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1.
J Clin Invest ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32027620

RESUMO

BACKGROUND: The anti-programmed cell death 1 (PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T-cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of advanced NSCLC patients, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC. METHODS: In total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1% were randomly allocated to group A (55 patients, pembrolizumab plus NK cells) and group B (54 patients, pembrolizumab alone). The patients received intravenous pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received two cycles of NK cell therapy as one course of treatment. RESULTS: In our study, Group A patients had better survival than group B patients (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months, P<0.05). In group A patients with a TPS ≥50%, the median OS and PFS were significantly prolonged. Moreover, the group A patients treated with multiple courses of NK cell infusion had better OS (18.5 months) than those who received a single course of NK cell infusion (13.5 months). CONCLUSIONS: Pembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1-positive advanced NSCLC.

2.
J Thorac Oncol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007598

RESUMO

INTRODUCTION: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR sensitizing and T790M resistant mutations. We assessed the safety, efficacy and pharmacokinetics (PK) of alflutinib in advanced NSCLC patients with confirmed T790M mutation, who progressed after the first- or second-generation EGFR-TKI therapy. METHODS: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. Primary endpoints were the safety, tolerability, and PK for the dose-escalation study, and the objective response rate (ORR, assessed by an independent radiological review committee) for the dose-expansion study. RESULTS: Between Nov 30, 2016, and Jul 24, 2018, 130 patients (14 in dose-escalation, 116 in dose-expansion) received alflutinib treatment (20, 40, 80, 160, or 240 mg once daily). By Oct 30, 2018, 79 (61%) patients remained on treatment. No dose limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40 - 240 mg), the overall ORR was 76.7% (89/116), and it was 70.6% (12/17) in patients with CNS metastases. 79% (103/130) of all patients had possibly treatment-related adverse events (AEs); 8% (11/130) had treatment-related grade ≥3 AEs. Serious adverse events (SAEs) were reported in 15% (20/130) of patients, and two SAEs were treatment related. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. CONCLUSIONS: Alflutinib was clinically effective with an acceptable toxicity profile in advanced NSCLC patients (including those with CNS metastases) with EGFR T790M mutation. Further investigation is ongoing.

3.
Nanoscale ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32009133

RESUMO

As an anode electrode material for lithium-ion batteries, SnS has high specific capacity and has received widespread attention, but its practical application is still hindered by the low reversibility of the conversion reaction and the large irreversible capacity caused by the solid electrolyte interphase (SEI). In this paper, SnS nanoparticles are encapsulated into a sulfur-doped graphene bubble film (SnS@G) by a scalable electrostatic self-assembly of SnS2/graphene oxide and hexadecyl trimethyl ammonium bromide, followed by the thermal decomposition of SnS2 and sulfur doping in graphene. Due to electrostatic attraction, the SnS nanoparticles are tightly wrapped in multilayer graphene sheets to form a flake-graphite-like structure. Compared with the disordered stacked SnS/graphene sheet composite, the closely packed SnS@G shows a much lower specific surface area and smaller irreversible Li+ consumption and surface film resistance after lithiation. The SnS@G composite anode exhibits great initial coulombic efficiency (83.2%), which is the highest value among the chemically synthesized SnS anodes. It also presents unprecedented cycling stability (1462 mA h g-1 after 200 cycles at 0.1 A g-1 and 1020 mA h g-1 after 500 cycles at 1 A g-1) and superior rate capabilities (750 mA h g-1 at 5 A g-1) upon Li storage, which demonstrates its excellent electrochemical performance and great potential as a negative electrode material for lithium-ion batteries.

4.
J Hazard Mater ; 392: 122283, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32086093

RESUMO

Nowadays, antibiotic resistance genes (ARGs) have been characterized as an emerging environmental contaminant, as the spread of ARGs may increase the difficulty of bacterial infection treatments. This study evaluates the combination of ultraviolet (UV) irradiation and chlorination, the two most commonly applied disinfection methods, on the degradation of sulphonamide resistance sul1 genes. The results revealed that although both of individual UV and chlorination processes were relatively less effective, two of the four combined processes, namely UV followed by chlorination (UV-Cl2) and simultaneous combination of UV and chlorination (UV/Cl2), delivered a better removal rate (up to 1.5 logs) with an observation of synergetic effects up to 0.609 log. The mechanisms analysis found that the difference of DNA size affected sul1 genes degradation by UV and chlorination; targeted genes on larger DNA fragments could be more effectively degraded by UV (1.09 logs for large fragments and 0.12 log for small fragments when UV dose reached 432 mJ/cm2), while to degrade ARGs on smaller DNA fragments required less free chlorine dosage (10 mg/L for small fragments and 40 mg/L for large fragments). The sequential combination of UV and chlorination (UV-Cl2) used the corresponding reactivity of both processes, which could be the reason for the synergetic effect. For UV/Cl2 process, the formation of reactive oxygen species (ROS) contributed to the synergetic effect. Scavenger analysis showed that the contribution of ROS to the sul1 gene reduction was 0.004 to 0.273 log (up to 45.5 % of the total synergy values), and among the two major reactive species in UV/Cl2 system, HO was the more important radical, while the contribution of Cl was negligible. Besides, UV/Cl2 process also used the corresponding reactivity of both processes to generate the remaining synergy values when excluding the contribution by reactive radicals. These findings provide a thorough understanding of the effects of UV and free chlorine on the degradation of ARGs and indicate the potential to utilize the combined processes of UV and free chlorine in water or wastewater treatment practice to control the dissemination of antibiotic resistance.

5.
Brief Bioinform ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047897

RESUMO

Long noncoding RNAs (lncRNAs) have been proven to play important roles in transcriptional processes and biological functions. With the increasing study of human diseases and biological processes, information in human H3K27ac ChIP-seq, ATAC-seq and DNase-seq datasets is accumulating rapidly, resulting in an urgent need to collect and process data to identify transcriptional regulatory regions of lncRNAs. We therefore developed a comprehensive database for human regulatory information of lncRNAs (TRlnc, http://bio.licpathway.net/TRlnc), which aimed to collect available resources of transcriptional regulatory regions of lncRNAs and to annotate and illustrate their potential roles in the regulation of lncRNAs in a cell type-specific manner. The current version of TRlnc contains 8 683 028 typical enhancers/super-enhancers and 32 348 244 chromatin accessibility regions associated with 91 906 human lncRNAs. These regions are identified from over 900 human H3K27ac ChIP-seq, ATAC-seq and DNase-seq samples. Furthermore, TRlnc provides the detailed genetic and epigenetic annotation information within transcriptional regulatory regions (promoter, enhancer/super-enhancer and chromatin accessibility regions) of lncRNAs, including common SNPs, risk SNPs, eQTLs, linkage disequilibrium SNPs, transcription factors, methylation sites, histone modifications and 3D chromatin interactions. It is anticipated that the use of TRlnc will help users to gain in-depth and useful insights into the transcriptional regulatory mechanisms of lncRNAs.

6.
Chin Med J (Engl) ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32004165

RESUMO

BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Jin Yin-tan Hospital of Wuhan, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. RESULTS: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown ß-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. CONCLUSION: A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32037091

RESUMO

The accessory sec system consisting of seven conserved components is commonly distributed among pathogenic Gram-positive bacteria for the secretion of serine-rich-repeat proteins (SRRPs). Asp1/2/3 protein complex in the system is responsible for both the O-acetylation of GlcNAc and delivering SRRPs to SecA2. However, the molecular mechanism of how Asp1/2/3 transport SRRPs remains unknown. Here, we report the complex structure of Asp1/2/3 from Streptococcus pneumoniae at 2.9 Å. Further functional assays indicated that Asp1/2/3 can stimulate the ATPase activity of SecA2. In addition, the deletion of asp1/2/3 gene resulted in the accumulation of a secreted version of PsrP with an altered glycoform in protoplast fraction of the mutant cell, which suggested the modification/transport coupling of the substrate. Altogether, these findings not only provide structural basis for further investigations on the transport process of SRRPs, but also uncover the indispensable role of Asp1/2/3 in the accessory sec system.

8.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012950

RESUMO

Cucurbitacin E (CuE), a highly oxygenated tetracyclic triterpene from Cucurbitaceae, has shown to exhibit potent cytotoxic and anti-proliferative properties against several human cancer cells. However, the underlying effects and mechanisms of CuE regarding hepatocellular carcinoma (HCC) have not been well understood. In the current study, unbiased RNA-sequencing (RNA-seq) and bioinformatics analysis was applied to elucidate the underlying molecular mechanism. CuE could significantly inhibit cell proliferation and migration of Huh7 cells, meanwhile CuE exhibited potent anti-angiogenic activity. RNA-seq analysis revealed that CuE negatively regulated 241 differentially expressed genes (DEGs) involved in multiple processes including cytoskeleton formation, angiogenesis and focal adhesion. Further analysis revealed that CuE effectually regulated diversified pharmacological signaling pathways such as MAPKs and JAK-STAT3. Our findings demonstrated the role of CuE in inhibiting proliferation and migration, providing an insight into the regulation of multiple signaling pathways as a new paradigm for anti-cancer treatment strategy.

9.
Pediatrics ; 145(2)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32015180

RESUMO

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

10.
Eur J Radiol ; 124: 108836, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006932

RESUMO

PURPOSE: To investigate the incidence, mechanism, and risk factors of aortic regurgitation (AR) in patients with hypertrophic cardiomyopathy (HCM) by using echocardiography and cardiac magnetic resonance (CMR). METHODS: 105 HCM patients, 52 hypertension (HTN) patients and 50 healthy controls (HC) were retrospectively recruited. HCM patients were divided into 38 with AR (HCMAR) subject and 67 without AR. The subaortic complex, D1 (the largest distance of the interventricular septum that protruded into the LVOT) and D3 (the LVOT effective width) were assessed and compared between the two groups of HCM patients. RESULTS: AR was more common in HCM than in HTN and HC (36 %, 17 %, and 10 %, respectively, P = 0.001). HCM patients with AR were older (58 ± 11 vs. 45 ± 16 years, P < 0.001) and had a higher incidence of hypertension (55 % vs. 33 %, P = 0.03). D1 was greater (13.5 ± 4.4 vs. 10.6 ± 4.0 mm, P = 0.001), and D3 was shorter in the HCMAR group (10.2 ± 5.3 vs. 13.7 ± 5.9 mm, P = 0.003). Anterior mitral leaflet length and left atrial diameter were greater in HCMAR group (all P < 0.05). On multivariable logistic regression analysis, the independent risk factors of AR in HCM patients were LVOTO and age. CONCLUSIONS: This study demonstrated that AR is a common comorbidity of HCM, especially in patients with LVOTO. LVOTO and age were independent risk factors of AR in HCM patient.

11.
Stem Cells Dev ; 29(4): 177, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32013774
12.
Biomed Pharmacother ; 125: 109913, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32006902

RESUMO

OBJECTIVE: Ginsenoside Rb1 (GRb1) is known to play an effective protection on myocardial infarction, yet its therapeutic mechanism on myocardial ischemia/reperfusion (I/R) injury has remained obscure. Here we sought to investigate the protective mechanism of GRb1 preconditioning on myocardial I/R injury in rats. METHODS AND RESULTS: We report here that GRb1 preconditioning could improve myocardial I/R injury induced-cardiac functions including LVDP, -dp/dt min and + dp/dt max; however, the heart rate (HR) was maintained at a level comparable to the I/R group. Additionally, in I/R injury group given GRb1 preconditioning, release of myocardial enzymes (CK-MB and Trop l) and CtsB was decreased. Moreover, GRb1 decreased the expression of apoptotic related proteins e.g. cleaved-caspase 3; however, the ratio of Bcl-2/Bax related to anti-apoptosis was decreased. The study was extended by injecting rapamycin intraperitoneally before GRb1 pretreatment. Thus, mTOR pathway was significantly upregulated after GRb1 pretreatment when compared with I/R. Remarkably, the anti-apoptosis protection of GRb1 pretreatment was attenuated by rapamycin. Furthermore, GRb1 effectively reduced the infarct size thus supporting its role in anti-myocardial I/R injury. CONCLUSIONS: It is concluded that GRb1 preconditioning can ameliorate myocardial I/R injury as manifested by the improvement of cardiac function indices; moreover, release of myocardial enzymes, namely, CK-MB, Trop l and CtsB was reduced. More importantly, we have shown that the protective effect of GRb1 against I/R injury induced cardiomyocyte apoptosis is associated with the activation of mTOR signal pathway as evident by the use of rapamycin.

13.
Sci Rep ; 10(1): 533, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953454

RESUMO

The clinical features, CMR characteristics and outcomes of arrhythmogenic left ventricular cardiomyopathy (ALVC), which is a very rare nonischemic cardiomyopathy, are currently not well studied. The purpose of the study is to investigate the clinical and cardiovascular magnetic resonance (CMR) imaging characteristics of arrhythmogenic left ventricular cardiomyopathy (ALVC). Fifty-three consecutive patients with ALVC were divided into two groups: ALVC patients without right ventricular (RV) involvement (n = 36, group 1) and those with RV involvement (n = 17, group 2). Clinical symptoms, cardiac electrophysiological findings, and CMR parameters (morphology, ventricular function, and myocardial fibrosis and fatty infiltration) were evaluated in both groups. The two groups showed no significant difference in age, gender, or presenting symptoms (P > 0.05). Right bundle branch block ventricular arrhythmia was less common in patients without RV involvement (50.0% vs.64.7%, P = 0.031). There were no significant differences in left ventricular function between the two groups, however right ventricular ejection fraction was significantly lower in group 2 (40.1 ± 4.0% vs. 48.7 ± 3.9%, P < 0.001). Inverse correlations of left ventricular ejection fraction with fat volume (r = -0.883, p = 0.001), late gadolinium enhancement (LGE) volume (r = -0.892, 0.013), ratio of fat/LGE (r = -0.848, p < 0.001), indexed left ventricular end diastolic volume (r = -0.877, p < 0.001) and indexed left ventricular end systolic volume (r = -0.943, p < 0.001) were all significant. ALVC is a rare disease with fibro-fatty replacement predominantly in the left ventricle, impaired left ventricular systolic function, and ventricular arrhythmias originating from the left ventricle. ALVC with right ventricular involvement may have a worse prognosis.

14.
Sci Rep ; 10(1): 175, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932743

RESUMO

Sepsis is typically triggered by an overwhelming systemic inflammatory response to pathogens, and may lead to severe organ dysfunction and/or death. Sepsis consequently has a high mortality rate and a high rate of complications for survivors, despite modern medical advances. Therefore, drug identification and validation for the treatment of sepsis is of the utmost importance. As a selective phosphodiesterase-4 inhibitor, rolipram also exhibits the abilities of inhibiting multiple pro-inflammatory cytokines production in macrophages and toxin-induced inflammation in mice. However, this drug has never been studied as a sepsis treatment method. We found that rolipram significantly improves survival in mice challenged with gram-negative bacterium E. coli, CLP, or E. coli derived lipopolysaccharide. We have also found that rolipram inhibits organ damage, pro-inflammatory cytokine production, and intracellular migration of early-stage inflammatory elements. Our results also show that rolipram increases anti-inflammatory cytokine production. The protective effects of rolipram on septic mice may result from inhibition of the MAP kinase and NF-κB signaling pathways. Rolipram may therefore be a potential novel sepsis treatment, one that would bypass the time-consuming and costly drug-discovery process.

15.
Immunopharmacol Immunotoxicol ; 42(1): 37-47, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31971040

RESUMO

Objective: The present study aimed to investigate whether recombinant human erythropoietin (rHuEPO) plays an immunomodulatory function by regulating the TLR4/NF-κB signaling pathway.Materials and methods: C57BL/6 mice were intraperitoneally injected with rHuEPO and, half an hour later, with 50% glycerol at the dose of 7.5 ml/kg to induce crush syndrome (CS)-acute kidney injury (AKI). The levels of TNF-α, IL-1ß, IL-6, serum creatinine (Scr), and creatine kinase (CK) were measured. The kidney tissues were analyzed by HE staining, and macrophage infiltration was detected by immunohistochemistry. Double immunofluorescence staining, RT-qPCR, and western blotting were conducted to analyze TLR4/NF-κB p65 expression. Ferrous myoglobin was co-cultured with RAW264.7 cells to mimic crush injury and the production of proinflammatory cytokines. The expression levels of TLR4 and NF-κB p65 were measured.Results: In vivo study results revealed that rHuEPO ameliorated renal function, tissue damage, production of proinflammatory cytokines, and macrophage infiltration in the kidneys. The protein and mRNA expression levels of genes involved in the TLR4/NF-κB signaling pathway in CS-induced AKI mice were upregulated (p < .05). Meanwhile, the expression levels of TLR4, NF-κB p65, and proinflammatory cytokines in RAW264.7 cells were downregulated in CS-AKI mice injected with rHuEPO (p < .05).Conclusions: Our results demonstrated the immunomodulatory capacity of rHuEPO and confirmed that rHuEPO exerts protective effects against CS-induced AKI by regulating the TLR4/NF-κB signaling pathway in macrophages. Therefore, our findings highlight the therapeutic potential of rHuEPO in improving the prognosis of CS-AKI patients.

16.
Nanoscale ; 12(3): 1697-1706, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894809

RESUMO

In this work, we demonstrate an interesting structural phase transition from SnS2/reduced graphene oxide to SnS/sulfur-doped graphene at a moderate calcination temperature of 500 °C under an inert atmosphere. It is discovered that SnS2 chemically bound to rGO with a weakened C-S bond is easier to break and decompose into SnS, whereas it is difficult for pure-phase crystalline SnS2 to experience phase transformation at this temperature. Moreover, the thin-layered structure of SnS2 and rGO is an important factor for the effective doping of the dissociated Sx into graphene. Density functional theory calculations also reveal the feasibility of the structural phase transition process. Morphology characterization shows that partial SnS maintains the original nanosheet structure (∼100 nm) and the others are decomposed into tiny nanoparticles (10-20 nm). A high S-doping amount reduces the irreversible lithium storage sites on graphene, and the first coulombic efficiency is as high as 81.7%. In addition, thin-layered and small-sized SnS can alleviate the structural damage caused by volume expansion and shrinkage; therefore, a high specific capacity of 893.9 mA h g-1 is retained after 100 cycles.

17.
J Ethnopharmacol ; 252: 112536, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31931161

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Previous studies have approved that Baoyuan decoction (BYD) exerted remarkable cardioprotective effects on heart failure (HF) due to its anti-apoptotic properties. As a novel biomarker and target of HF, Cardiac ankyrin repeat protein (CARP) can exacerbate apoptosis via activation by angiotensin type 1 receptor (AT1) and subsequently deteriorate heart function. Transcriptome results in our previous study indicated BYD was beneficial to HF post-acute myocardial infarction (AMI) with a promising effect on CARP. However, the mechanism remains to be validated. AIM OF THE STUDY: This study aims to elucidate whether BYD ameliorates apoptosis to protect against HF via AT1-CARP signaling pathway. MATERIALS AND METHODS: Left anterior descending ligation was applied to induce an HF rat model, Ang Ⅱ-stimulated H9C2 cells apoptotic model and overexpression of Ankrd1/CARP H9C2 cells were established to clarify the effects and potential mechanism of BYD. Ethanol extracts of BYD (0.64; 1.28; 2.57 g/kg) were orally administered for four weeks and Fosinopril (4.67 mg/kg) was selected as a positive group in vivo. In vitro, BYD (400, 600, 800 µg/ml) or RNH6270 (an inhibitor of AT1, 1 µM) was co-cultured with Ang Ⅱ stimulation for 48 h in H9C2 cells. Overexpression of Ankrd1/CARP was conducted by transient transfection with H9C2 cells to further confirm the exact mechanism. Finally, to define the active ingredients of anti-cardiomyocyte apoptosis in BYD, we furtherly used the Ang Ⅱ-induced cardiomyocyte apoptosis model to evaluate the effects. RESULTS: Echocardiography and TUNEL results showed that BYD in different doses remarkably improved heart function and inhibited apoptosis in vivo. Further study demonstrated that AT1 and CARP expressions in cardiac tissue were suppressed by BYD, accompanied with upregulation of B cell lymphoma-2 (Bcl-2) and downregulation of several pro-apoptotic molecules, including p53, Bcl-2 Associated X Protein (Bax) and Cleaved caspase 3. In parallel with the vivo experiment, in vitro research indicated BYD dramatically reduced the apoptotic cells and regulated expressions of critical apoptosis-related molecules mediated through downregulation of AT1 and CARP simultaneously which were consistent with the results in vivo experiment. Transiently transfected CARP over-expression further confirmed that BYD could suppress severe cardiomyocytes apoptosis induced by overexpression of CARP. Especially, the active ingredients of BYD including Astragaloside IV, Ginsenoside Rg3, Rb1, Rc and Re showed significantly anti-apoptosis effects. CONCLUSION: BYD improves cardiac function and protects against cardiomyocytes injury by inhibiting apoptosis via regulating the AT1-CARP signaling pathway.

18.
J Cardiovasc Magn Reson ; 22(1): 1, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898543

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in hypertrophic cardiomyopathy (HCM) and is associated with adverse outcomes in HCM patients. Although the left atrial (LA) diameter has consistently been identified as a strong predictor of AF in HCM patients, the relationship between LA dysfunction and AF still remains unclear. The aim of this study is to evaluate the LA function in patients with non-obstructive HCM (NOHCM) utilizing cardiovascular magnetic resonance feature tracking (CMR-FT). METHODS: Thirty-three patients with NOHCM and 28 healthy controls were studied. The global and regional LA function and left ventricular (LV) function were compared between the two groups. The following LA global functional parameters were quantitively analyzed: reservoir function (total ejection fraction [LA total EF], total strain [εs], peak positive strain rate [SRs]), conduit function (passive ejection fraction [LA passive EF], passive strain [εe], peak early-negative SR [SRe]), and booster pump function (active ejection fraction [LA active EF], active strain [εa], peak late-negative SR [SRa]). The LA wall was automatically divided into 6 segments: anterior, antero-roof, inferior, septal, septal-roof and lateral. Three LA strain parameters (εs, εe, εa) and their corresponding strain rate parameters (SRs, SRe, SRa) during the reservoir, conduit and booster pump LA phases were segmentally measured and analyzed. RESULTS: The LA reservoir (LA total EF: 57.6 ± 8.2% vs. 63.9 ± 6.4%, p < 0.01; εs: 35.0 ± 12.0% vs. 41.5 ± 11.2%, p = 0.03; SRs: 1.3 ± 0.4 s- 1 vs. 1.5 ± 0.4 s- 1, p = 0.02) and conduit function (LA passive EF: 28.7 ± 9.1% vs. 37.1 ± 10.0%, p < 0.01; εe: 18.7 ± 7.9% vs. 25.9 ± 10.0%, p < 0.01; SRe: - 0.8 ± 0.3 s- 1 vs. -1.1 ± 0.4 s- 1, p < 0.01) were all impaired in patients with NOHCM when compared with healthy controls, while LA booster pump function was preserved. The LA segmental strain and strain rate analysis demonstrated that the εs, εe, SRe of inferior, SRs, SRe of septal-roof, and SRa of antero-roof walls (all p < 0.05) were all decreased in the NOHCM cohort. Correlations between LA functional parameters and LV conventional function and LA functional parameters and baseline parameters (age, body surface area and NYHA classification) were weak. The two strongest relations were between εs and LA total EF(r = 0.84, p < 0.01), εa and LA active EF (r = 0.83, p < 0.01). CONCLUSIONS: Compared with healthy controls, patients with NOHCM have LA reservoir and conduit dysfunction, and regional LA deformation before LA enlargement. CMR-FT identifies LA dysfunction and deformation at an early stage.

19.
Biomacromolecules ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31895550

RESUMO

Regulating cell migration dynamics is of significance in tissue engineering and regenerative medicine. A 3D scaffold was created to provide various topographies based on a poly(ε-caprolactone) (PCL) self-induced nanohybrid shish-kebab structure, which consisted of aligned PCL nanofibers and spaced PCL crystal lamellae grown on the fibers. Electrospinning was applied followed by self-induced crystallization. The results resembled natural collagen fibrils in an extracellular matrix. This variable microstructure enabled control of cell adhesion and migration. The kebab size was controlled by initial PCL concentrations. The geometry of cells seeded on the fibers was less elongated, but the adhesion was more polarized with a higher nuclear shape index and faster migration speed. These results could aid in rapid endothelialization in tissue engineering.

20.
Stem Cells Dev ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31918626

RESUMO

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease with high rates of morbidity and mortality. Microglia, the resident immune cells of the central nervous system, are involved in initiating inflammatory response post-SAH through releasing a variety of inflammatory mediators. Regulation of neuroinflammation triggered by activated microglia has become a promising therapeutic strategy for SAH. Recent studies reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) have therapeutic effects, resulting from the regulation of microglia activation and production of inflammatory cytokines post-SAH. However, the underlying molecular mechanisms of BM-MSCs in targeting microglia-mediated neuroinflammation after SAH are still unclear. In this study, we used murine microglia cell line BV2 treated with oxyhemoglobin (OxyHb) to mimic the SAH conditions in vitro. The results showed that BM-MSCs coculture modulated OxyHb-induced BV2 activation as well as polarization. We further implemented RNA-seq approaches to investigate differences in transcriptomes between OxyHb-stimulated BV2 cocultured with and without BM-MSCs. The RNA-seq results suggested that the levels of inflammatory genes were strongly altered when OxyHb-stimulated BV2 cells were cocultured with BM-MSCs. Moreover, we identified epigenetic regulators involved in the regulation of microglia-mediated inflammation by BM-MSCs. This study clarifies detailed transcriptomic mechanisms underlying the interaction between BM-MSCs and activated microglia and may lead to a new therapeutic strategy using stem cell therapy for SAH.

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