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1.
Artigo em Inglês | MEDLINE | ID: mdl-32415497

RESUMO

PURPOSE: Previous studies have indicated that transient receptor potential (TRP) channels can influence cancer development. The TRPC subfamily consists of seven subtypes, TRPC1 - TRPC7. Interestingly, the expression levels of TRPC1 have been shown to be totally different in different breast cancer cell lines. Nevertheless, the underlying mechanism remains unknown. In this study, we explore the significance of TRPC1 expression in breast cancer. METHODS: Immunohistochemical TRPC1 staining was performed in 278 samples. TRPC1 expression in different breast tissues were examined. Then, the influence of TRPC1 on migration, invasion and proliferation was explored. We analyzed the protein of TRPC1 by Western blot to prove which pathway may be involved in. Finally, we use online database to predict the prognosis of TRPC1 in breast cancer. RESULTS: Through immunohistochemistry and in vitro experiments, we found that the expression level of TRPC1 was higher in breast cancer cells as compared with that in normal breast epithelial cells. Moreover, the expression level of TRPC1 was different between estrogen receptor-positive (ER +) and -negative (ER -) breast cancer. It was shown that TRPC1 inhibited MCF7 cell proliferation, migration, and invasion in vitro. Western blotting revealed that TRPC1 inhibited the PI3K/AKT pathway and epithelium-mesenchymal transformation, leading to subsequent inhibition of cell proliferation and metastasis. In luminal A and luminal B patients, those with high TRPC1 expression had a better prognosis. On the contrary, in basal-like and triple-negative breast cancer (TNBC) subtypes, patients with high-TRPC1 expression had a worse prognosis. CONCLUSIONS: We confirmed that TRPC1 was high expression in breast cancer. Overexpression of TRPC1 inhibits proliferation and migration of ER + breast cancer and gives a better prognosis by inhibiting PI3K/AKT pathway activation. TRPC1 may be an independent prognostic predictor in breast cancer patients.

2.
J Ethnopharmacol ; 258: 112895, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32330511

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR, Huangqi in Chinese), the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge., possesses diverse therapeutic effects against fatigue, dyspepsia, diarrhea, heart diseases, hepatitis, and anemia. In recent years, increasing evidence has indicated the multiple immunomodulatory activities of AR in preclinical and clinical studies. AIM OF THE REVIEW: This review attempts to elaborate the immunomodulatory effects of AR and its potential application in the treatment of immune related diseases. MATERIALS AND METHODS: A comprehensive literature search AR was carried out using multiple internationally recognized databases (including Web of Science, Google Scholar, PubMed, ScienceDirect, Wiley, ACS, Springer, Taylor & Francis, and CNKI). RESULTS: The immunomodulatory effects of AR are closely attributed to its active constituents such as polysaccharides, saponins, and flavonoids. We also demonstrate that AR can be used as a potential therapeutic intervention for immune related diseases through regulating immune organs, mucosal immune, and immune system (innate immunity and acquired immunity). CONCLUSION: AR promotes the development of immune organs, enhances mucosal immune function, increases the quantity and phagocytic capacity of innate immunity, promotes the maturation and differentiation of acquired immunity cells, and improves the expression of antibodies in acquired immunity. We believe that AR has a broad research space in the adjuvant treatment of immune related diseases, which could be a breakthrough point to improve the application value of AR.

3.
Water Res ; 178: 115818, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32344269

RESUMO

The effect of extracellular polysaccharides on the structural stability of granular sludge is widely recognized, and determining their mechanism of action on the stability of granules remains challenging. Herein, enzymatic experiments were used to systematically study the stability changes and internal mechanisms of anammox granular sludge following hydrolysis of extracellular proteins and polysaccharides (PS). The results revealed that the selective hydrolysis of the proteins hardly affected the stability of the granules, while the hydrolysis of the PS branched chains caused the granules to disintegrate. The hydrolysis of the PS chains in the EPS matrix decreased the degree of branching, width and height via nuclear magnetic resonance (NMR) spectroscopy and atomic force microscopy (AFM), and these parameters are closely related to granular stability. Moreover, scanning electron microscopy (SEM) showed a large number of pores and cracks on the granules, bacterial adhesion decreased, and the EPS adhered to the surface of the granules dissolved. The changes in the gel characteristics of the granules were studied by rheology, and the mechanical strength and viscosity of the granular sludge decreased. For the surface characteristics of granules, the zeta potential and hydrophobicity both decreased, revealing that changes in the branched-chain configuration of the PS and the degree of branching caused granular disintegration. Spectral analysis showed that the hydrolysis of the branch points and the branched glycosides of PS led to a higher proportion of hydrophilic and electronegative groups in the EPS matrix, which hindered bacterial aggregation and reduced anammox granule stability. This investigation clarifies the impact of the branched-chain configuration of the PS and their degree of branching on anammox granule stability, which will promote the further application of anammox granules.


Assuntos
Reatores Biológicos , Esgotos , Bactérias , Hidrólise , Reologia
4.
Phys Chem Chem Phys ; 22(17): 9349-9361, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32309835

RESUMO

The fundamental understanding of the cooperativity of a Brønsted acid together with its anion for cellulose conversion in an aqueous solution is limited at present, in which cellobiose has usually been regarded as a bridge that connects monosaccharides and cellulose. The mechanism of ß-cellobiose conversion to 5-hydroxymethylfurfural (HMF) catalyzed by a Brønsted acid (H3O+) accompanied by counteranions in an aqueous solution has been studied using quantum chemical calculations at the M06-2X/6-311++G(d,p) level under a polarized continuum model (PCM-SMD). For the formation of the first HMF from cellobiose, there are three reaction pathways, i.e., through cellobiulose and glycosyl-HMF (C/H), through cellobiulose and fructose (C/F/H), and through glucose (C/G/H). For these three reaction pathways, the rate-determining steps are associated with the intramolecular [1,2]-H shift in the aldose-ketose tautomerization. C/H is the thermodynamically predominant pathway, while C/G/H is the kinetically dominant pathway. From cellobiose, the origin of the first HMF results kinetically from a small proportion of both C/H and C/F/H and from a large proportion of C/G/H. For the role of the counteranion in the catalytic activity of H3O+, the halide anions (Cl- and Br-) act as promoters, whereas both NO3- anions and carboxylate-containing anions behave as inhibitors. The roles of these anions in ß-cellobiose conversion to HMF can be correlated with their electrostatic potential and atomic number, which may cause a decrease in the relative enthalpy energy and the value of entropy on interacting with the cation moiety. These insights may advance the novel design of sustainable conversion systems for cellulose conversion into HMF.

5.
Phys Chem Chem Phys ; 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32309829

RESUMO

The quaternary chalcogenides consisting of earth-abundant elements such as Cu2ZnSnSe4 (CZTSe) have promising electrical and optical properties prompting enormous technological interest. Understanding different types of defects including Cu/Zn ordering is believed to be the key point to tackle technological challenges such as a large open circuit voltage deficit in CZTSe. The Te doped Cu2.2Zn0.8SnSe4-xTex (x = 0.01-0.04) were investigated using X-ray absorption fine structure spectroscopy at the Cu, Zn, and Se K-edges as well as at the Te L3-edge. Cu at the zinc site with anti-site defects and oxygen interstitials are identified. The detailed electronic structure upon Te doping is studied, providing insights into the rich defect chemistry present in this compound.

6.
Sci Rep ; 10(1): 4998, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193501

RESUMO

Trigeminal neuralgia (TN), a sudden, needle-like pain in the distribution area of the trigeminal nerve, can seriously affect the physical and mental health of patients. In chronic pain conditions including TN, increased levels of brain-derived neurotrophic factor (BDNF) may enhance pain transmission. This study compares the effect of palmatine administration on the expression of BDNF and its receptor TrkB (tropomyosin receptor kinase B) in trigeminal ganglion cells of Sprague-Dawley rats in a sham versus TN model group. Within 14 days of surgery, the mechanical allodynia threshold of the TN group was significantly lower than that of the sham group, while the TN + palmatine group had a higher mechanical pain sensitivity threshold than the TN group (p < 0.05). Real-time quantitative PCR, immunohistochemistry, and immunofluorescence showed that BDNF and TrkB expression in the TN group was higher than that in the sham group, while palmatine treatment could reverse these changes. Western blotting showed that palmatine treatment could reduce the elevated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in TN rats. Thus, the BDNF/TrkB pathway may be involved in the pain transmission process of TN, and palmatine treatment may reduce pain transmission by inhibiting the BDNF/TrkB pathway and suppressing ERK1/2 phosphorylation.

7.
BMC Pediatr ; 20(1): 115, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164622

RESUMO

BACKGROUND: Respiratory infections are one of three leading causes of childhood mortality, and worldwide increase and recent plateau in childhood asthma has been reported. However, data on trends of respiratory diseases over long period of time is limited. This study aimed to determine the trends of respiratory disease outpatient visits (ROVs) and diagnoses (RODs) in one of the largest children's teaching hospitals in China between 2009 and 2018. METHODS: A retrospective study based on routine administrative data was designed and implemented according to the RECORD statement. Demographic details and diagnoses of the outpatients < 18 years visiting the respiratory department of the hospital were extracted from the Hospital Information System. Age- and gender-specific trends were illustrated by calculating average annual growth rate (AAGR) for ROVs and comparing change of proportion for different RODs over time. RESULTS: There were 698,054 ROVs from 285,574 children (40.4% female). AAGR of ROVs was 15.2%. Children aged 4 to < 7 years had a faster increase than other age groups. Bronchitis (27.6%), pneumonia (18.5%), pneumonia affecting other systems (18.4%), asthma and status asthmaticus (10.7%), and vasomotor and allergic rhinitis (9.2%) accounted for 84.4% of all RODs. The proportion of bronchitis decreased across years, with the concomitant increasing trend in the proportion of pneumonia. Age-specific trend in diagnoses showed greater proportion of asthma in all visits for the children aged 7 to < 18 years than younger children. Gender-specific trend in diagnoses showed the proportion of asthma was greater for males but the AAGR was greater for females. CONCLUSION: The persistent upward trend in ROVs was observed among children at different ages and a gender difference was also seen. In contrast to what has been reported, burden of asthma and allergies diseases continues to increase locally.

8.
Nanotechnology ; 31(22): 225206, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050184

RESUMO

A multiple-layer thin film of Pt/Ga2O3-x/SiC/Pt-based resistive switching is systematically investigated. Excellent bipolar resistive switching behavior is observed with a high resistance switching ratio of OFF/ON up to 103. The current-voltage relations plot implies the Ohmic conductance of the ON state, while the space and interface charge limited the current of the OFF state. The micro mechanism of resistive switching is explained by the formation/rupture of conductive filaments formed out of oxygen vacancies within the Ga2O3-x and SiC region. In particular, these devices exhibit excellent stability. The high OFF/ON resistance ratio can be completely retained for a number of days without degradation.

9.
Nanotechnology ; 31(21): 215711, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050171

RESUMO

Adhesion is a major factor in film failure. Based on the basic theory of interfacial toughness, the relationship between film thickness and internal stress and adhesion is qualitatively analyzed. The adhesive properties of silicon nitride deposited on stainless steel substrate by plasma enhanced chemical vapor deposition methods is discussed. The case where nickel, nickel-chromium and alumina films are respectively used as transition layers is compared. After vacuum annealing thermal treatment of these films, the results show that the alumina film has better matching performance with 304 stainless steel, and the interface toughness is improved by 51.2% compared with the silicon nitride film. After the samples are stretched, the silicon nitride film show a large number of cracks when the transition layer is nickel or nickel-chromium, possibly due to the large thermal stress in the film. At the same time, the process parameters of magnetron sputtered alumina are optimized, and the optimal deposition rate of alumina film is determined to be 40.25 nm min-1. Then, the effect of film thickness on adhesion is investigated by theoretical analysis and tape breakage test. As the film thickness ratio of alumina and silicon nitride increases, the adhesion is optimal.

10.
Plant Cell Rep ; 39(5): 567-575, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32025801

RESUMO

KEY MESSAGE: NADPH oxidase-mediated H2O2 maintains proline concentration under NaCl stress through regulating its biosynthesis and degradation, conferring salt tolerance to wheat plants. Considerable attention has been paid to the specific role of hydrogen peroxide (H2O2) in plant stress responses. Here, using microscopic, pharmacological and biochemical approaches, we explored H2O2 production and its roles in redox control under salt stress in wheat roots. Exogenous H2O2 pretreatment decreased salt-induced lipid peroxidation, while increased proline content in wheat roots. Salt stress led to a transient increase in NADPH oxidase activity accompanied by accumulation of H2O2 and proline in roots. The elevated proline accumulation in the presence of NaCl was significantly suppressed by diphenyleneiodonium, an inhibitor of NADPH oxidase, and dimethylthiourea, a scavenger of H2O2. The rate-limiting enzyme involved in proline biosynthesis, Δ1-pyrroline-5-carboxylate synthetase (P5CS), was induced by NaCl, whereas the house-keeping enzyme in proline degradation, proline dehydrogenase (ProDH), was inhibited. After 6 h, the activity of P5CS increased by 1.5-fold, whereas ProDH decreased by 13.9%. The levels of these enzymes, however, were restored by NADPH oxidase inhibitor or H2O2 scavenger. After treatment with H2O2, the effects of diphenyleneiodonium and or dimethylthiourea on proline content and activities of P5CS and ProDH were reversed. These results suggested that NADPH oxidase-mediated H2O2 alleviates oxidative damage induced by salt stress through regulating proline biosynthesis and degradation.

11.
J Clin Invest ; 130(3): 1252-1270, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039918

RESUMO

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-ß signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

12.
Bioresour Technol ; 303: 122849, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32035389

RESUMO

The goal of this work was to explore the effect of Fenton pretreatment combined with bacteria inoculation on the formation of humic substances (HS) during rice straw composting. In this study, the compound bacterial agents were inoculated after Fenton pretreatment during rice straw composting. The results suggested that the coupling effects of Fenton pretreatment and bacteria inoculation promoted the humification process, which might be the reason of organic fractions degradation and transformation. In addition, the bacterial communities structure and diversity were changed by Fenton pretreatment and inoculation. Key microbial genera linking to the transformation of organic fractions were determined by network analysis. Redundancy analysis and structural equation model analysis indicated that Fenton pretreatment, inoculation, amino acid, soluble sugar and beta-diversity as the key factors affecting organic fractions transformation during composting. Therefore, the combined application Fenton pretreatment with bacteria inoculation provided a new method to promote the HS amount.


Assuntos
Compostagem , Oryza , Bactérias , Biomassa , Substâncias Húmicas , Lignina , Solo
13.
Toxicol Appl Pharmacol ; 389: 114882, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953203

RESUMO

Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural dinorditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-ß1 (TGF-ß1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-ß1-induced expression of fibrotic markers including type I and III collagen, fibronectin, α-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-ß1-induced up-regulation of TßR I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TßR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.

14.
Curr Biol ; 30(4): 645-656.e4, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-31956029

RESUMO

Akin to all damselflies, Calopteryx (family Calopterygidae), commonly known as jewel wings or demoiselles, possess dichoptic (separated) eyes with overlapping visual fields of view. In contrast, many dragonfly species possess holoptic (dorsally fused) eyes with limited binocular overlap. We have here compared the neuronal correlates of target tracking between damselfly and dragonfly sister lineages and linked these changes in visual overlap to pre-motor neural adaptations. Although dragonflies attack prey dorsally, we show that demoiselles attack prey frontally. We identify demoiselle target-selective descending neurons (TSDNs) with matching frontal visual receptive fields, anatomically and functionally homologous to the dorsally positioned dragonfly TSDNs. By manipulating visual input using eyepatches and prisms, we show that moving target information at the pre-motor level depends on binocular summation in demoiselles. Consequently, demoiselles encode directional information in a binocularly fused frame of reference such that information of a target moving toward the midline in the left eye is fused with information of the target moving away from the midline in the right eye. This contrasts with dragonfly TSDNs, where receptive fields possess a sharp midline boundary, confining responses to a single visual hemifield in a sagittal frame of reference (i.e., relative to the midline). Our results indicate that, although TSDNs are conserved across Odonata, their neural inputs, and thus the upstream organization of the target tracking system, differ significantly and match divergence in eye design and predatory strategies. VIDEO ABSTRACT.

15.
J Cell Physiol ; 235(5): 4268-4278, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31608996

RESUMO

The relationship between age and breast cancer is ambiguous. Here, we analyzed the differential expression pattern of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in different age groups to provide an effective association between age and breast cancer risk at the molecular level. We integrated the microarray information from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. The patients were divided into young ( < 50 years) and old ( ≥ 50 years) age groups and evaluated by differential gene expression, weighted gene correlation network analysis (WGCNA), functional enrichment analyses, and coexpression analysis. To determine their potential clinical significance, univariate Cox regression analysis and survival assessment were conducted. We identified two lncRNAs (AL139280.1 and AP000851.1) and three mRNAs (MT1M, HBB, and TFPI2) as the risk markers, and Gene set enrichment analysis (GSEA) focusing on a single gene revealed that "pyrimidine metabolism," "cell cycle," and "P53 signaling pathway" were coenriched. These data demonstrated that age may be a risk factor for breast carcinogenesis and prognosis and provide an in-depth molecular characterization based on the expression patterns of lncRNAs and mRNAs.

16.
J Cell Physiol ; 235(4): 3973-3983, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31617204

RESUMO

Recently, increasing evidences show that circular RNAs (circRNAs) are important regulators of various diseases, especially cancer. However, the regulatory role and the potential mechanism of action of circRNAs in breast cancer remain largely unknown. In this study, weighted gene co-expression network analysis was conducted with the differentially expressed miRNAs and mRNAs in breast cancer from The Cancer Genome Atlas database to identify the key modules associated with the carcinogenesis of breast cancer. In the significant turquoise and brown modules, 22 miRNAs and 1877 mRNAs were identified, respectively. Then, We compared and predicted the target genes and performed survival analysis to identify the miRNAs and mRNAs related to the prognosis of breast cancer. A circRNA-related competitive endogenous RNA network was identified by database co-screening, and deleted in liver cancer 1 (DLC1) was identified as a key gene. Finally, to assess how genes in key modules and key genes contribute to the development of breast cancer, relevant pathway information was obtained through DAVID and Gene Set Enrichment Analysis. These data demonstrated that three circRNAs (hsa-circ-0083373, hsa-circ-0083374, and hsa-circ-0083375) that regulate DLC1 expression via hsa-mir-511 and are involved in the pathogenesis and development of breast cancer.

17.
J Allergy Clin Immunol ; 145(1): 402-414, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31647966

RESUMO

BACKGROUND: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 µm or less in diameter (PM2.5) aggravates asthma. OBJECTIVE: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. METHODS: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell-specific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. RESULTS: PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. CONCLUSIONS: The AhR-hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.

18.
Cell Biol Int ; 44(2): 488-498, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31631456

RESUMO

Cardiomyocyte apoptosis contributes to the development of coxsackievirus B3 (CVB3)-induced myocarditis, but the mechanism for the apoptosis by CVB3 infection remains unclear. Here, we showed that CVB3-induced endoplasmic reticulum (ER) stress response and apoptosis in cultured H9c2 cardiomyocytes. We found that Ca2+ -calmodulin-dependent kinase II (CaMKII) was activated by ER stress-dependent intracellular Ca2+ overload in the CVB3-infected H9c2 cardiomyocytes. Treatment with an inhibitor of ER stress, 4-phenylbutyric acid (4-PBA), attenuated intracellular Ca2+ accumulation indirectly and reduced CaMKII activity. Inhibition of CaMKII with pharmacological inhibitor (KN-93) or short hairpin RNA reduced CVB3-induced H9c2 apoptosis and repressed cytochrome c release from mitochondria to cytoplasm; whereas overexpression of the activated mutant of CaMKII (CaMKII-T287D) enhanced CVB3-induced H9c2 apoptosis and mitochondrial cytochrome c release, which could be alleviated by blocking of mitochondrial Ca2+ uniporter or mitochondrial permeability transition pore. Further in vivo investigation revealed that blocking of CaMKII with KN-93 prevented cardiomyocytes apoptosis and improved cardiac contractile function in CVB3-infected mouse heart. Collectively, these findings provide a novel evidence that CaMKII plays a vital role in the promotion of CVB3-induced cardiomyocyte apoptosis, which links ER stress and mitochondrial Ca2+ uptake.

19.
Cell Res ; 30(1): 21-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31729468

RESUMO

Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-to-hematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCRαß repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.

20.
Am J Physiol Heart Circ Physiol ; 318(1): H189-H202, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834840

RESUMO

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

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