophospholipids and fatty acyls, and 15 significantly downregulated metabolites, such as moracetin, sphinganine, and lactulose in the AOB group. Metabolic pathway analysis of the different metabolites revealed that the sphingolipid signaling pathway was significantly enriched, together with glycerophospholipid metabolism, sphingolipid metabolism, and necroptosis in response to AOB supplementation. Several typical metabolites were highly correlated with specific ruminal bacteria, demonstrating a functional correlation between the milk microbiome and the associated metabolites. These insights into the complex mechanism and corresponding biological responses highlight the potential function of AOB, warranting further investigation into the regulatory role of specific pathways in the metabolism.

9.
Ann Clin Lab Sci ; 51(5): 638-645, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34686505

RESUMO

OBJECTIVE: Repopulation during radiation is a classic theory in radiobiology. The long intervals between cycles of chemotherapy provide better micro-circumstance than radiation for the repopulation of cancer cells. METHODS: Patients with inoperable stage III and stage IV lung cancer were enrolled prospectively. Peripheral blood and tumor tissues were obtained before treatment and each cycle of chemotherapy to detect the serum let-7a expression and Ki-67 index. RESULTS: Fifty-two consecutive consenting patients were enrolled prospectively. The median follow-up was 13 months (range: 2-62 months). A strong correlation was found between the Ki-67 index and serum let-7a before treatment (r =-0.667, P<0.001). The serum let-7a expression levels were upregulated or downregulated significantly during chemotherapy. Patients with relatively low baseline let-7a expression levels had significantly worse overall survival (OS) and progression-free survival (PFS) than patients with relatively high baseline serum let-7a levels (P<0.001, P=0.005, respectively). CONCLUSION: This prospective study demonstrated that let-7a was correlated with tumor proliferation in lung cancer, with high prognostic value. Furthermore, it showed that repopulation, as correlated with let-7a, may exist during chemotherapy, which would give us a new perspective in overcoming the chemoresistance of lung cancer and would help in determining individual treatment strategies.

10.
Nucleic Acids Res ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591960

RESUMO

Regeneration plays an instrumental role in biological development and damage repair by constructing and replacing cells, tissues, and organs. Since regenerative capacity declines with age, promoting regeneration is heralded as a potential strategy for delaying aging. On this premise, mechanisms that regulate regeneration have been extensively studied across species and in different tissues. However, an open and comprehensive database collecting and standardizing the abundant data generated in regeneration research, such as high-throughput sequencing data, remains to be developed. In this work, we constructed Regeneration Roadmap to systematically and comprehensively collect such information over 2.38 million data entries across 11 species and 36 tissues, including regeneration-related genes, bulk and single-cell transcriptomics, epigenomics, and pharmacogenomics data. In this database, users can explore regulatory and expression changes of regeneration-associated genes in different species and tissues. Regeneration Roadmap provides the research community with a long-awaited and valuable data resource featuring convenient computing and visualizing tools, which is publicly available at https://ngdc.cncb.ac.cn/regeneration/index.

11.
Nucleic Acids Res ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570235

RESUMO

Single-cell bisulfite sequencing methods are widely used to assess epigenomic heterogeneity in cell states. Over the past few years, large amounts of data have been generated and facilitated deeper understanding of the epigenetic regulation of many key biological processes including early embryonic development, cell differentiation and tumor progression. It is an urgent need to build a functional resource platform with the massive amount of data. Here, we present scMethBank, the first open access and comprehensive database dedicated to the collection, integration, analysis and visualization of single-cell DNA methylation data and metadata. Current release of scMethBank includes processed single-cell bisulfite sequencing data and curated metadata of 8328 samples derived from 15 public single-cell datasets, involving two species (human and mouse), 29 cell types and two diseases. In summary, scMethBank aims to assist researchers who are interested in cell heterogeneity to explore and utilize whole genome methylation data at single-cell level by providing browse, search, visualization, download functions and user-friendly online tools. The database is accessible at: https://ngdc.cncb.ac.cn/methbank/scm/.

12.
Life (Basel) ; 11(9)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34575074

RESUMO

Tumour immunotherapy combined with molecular typing is a new therapy to help select patients. However, molecular typing algorithms related to tumour immune function have not been thoroughly explored. We herein proposed a single sample immune signature network (SING) method to identify new immune function-related subtypes of cutaneous melanoma of the skin. A sample-specific network and tumour microenvironment were constructed based on the immune annotation of cutaneous melanoma samples. Then, the differences and heterogeneity of immune function among different subtypes were analysed and verified. A total of 327 cases of cutaneous melanoma were divided into normal and immune classes; the immune class had more immune enrichment characteristics. After further subdividing the 327 cases into three immune-related subtypes, the degree of immune enrichment in the "high immune subtype" was greater than that in other subtypes. Similar results were validated in both tumour samples and cell lines. Sample-specific networks and the tumour microenvironment based on immune annotation contribute to the mining of cutaneous melanoma immune function-related subtypes. Mutations in B2M and PTEN are considered potential therapeutic targets that can improve the immune response. Patients with a high immune subtype can generally obtain a better immune prognosis effect, and the prognosis may be improved when combined with TGF-ß inhibitors.

13.
Front Cell Dev Biol ; 9: 723817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532318

RESUMO

Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients' response to immunotherapy and promoting individualized tumor immunotherapy in the future.

14.
Medicine (Baltimore) ; 100(33): e26896, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414945

RESUMO

PURPOSE: Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer. METHOD: We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan-Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated. RESULTS: LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan-Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein-protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation. CONCLUSION: Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Leptina/genética , Neoplasias da Mama/mortalidade , Correlação de Dados , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
15.
J Med Virol ; 93(12): 6544-6550, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34255379

RESUMO

We developed a rapid and simple magnetic chemiluminescence enzyme immunoassay on the Real Express-6 analyzer, which could simultaneously detect immunoglobulin G and immunoglobulin M antibodies against SARS-CoV-2 virus in human blood within 18 min, and which could be used to detect clinical studies to verify its clinical efficacy. We selected blood samples from 185 COVID-19 patients confirmed by polymerase chain reaction and 271 negative patients to determine the clinical detection sensitivity, specificity, stability, and precision of this method. Meanwhile, we also surveyed the dynamic variance of viral antibodies during SARS-CoV-2 infection. This rapid immunoassay test has huge potential benefits for rapid screening of SARS-CoV-2 infection and may help clinical drug and vaccine development.


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Imunoglobulina G/sangue , Imunoglobulina M/sangue , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Reações Cruzadas/imunologia , Diagnóstico Precoce , Feminino , Humanos , Imunoensaio/métodos , Medições Luminescentes , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Adulto Jovem
16.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(7): 671-676, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34266522

RESUMO

OBJECTIVE: To study the efficacy and safety of lactase additive in improving lactose intolerance in preterm infants. METHODS: A total of 60 preterm infants with lactose intolerance who were admitted to the Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2018 to December 2019 were randomly divided into a lactase treatment group and a control group, with 30 infants in each group. The infants in the lactase treatment group were given 4 drops of lactase additive (180 mg) added into preterm formula or breast milk, and those in the control group were given placebo, oral administration of probiotics (live combined Bifidobacterium, Lactobacillus and Enterococcus powder) at half an hour after feeding (1 g each time, twice a day), and clockwise abdominal massage around the belly button at 1 hour after feeding for 15 minutes each time, 3 times a day. Fecal pH, fecal reducing sugar, growth indicators, symptoms of lactose intolerance, and laboratory markers were measured at the end of the first and second weeks after intervention. RESULTS: Finally 29 infants in the lactase treatment group and 26 infants in the control group completed the trial. At the end of the first week after intervention, compared with the control group, the lactase treatment group had significantly lower frequency of daily milk vomiting and gastric retention amount (P < 0.05) and a significantly higher proportion of infants with fecal pH > 5.0 (P < 0.05). At the end of the second week after intervention, compared with the control group, the lactase treatment group had significantly lower frequency of daily milk vomiting and 24-hour abdominal circumference difference (P < 0.05) and a significantly higher proportion of infants with the absence of gastric retention, fecal pH > 5.0, or negative reducing sugar in feces (P < 0.05). No adverse reactions associated with the lactase additive or probiotics were observed during the trial. CONCLUSIONS: Lactase additive can safely and effectively improve the clinical symptoms caused by lactose intolerance in preterm infants.


Assuntos
Lactase , Intolerância à Lactose , China , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Lactose , Intolerância à Lactose/tratamento farmacológico , Estudos Prospectivos
17.
Toxicol Lett ; 349: 84-91, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153408

RESUMO

AIM: Smoking has been considered as a risk factor of chronic pancreatitis (CP), but the potential mechanism is still unknown. The major pathological feature of CP is pancreatic fibrosis, whose major functional cells are pancreatic stellate cells (PSCs). Nicotine is the major component of cigarette smoke, our recent study suggested that nicotine has the potential to facilitate pancreatic fibrosis in CP. This study was aimed to analyze the function and mechanism of nicotine on PSCs and pancreatic fibrosis in rats. MATERIALS AND METHODS: In vivo, a rat CP model was induced by intraperitoneal injection of 20 % L-arginine hydrochloride (200 mg/100 g) at 1 h intervals twice per week, nicotine was injected subcutaneously at a dose of 1 mg/kg body weight per day. After four weeks, the pancreatic tissue was collected for H&E, Masson and immunohistochemical staining. In vitro, primary rPSCs were isolated from rats and treated with nicotine (0.1 µM and 1 µM). The proliferation、apoptosis、α-SMA expression、extracellular matrix (ECM) metabolism and α7nAChR-mediated JAK2/STAT3 signaling pathway of rPSCs were detected by CCK-8 assay、flow cytometry、real-time Q-PCR and western blotting analysis. The α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS: Nicotine increased pancreatic damage, collagen deposition and activation of PSCs in the CP rat model. In rPSCs, the proliferation, α-SMA expression and ECM formation were significantly promoted by nicotine in a dose-dependent manner. Meanwhile, the apoptosis of rPSCs was significantly reduced after nicotine treatment. Moreover, nicotine also activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in rPSCs. These effects of nicotine on rPSCs were blocked by α-BTX. SIGNIFICANCE: Our finding in this research suggests that nicotine facilitates pancreatic fibrosis by promoting activation of pancreatic stellate cells via α7nAChR-mediated JAK2/STAT3 signaling pathway in rats, partly revealing the mechanism of smoking on chronic pancreatitis.


Assuntos
Janus Quinase 2/metabolismo , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Células Estreladas do Pâncreas/efeitos dos fármacos , Pancreatite Crônica/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Masculino , Células Estreladas do Pâncreas/enzimologia , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/enzimologia , Pancreatite Crônica/patologia , Ratos Wistar , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
18.
Pain ; 162(7): 1960-1976, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34130310

RESUMO

ABSTRACT: The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.


Assuntos
Adenosina , Metiltransferases , Animais , Dor/genética , RNA , RNA Mensageiro
19.
Mol Cell ; 81(14): 2960-2974.e7, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111398

RESUMO

The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that fails to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER complex. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1. This nonproteolytic action stimulates XRCC1's interaction with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that Uhrf2-fostered TDG-RAD23B-BER complex is functionally linked to the completion of DNA demethylation at active promoters and that Uhrf2 ablation impedes DNA demethylation on latent enhancers that undergo poised-to-active transition during neuronal commitment. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.


Assuntos
5-Metilcitosina/análogos & derivados , Regulação Alostérica/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , 5-Metilcitosina/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Desmetilação do DNA , Metilação de DNA/genética , Reparo do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética
20.
Front Microbiol ; 12: 675020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163451

RESUMO

Cronobacter sakazakii (C. sakazakii) is an emerging opportunistic foodborne pathogen that can cause neonatal necrotizing enterocolitis, meningitis, sepsis in neonates and infants with a relatively high mortality rate. Bacterial transcytosis across the human brain microvascular endothelial cells (HBMEC) is vital for C. sakazakii to induce neonatal meningitis. However, few studies focus on the mechanisms by which C. sakazakii translocates HBMEC. In this study, the translocation processes of C. sakazakii on HBMEC were explored. C. sakazakii strains could effectively adhere to, invade and intracellularly survive in HBMEC. The strain ATCC 29544 exhibited the highest translocation efficiency across HBMEC monolayer among four tested strains. Bacteria-contained intracellular endosomes were detected in C. sakazakii-infected HBMEC by a transmission electron microscope. Endocytosis-related proteins CD44, Rab5, Rab7, and LAMP2 were increased after infection, while the level of Cathepsin L did not change. C. sakazakii induced TLR4/NF-κB inflammatory signal pathway activation in HBMEC, with increased NO production and elevated mRNA levels of IL-8, IL-6, TNF-α, IL-1ß, iNOS, and COX-2. C. sakazakii infection also caused LDH release, caspase-3 activation, and HBMEC apoptosis. Meanwhile, increased Dextran-FITC permeability and decreased trans epithelial electric resistance indicated that C. sakazakii disrupted tight junction of HBMEC monolayers, which was confirmed by the decreased levels of tight junction-related proteins ZO-1 and Occludin. These findings suggest that C. sakazakii induced intracellular bacterial endocytosis, stimulated inflammation and apoptosis, disrupted monolayer tight junction in HBMEC, which all together contribute to bacterial translocation.

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