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1.
Blood Adv ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521107

RESUMO

Single antigen-targeted chimeric antigen receptor (CAR) T-cell therapy may be insufficient to induce a durable response in pediatric aggressive B-cell lymphomas. The clinical trial (ChiCTR1800014457) examined the feasibility of sequential different B cell antigen-targeted CAR T-cell therapy for pediatric refractory/relapsed Burkitt lymphoma. Twenty-three patients received the first CD19 CAR T-cell infusion. The patients who did not achieve an ongoing complete response sequentially underwent one or more additional infusions of CAR T-cell targeting CD22 followed by CD20 according to their disease status and CAR T-cell persistence after each infusion. The median time from the last infusion to cutoff date was 17 months (range, 15 to 23). The estimated 18-month complete response rate was 78% (95% confidence interval [CI], 54 to 91). The estimated 18-month progression-free survival rate was 78% (95% CI, 55 to 90), with 78% (95% CI, 37 to 94) in patients with bulky diseases and 60% (95% CI, 25 to 83) in patients with central nervous system (CNS) involvement. During the first CD19 CAR T-cell infusion, grade 3 or higher cytokine release syndrome (CRS) and neurotoxicity occurred in 34.8% and 21.7% of all patients, respectively. During subsequent infusions, few incidences of higher than grade 2 CRS and neurotoxicity were observed. All adverse events were reversible. The severity of neurotoxicity was not significantly different between patients with CNS and non-CNS involvement. Sequential CAR T-cell therapy may result in a durable response and is safe in pediatric refractory/relapsed Burkitt lymphoma. Patients with CNS involvement may benefit from sequential CAR T-cell therapy. This trial was registered at www.chictr.org.cn/index.aspx as ChiCTR1800014457.

2.
J Chem Inf Model ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34521197

RESUMO

Protein tyrosine phosphatase 1B (PTP1B) is an intractable target for drug discovery due to its conservative and cationic catalytic site. Targeting alternative allosteric sites of PTP1B is a promising strategy to achieve specificity and bioavailability. A hierarchical virtual screening based on a previously identified allosteric site was applied to search for potential PTP1B inhibitors with better pharmacological profiles. Four potent PTP1B inhibitors (H1, H3, H7, and H9) with structures distinct from known inhibitors were identified. Among them, H3 and H9 demonstrated evident selectivity to PTP1B over homologous T-cell protein tyrosine phosphatase (TCPTP) and SHP2. Molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) calculations recognized Phe280, Phe196, Leu192, and Asn193 as key residues responsible for potent allosteric inhibition and excellent PTP selectivity. The results not only expand the structural diversity but also aid the future molecular design of PTP1B allosteric inhibitors.

3.
Macromol Rapid Commun ; : e2100544, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523771

RESUMO

Polymer-based pure organic room temperature phosphorescence (RTP) materials have garnered considerable interest in recent years, among which RTP systems with prolonged lifetimes and tunable emission colors are promising for applications in sensing, flexible electronics, bioassay, anti-counterfeiting, and data encryption. Herein, we report on a facile doping method based on two types of copolymers with benzene/biphenyl-based light-emitting cores as their side chains, whereby the two copolymers are robustly crosslinked via noncovalent interactions including hydrogen bonding and halogen bonding that occur between the light-emitting cores and polyacrylamide backbones. Persistent RTP emission with prolonged lifetime up to 1.9 s and phosphorescence quantum yield as high as 40.1% are obtained in single copolymers, attributed to the conformation restriction of phosphorescent dyes originating from the rigid microenvironment. Furthermore, multicolor phosphorescence signals are observed in the doped binary luminescent copolymer systems that can be effectively regulated by the feed ratio of luminescent cores and irradiation wavelengths. Possible mechanisms for this efficient and long-lived color-tunable RTP system are also discussed on the basis of the experimental data and theoretical calculations. In addition, we also demonstrate that the color-tunable RTP emission of the doped copolymer systems under ambient conditions allows for further exploitation in the application of dynamic information encryption. This article is protected by copyright. All rights reserved.

4.
Arch Virol ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524537

RESUMO

Porcine circovirus type 2 (PCV2) is the etiological agent of post-weaning multisystemic wasting syndrome (PMWS). The original prevalent genotype, PCV2a, has been replaced by genotypes 2b and 2d in the swine population worldwide. The Rep protein is critical for viral replication. Comparison of a large number of Rep protein amino acid (aa) sequences showed that three sites distinguish genotype 2b from genotype 2d. In order to analyze the effect of exchanging the amino acids (asparagine and serine) at position 6 in the Rep proteins of PCV2b and PCV2d, two wild-type and two mutant viruses were rescued. Real-time quantitative PCR and a one-step growth curve were used to determine the viral load to assess the replication ability of the rescued viruses. The results showed that there was no significant difference in in vitro performance between the wild-type PCV2b and the mutated virus, while the mutation of PCV2d enhanced viral replication.

5.
Chemosphere ; 287(Pt 2): 132126, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492407

RESUMO

A novel carbon quantum dots (CQDs) sensitized 2D/2D carbon nitride nanosheets and bismuth tungstate composite (CQD-CNs/BWO) was successfully prepared via the facile hydrothermal method and used for the photocatalytic degradation of norfloxacin (NOR). During 120 min irradiation test, CQD-CNs/BWO exhibited 9 and 1.76 times higher photocatalytic activity than CNs and BWO, respectively. CQDs and constructed 2D/2D structure could not only improve the light harvesting but also promote the generation and separation of electron-holes. The existing inorganic ions in solution (e.g. bicarbonate ions, chlorine ions, and sulfate ions) could inhibit NOR degradation. Based on the electron spin resonance and free radicals inhibition tests, the holes and superoxide radicals rather than hydroxyl radicals were the main reactive species. The intermediates and possible pathways were proposed, and the antibacterial activity of the treated solution after the reaction was evaluated via bacteriostatic tests. The prepared composite material with high photocatalytic activity and stability is potentially effective for the degradation of antibiotics in wastewater.

6.
Aging (Albany NY) ; 13(undefined)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34516406

RESUMO

In this study, we investigated the mechanisms through which astrocyte-derived exosomes (AS-Exos) alleviate traumatic brain injury (TBI)-induced neuronal defects in TBI model rats and mice. Treatment with AS-Exos alleviated neurobehavioral deficits, cognitive impairment, and brain edema in TBI rats. AS-Exos also significantly reduced neuronal cell loss and atrophy in the TBI rats. AS-Exos significantly reduced oxidative stress and mitochondrial H2O2 levels by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the hippocampal neurons of TBI rats. TUNEL-staining assays showed that AS-Exos significantly reduced TBI-induced neuronal apoptosis. Mechanistically, AS-Exos ameliorated oxidative stress by activating Nrf2/HO-1 signaling in the hippocampus of TBI rats. In addition, the neuroprotective effects of AS-Exos were abrogated in brain-specific Nrf2-knockout mice subjected to TBI. These findings demonstrate that AS-Exos protects against TBI-induced oxidative stress and neuronal apoptosis by activating Nrf2 signaling in both rat and mouse models.

7.
Allergol Immunopathol (Madr) ; 49(5): 49-56, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34476922

RESUMO

BACKGROUND: In recent times, the medical science has developed by leaps and bounds, however, the molecular mechanism of pediatric pneumonia is still unclear. Although prior researches have shown that methyltransferase-like 3 (METTL3) is up-regulated in a variety of inflammatory diseases, its role and mechanism has been rarely studied in pediatric pneumonia, and need to be defined elaborately. OBJECTIVE: In this study, the related molecular mechanism of METTL3 on inflammation and cell apoptosis in a pediatric pneumonia was investigated. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qPCR) and western blot assays were employed to examine the mRNA and protein expression level of METTL3 and EZH2 in peripheral blood monocytes from pediatric pneumonia patients or cell model (WI-38). Then, qPCR and ELISA assay were applied to verify the inflammatory response in LPS-treated WI-38 cell lines after knockdown of METTL3. Besides, MTT cell viability assays, flow cytometry, and western blot assays were applied to examine the cell viability and cell apoptosis of LPS-treated WI-38 cell after knockdown of METTL3. Further, the western blot assays were employed to examine the protein expression levels of p-JAK2, JAK2, p-STAT3, STAT3, and EZH2 in LPS-treated WI-38 cell after knockdown of METTL3. Finally, ELISA and western blot were applied to verify the inflammatory response and cell apoptosis of LPS-treated WI-38 cell after knockdown of METTL3 and overexpression of EZH2. RESULTS: In this study, the results showed that METTL3 and EZH2 were highly expressed in pediatric pneumonia patients and cell models (WI-38), respectively. Besides, downregulation of METTL3 inhibited LPS-induced inflammatory response and cell apoptosis. Then, the fact that METTL3 regulates the JAK2/STAT3 signaling pathway through EZH was proved. Furthermore, downregulation of METTL3 inhibits inflammation and apoptosis through EZH2. CONCLUSION: This study found that METTL3 promotes inflammation and cell apoptosis in a pediatric pneumonia model by regulating EZH2.

8.
Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

9.
Mater Sci Eng C Mater Biol Appl ; 128: 112297, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474848

RESUMO

INTRODUCTION: Peri-implantitis is a bacterially induced inflammatory disease which affects the hard and soft tissues around a dental implant. Microbial biofilm formation is an important causative factor in peri-implantitis. The aim of this study is to develop an effective multifunctional surface coating for antimicrobial property and to counteract oral biofilm-associated infections via a single polydopamine copper coating (PDAM@Cu) on titanium implant surface to regulate endogenous nitric oxide (NO) generation. METHODS: PDAM@Cu coatings were made with different concentrations of CuCl2 on titanium surfaces with a simple dip coating technique. Coatings were characterised to evaluate Cu concentrations as well as NO release rates from the coatings. Further, salivary biofilms were made on the coatings using Brain Heart Infusion (BHI) media in an anaerobic chamber. Biofilms were prepared with three different mixtures, one of which was saliva only, the second had an addition of sheep's blood, and the third was prepared with NO donors S-nitrosoglutathione (GSNO) and L-glutathione (GSH) in the mixture of saliva and blood to evaluate the effects of endogenously produced NO on biofilms. The effectiveness of coated surfaces on biofilms were assessed using four different methods, namely, crystal violet assay, scanning electron microscopy imaging, 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) metabolic assay, and live/dead staining. RESULTS: NO release rates could be controlled with different Cu concentration in PDAM@Cu coatings. NO generated from the PDAM@Cu coatings effectively induced dispersal of biofilms shown by the reduction in biofilm biomass as well as reduced biofilm attachment in samples prepared with blood and NO donors. Cu ions released from the PDAM@Cu coatings resulted in killing of the dispersed bacteria, which was evidenced by the live/dead cell staining and reduced metabolic activity noted from the XTT assay. In contrast, samples prepared with saliva showed no significant reduction in biofilms, indicating the important effect of endogenously generated NO on biofilm dispersal. CONCLUSION: In conclusion, PDAM@Cu coatings with NO generating surfaces have a dual anti-biofilm function, with a synergistic effect on biofilm dispersal from regulated NO generation and bactericidal effects from Cu ions from the coatings.


Assuntos
Cobre , Óxido Nítrico , Animais , Biofilmes , Materiais Revestidos Biocompatíveis/farmacologia , Cobre/farmacologia , Homicídio , Indóis , Polímeros , Ovinos , Propriedades de Superfície , Titânio/farmacologia
10.
Chem Soc Rev ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491253

RESUMO

Porous organic polymers (POPs), as a new category of advanced porous materials, have received broad research interests owing to the advantages of light-weight, robust scaffolds, high specific surface areas and good functional tailorability. According to the long-range ordering of polymer skeletons, POPs can be either crystalline or amorphous. Macrocycles with inherent cavities can serve as receptors for recognizing or capturing specific guest molecules through host-guest interactions. Incorporating macrocycles in POP skeletons affords win-win merits, e.g. hierarchical porosity and novel physicochemical properties. In this review, we focus on the recent progress associated with new architectures of macrocycle-based POPs. Herein, these macrocycles are divided into two subclasses: non-planar (crown ether, calixarene, pillararene, cyclodextrin, cyclotricatechylene, etc.) and planar (arylene-ethynylene macrocycles). We summarize the synthetic methods of each macrocyclic POP in terms of the functions of versatile building blocks. Subsequently, we discuss the performance of macrocyclic POPs in environmental remediation, gas adsorption, heterogeneous catalysis, fluorescence sensing and ionic conduction. Although considerable examples are reported, the development of macrocyclic POPs is still in its infancy. Finally, we propose the underlying challenges and opportunities of macrocycle-based POPs.

11.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166262, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34481059

RESUMO

Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.

12.
Artigo em Inglês | MEDLINE | ID: mdl-34499729

RESUMO

BACKGROUND: The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin. OBJECTIVES: To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin. METHODS: A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time-kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis. RESULTS: We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time-kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration. CONCLUSIONS: Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin.

13.
Org Lett ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505792

RESUMO

In palladium/norbornene (Pd/NBE) chemistry, the "ortho effect" has been proven to be a key factor in the process of ß-carbon elimination to extrude NBE. Herein, we found that the o-iodoaniline protected by a p-methoxybenzenesulfonyl group can recover the "ortho effect" and then undergo N-S bond cleavage with vinyl palladium, thus achieving a highly selective C-N coupling reaction in the Catallani-Lautens reaction system. On the basis of this discovery, a one-step synthesis of highly functionalized tricyclic indole derivatives was realized.

14.
J Chem Inf Model ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467754

RESUMO

While small molecule internal strain is crucial to molecular docking, using it in evaluating ligand scores has remained elusive. Here, we investigate a technique that calculates strain using relative torsional populations in the Cambridge Structural Database, enabling fast precalculation of these energies. In retrospective studies of large docking screens of the dopamine D4 receptor and of AmpC ß-lactamase, where close to 600 docking hits were tested experimentally, including such strain energies improved hit rates by preferentially reducing the ranks of strained high-scoring decoy molecules. In a 40-target subset of the DUD-E benchmark, we found two thresholds that usefully distinguished between ligands and decoys: one based on the total strain energy of the small molecules and another based on the maximum strain allowed for any given torsion within them. Using these criteria, about 75% of the benchmark targets had improved enrichment after strain filtering. Relying on precalculated population distributions, this approach is rapid, taking less than 0.04 s to evaluate a conformation on a standard core, making it pragmatic for precalculating strain in even ultralarge libraries. Since it is scoring function agnostic, it may be useful to multiple docking approaches; it is openly available at http://tldr.docking.org.

15.
BMJ Open ; 11(8): e050254, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404713

RESUMO

OBJECTIVES: To determine the relationship between depressive symptoms and progression of carotid intima-media thickness (cIMT) in a Beijing community-based population. DESIGN: Prospective cohort study between 2014 and 2018. SETTING: Dwellers without cardiovascular disease, hypertension or diabetes from a Beijing community. PARTICIPANTS: 3849 Chinese community-dwelling individuals who underwent baseline screening for depressive symptoms were invited to participate in the study in 2014 and follow-up visit in 2018. Among them, 2124 participants completed carotid ultrasound examination both at baseline and a follow-up visit. After further excluding patients with a history of stroke, myocardial infarction or lower extremity arterial stenosis and those with a diagnosis of hypertension or diabetes and ankle-brachial index ≤0.9 at baseline, 1011 eligible participants were finally included. PRIMARY OUTCOME MEASURE: The rate of mean cIMT change. RESULTS: Over a median follow-up period of 4.40 years, the overall rate of mean cIMT change was 2.23% (-5.64% to 9.51%). After adjustment for 13 covariates, there was an increase of 2.36% (ß=2.36, 95% CI: 0.37 to 4.36, p=0.020) for the rates of mean cIMT change in the depressive group compared with the control group. Furthermore, this association was modified by drinking status (ß=3.22, 95% CI: 1.25 to 5.19, P-interaction=0.006). CONCLUSION: Depressive symptoms were independently associated with progression of mean cIMT in a community-based cohort in Beijing, China. Furthermore, this relationship was modified by drinking status.


Assuntos
Espessura Intima-Media Carotídea , Infarto do Miocárdio , Pequim/epidemiologia , China/epidemiologia , Estudos de Coortes , Depressão/epidemiologia , Humanos , Estudos Prospectivos
16.
Mar Drugs ; 19(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34436268

RESUMO

RKC-B1 is a novel fermentation product obtained from the marine micromonospora FIM02-523A. Thus far, there have been few reports about the pharmacological activity of RKC-B1. In our present study, we investigated the anti-neuroinflammatory effects and the possible mechanism of RKC-B1 in LPS-stimulated mice. After treatment with RKC-B1, RNA-seq transcriptome of the cerebral cortex tissue was conducted to find the differentially expressed genes (DEGs). Inflammatory cytokines and proteins were evaluated by ELISA and WB. In RNA-seq analysis, there were 193 genes screened as core genes of RKC-B1 for treatment with neuroinflammation. The significant KEGG enrichment signaling pathways of these core genes were mainly included TNF signaling pathway, IL-17 signaling pathway, NOD-like receptor signaling pathway, NF-κB signaling pathway and others. The corresponding top five KEGG enrichment pathways of three main clusters in PPI network of core genes were closely related to human immune system and immune disease. The results showed that RKC-B1 reduced the levels of pro-inflammatory factors (IL-6, IL-1ß, MCP-1, and ICAM-1) and the expression of COX2 in cerebral cortex tissue. Additionally, we found that the anti-neuroinflammation activity of RKC-B1 might be related to suppress activating of NF-κB and NLRP3/cleaved caspase-1 signaling pathways. The current findings suggested that RKC-B1 might be a promising anti-neuroinflammatory agent.

17.
Viruses ; 13(8)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34452298

RESUMO

Influenza A viruses are serious zoonotic pathogens that continuously cause pandemics in several animal hosts, including birds, pigs, and humans. Indole derivatives containing an indole core framework have been extensively studied and developed to prevent and/or treat viral infection. This study evaluated the anti-influenza activity of several indole derivatives, including 3-indoleacetonitrile, indole-3-carboxaldehyde, 3-carboxyindole, and gramine, in A549 and MDCK cells. Among these compounds, 3-indoleacetonitrile exerts profound antiviral activity against a broad spectrum of influenza A viruses, as tested in A549 cells. Importantly, in a mouse model, 3-indoleacetonitrile with a non-toxic concentration of 20 mg/kg effectively reduced the mortality and weight loss, diminished lung virus titers, and alleviated lung lesions of mice lethally challenged with A/duck/Hubei/WH18/2015 H5N6 and A/Puerto Rico/8/1934 H1N1 influenza A viruses. The antiviral properties enable the potential use of 3-indoleacetonitrile for the treatment of IAV infection.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34427958

RESUMO

BACKGROUND: ß-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, ß-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown. METHODS: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients. RESULTS: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms). CONCLUSIONS: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.

19.
Pacing Clin Electrophysiol ; 44(9): 1523-1531, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34337768

RESUMO

BACKGROUND: His bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique. OBJECTIVE: To evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF). METHODS: Consecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation. RESULTS: Both HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5  vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3  vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2  vs. 3.1 ± 12.7 ms, p < .01; Ts-LV-RV, 37.9 ± 10.7  vs. 18.5 ± 10.8 ms, p < .001). CONCLUSIONS: Although LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.

20.
Ecotoxicol Environ Saf ; 224: 112661, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34416640

RESUMO

Some epidemiological evidences showed exposure of airborne fine particulate matter (PM2.5) was associated with lung dysfunction. However, the adverse effects of PM2.5 from mid-scale city of China on the respiratory system were unknown. Correspondingly, the mechanisms, especially the epigenetic mechanism regulated by miRNAs, involved in PM2.5-induced lung injury has not been fully understood. In this study, male Balb/C mice were exposed to PM2.5 collected from mid-scale city (Baoji), China for 8 weeks (mean concentration 298.52 ± 25.86 µg/m3 at exposure chamber) using a whole-body exposure system. The carbon component was the main ingredient (45.80%) of PM2.5 followed by ions (43.19%). Meanwhile, the sum concentrations of polycyclic aromatic hydrocarbons (PAHs) and n-alkanes (C18-C33) were 570.48 and 2029.13 ng/m3 in the exposure chamber, respectively. Obvious lung injury including pulmonary inflammation and fibrosis (p < 0.05 compared with the control) were found from PM2.5 exposure group determined by micro-CT and histopathological assays, respectively, suggesting the health risk posed by PM2.5 from mid-scale city of China should be concerned. The integrated analysis between mRNA-seq and miRNA-seq revealed the differentially expression genes in lung tissues were enriched in immune pathways including B cell receptor signaling (p = 0.078) and cell adhesion molecules (CAMs) (p = 0.0068). The expression profiles of the genes and corresponding mRNAs involved into the immune pathways determined by RT-qPCR analysis were consistent with them conducted by transcriptome. Moreover, the expression levels of the proteins (i.e., CD19, CD81, PIK3CD, and CD22) involved into B cell receptor signaling pathway from exposure group were 1.71- to 6.948- folds compared with the control, validating the results of the genes expression profiles. Further, canonical correlation analysis (CCA) and multiple correlation analysis between the target genes and components of PM2.5 documented the organic compounds (i.e., Benzo(a)pyrene (p = 0.012) and octadecane (p = 0.05)) and inorganic elements (i.e., Cl-, Ti, Al, and Zn) was the key environmental factors. Cd19, Pik3cd, and Cd8b1 might be the key genes for lung dysfunction induced by PM2.5 illuminated using interactive analysis (p < 0.05). This work for the first time showed the adverse effects of PM2.5 in mid-scale city in China on respiratory system should be concerned, and the associated epigenetic mechanism regulated by miRNA were revealed. These results may provide new insight into the development of future assessment on the air pollution associated respiratory disease.

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