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1.
Front Cardiovasc Med ; 8: 736911, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790705

RESUMO

Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Using Zincpyr1 staining, we found a significant decrease of intracellular Zinc concentration in phenylephrine (PE)-induced hypertrophy of neonatal rat ventricular myocytes (NRVMs). We then screened SLC39 family members responsible for zinc uptake and identified Slc39a2 as the only one altered by PE treatment. Slc39a2 knockdown in NRVMs reduced the intracellular Zinc level, and exacerbated the hypertrophic responses to PE treatment. In contrast, adenovirus-mediated Slc39a2 overexpression enhanced zinc uptake and suppressed PE-induced Nppb expression. RNA sequencing analysis showed a pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune signaling pathways, including NOD signaling, TOLL-like receptor, NFκB, and IRFs, were remarkably enriched in the Slc39a2-regulated genes. Slc39a2 deficiency enhanced the phosphorylation of P65 NFκB and STAT3, and reduced the expression of IκBα. Finally, the expression of IRF7 was significantly increased by Slc39a2 knockdown, which was in turn suppressed by IRF7 knockdown. Our data demonstrate that zinc homeostasis mediated by a Slc39a2/IRF7 regulatory circuit contributes to the alteration of innate immune signaling in cardiomyocyte hypertrophy.

2.
Front Med (Lausanne) ; 8: 710386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650993

RESUMO

The purpose of this study was to evaluate the clinicopathological features of different degrees of extraglomerular renal vascular lesions (RVLs) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis and explore their clinical determinants. This is a retrospective study of 186 patients with ANCA-associated renal vasculitis diagnosed at the First Affiliated Hospital of Zhengzhou University from January 2014 to April 2019. The patients who met the inclusion criteria were divided into non-renal RVLs, mild RVLs, moderate RVLs, and severe RVLs. It was found that there were significant differences in serum creatinine (SCR), estimated glomerular filtration rate (eGFR), erythrocyte sedimentation rate (ESR), high-density lipoprotein (HDL), systolic blood pressure (SBP), the prevalence rate of hypertension, the proportion of normal glomeruli, and the proportion of sclerotic glomeruli and interstitial fibrosis integral. SCR and ESR are independent risk factors for RVLs. The participants were followed up for 1 year, and the progression to end-stage renal disease (ESRD) and death was defined as endpoint events. We found that the survival rate of patients without RVLs was significantly higher than that of patients with RVLs and that the RVLs were an independent risk factor for ESRD or death. Early intervention in the progression of RVLs can improve the prognosis.

3.
Sci Rep ; 11(1): 18407, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526634

RESUMO

The main objective of this study is to analyze the clinical and pathological features and prognosis of patients with Hepatitis B associated membranous nephropathy (HBV-MN) and idiopathic membranous nephropathy (IMN) complicated with hepatitis B virus (HBV) infection. This study will provide more basis for diagnosis and prognosis evaluation. A total of 50 patients with HBV-MN were included in this study. 56 IMN patients complicated with HBV infection diagnosed during the same period formed the control group. Parameters including blood routine, urine routine and plasma levels of albumin (ALB), serum creatinine (SCR), blood urea nitrogen (BUN), urea acid (UA), total cholesterol (T-CHO), triglycerides (TG), complement C3 and C4, glutamic pyruvic transaminase (ALT), glutamic pyruvic transaminase (AST), 24-h urinary protein quantification (24 h-TP), renal phospholipase A2 receptor (PLA2R) and HBV related markers during the hospitalization and outpatient follow-up study period were collected for all the patients. The proportion of male patients was high in both groups. The average age of the HBV-MN group was 37.2 ± 14.187 years old, it was younger compared with the IMN group (P = 0.003). Nephrotic syndrome was the major clinical manifestation among patients. There was no significant difference between the two groups in the levels of anemia, microscopic hematuria, renal dysfunction, liver dysfunction, liver cirrhosis. The level of serum C3 and C4 in the HBV-MN group was lower compared with the IMN group (P = 0.002, P = 0.014). In the HBV-MN group, serum HBV markers were negative in 6 (12%) patients, 4 patients (8%) were positive for PLA2R in serum, and 5 patients (10%) were positive for PLA2R in renal tissue. Stronger IgG1 and C1q and weaker IgG4 staining were found in HBV-MN group renal tissues (P = 0.003, P = 0.025, and P = 0.001, respectively). There were no statistical differences compared with serum and renal PLA2R between HBV-MN and IMN groups (P = 0.098, P = 0.109). During the 1-year follow-up, there was no significant difference in complete remission rate between the two groups (P = 0.7739). Renal biopsy is crucial to diagnose HBV-MN. IgG subtypes in the HBV-MN group were mainly IgG1 deposition, while those in IMN complicated with HBV infection group were mainly IgG4 deposition. When HBV-associated antigen and PLA2R are present in renal tissue, lower level of serum C3 and C4, high intensity of renal C1q and IgG1 is more supportive of HBV-MN. The positive of PLA2R in serum and renal tissue in differentiating HBV from IMN complicated with HBV infection remains to be discussed.

4.
Comput Intell Neurosci ; 2021: 6370526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367271

RESUMO

Accurate segmentation of the tongue body is an important prerequisite for computer-aided tongue diagnosis. In general, the size and shape of the tongue are very different, the color of the tongue is similar to the surrounding tissue, the edge of the tongue is fuzzy, and some of the tongue is interfered by pathological details. The existing segmentation methods are often not ideal for tongue image processing. To solve these problems, this paper proposes a symmetry and edge-constrained level set model combined with the geometric features of the tongue for tongue segmentation. Based on the symmetry geometry of the tongue, a novel level set initialization method is proposed to improve the accuracy of subsequent model evolution. In order to increase the evolution force of the energy function, symmetry detection constraints are added to the evolution model. Combined with the latest convolution neural network, the edge probability input of the tongue image is obtained to guide the evolution of the edge stop function, so as to achieve accurate and automatic tongue segmentation. The experimental results show that the input tongue image is not subject to the external capturing facility or environment, and it is suitable for tongue segmentation under most realistic conditions. Qualitative and quantitative comparisons show that the proposed method is superior to the other methods in terms of robustness and accuracy.


Assuntos
Algoritmos , Processamento de Imagem Assistida por Computador , Diagnóstico por Computador , Humanos , Redes Neurais de Computação , Língua
5.
J Contin Educ Nurs ; 52(8): 362-366, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34324376

RESUMO

Ambulation is one of the most frequently reported components of unfinished nursing care, yet early mobilization can prevent patient deconditioning. This project was designed as an interprofessional mobility training program by using educational neuroscience theory to engage learners in appreciating the need for early ambulation and change behaviors. This article reviews one initiative that incorporated neuroscience and learning science in the teaching methodologies to achieve high rates of successful educational outcomes. [J Contin Educ Nurs. 2021;52(8):362-366.].


Assuntos
Deambulação Precoce , Educação Continuada em Enfermagem , Educação Interprofissional , Difusão de Inovações , Deambulação Precoce/enfermagem , Educação Continuada em Enfermagem/métodos , Humanos
6.
Sheng Li Xue Bao ; 73(3): 459-470, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34230947

RESUMO

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O2 consumption at state III with either complex I substrates or complex II substrate, compared with those from FVB/nJ mice. ISO treatment did not affect mitochondrial respiratory control rate (RCR), but significantly suppressed the ADP/O ratio generated from the complex II substrate in both strains. The ADP/O ratio generated from the complex I substrates in A/J mice declined by 50% after ISO treatment, whereas FVB/nJ mice were not affected. These results suggest that, compared with FVB/nJ mice, A/J mice possesses a poor integrity of mitochondrial respiratory chain that might contribute to its vulnerability to ISO-induced cardiac hypertrophy.


Assuntos
Cardiomegalia , Insuficiência Cardíaca , Animais , Cardiomegalia/induzido quimicamente , Isoproterenol/metabolismo , Isoproterenol/toxicidade , Camundongos , Mitocôndrias , Miócitos Cardíacos/metabolismo
7.
J Mol Cell Cardiol ; 159: 120-129, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34175302

RESUMO

Cardiac hypertrophy is an adaptive response of the heart to increased workload induced by various physiological or pathological stimuli. It is a common pathological process in multiple cardiovascular diseases, and it ultimately leads to heart failure. The development of cardiac hypertrophy is accompanied by gene expression reprogramming, a process that is largely dependent on epigenetic regulation. Histone modifications such as methylation and acetylation are dynamically regulated under cardiac stress. These consequently contribute to the pathogenesis of cardiac hypertrophy via compensatory or maladaptive transcriptome reprogramming. Histone methylation and acetylation modifiers play crucial roles in epigenetic remodeling during the pathogenesis of cardiac hypertrophy. Regulation of histone methylation and acetylation modifiers serves as a bridge between signal transduction and downstream gene reprogramming. Exploring the role of histone modifiers in cardiac hypertrophy provides novel therapeutic strategies to treat cardiac hypertrophy and heart failure. In this review, we summarize the recent advancements in functional histone methylation and acetylation modifiers in cardiac hypertrophy, with an emphasis on the underlying mechanisms and the therapeutic potential.

8.
J Nutr ; 151(8): 2175-2187, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-33979839

RESUMO

BACKGROUND: Dynamic orchestration of metabolic pathways during continuous fasting remains unclear. OBJECTIVE: We investigated the physiological effects of Bigu-style fasting and underlying metabolic reprogramming in healthy adults. METHODS: We conducted a 5-d Bigu trial in 43 healthy subjects [age 23.2 ± 2.4 y; BMI (in kg/m2) 22.52 ± 1.79]. Physiological indicators and body composition were monitored daily during fasting day 1 (F1D) to F5D and after 10-d refeeding postfasting (R10D) and R30D. Blood samples were collected in the morning. Risk factors associated with inflammation, aging, cardiovascular diseases, malnutrition, and organ dysfunction were evaluated by biochemical measurements. Untargeted plasma metabolomics and gut microbial profiling were performed using plasma and fecal samples. Data were analyzed by repeated measures ANOVA with Greenhouse-Geisser correction. Correlation analyses for metabolite modules and taurine were analyzed by Spearman's rank and Pearson tests, respectively. RESULTS: Heart rate was accelerated throughout the fasting period. Risk factors associated with inflammation and cardiovascular diseases were significantly lowered during or after Bigu (P < 0.05). Body composition measurement detected an overconsumption of fat starting from F3D till 1 mo after refeeding. Metabolomics unveiled a coupling between gluconeogenesis and cholesterol biosynthesis beyond F3D. Plasma taurine significantly increased at F3D by 31%-46% followed by a reduction to basal level at F5D (P < 0.001), a pattern inversely correlated with changes in glucose and de novo synthesized cholesterol (r = -0.407 and -0.296, respectively; P < 0.001). Gut microbial profiling showed an enrichment of taurine-utilizing bacteria at F5D, which was completely recovered at R10D. CONCLUSIONS: Our data demonstrate that 5-d Bigu is potentially beneficial to health in young adults. A starvation threshold of 3-d fasting is necessary for maintaining glucose and cholesterol homeostasis via a taurine-microbiota regulatory loop. Our findings provide novel insights into the physiological and metabolic responses of the human body to continuous Bigu-style fasting. This trial was registered at http://www.chictr.org.cn as ChiCTR1900022917.

9.
Ren Fail ; 43(1): 729-736, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33904354

RESUMO

INTRODUCTION: Primary membranous nephropathy (PMN) is one common cause of end-stage kidney disease. There is no optimal treatment for PMN patients with sub-nephrotic proteinuria currently. Tripterygium wilfordii polyglycoside (TWG) is a widely used traditional medicine in China and has been used to treat nephropathy for decades. OBJECTIVE: To investigate the effect of TWG combined with angiotensin receptor blocker (ARB) on the treatment of PMN with sub-nephrotic proteinuria. METHODS: Biopsy-proven sub-nephrotic PMN patients with normal kidney function and treated with TWG combined with ARB or ARB alone were retrospectively analyzed. The primary outcome was remission rate (complete or partial remission), and the secondary outcomes included proteinuria, serum albumin levels, estimated glomerular filtration rate (eGFR), relapse rate, and adverse events. RESULTS: The clinical trial included 55 patients. The overall remission rates for the TWG + ARB and ARB groups after 9 months of treatment were 74.3% and 35%, respectively (p = 0.004). Moreover, the complete remission (CR) rate for the TWG + ARB and ARB groups in the 9th month were 45.7% and 15%, respectively (p = 0.044). Treatment with TWG + ARB was the independent predictor of complete remission of proteinuria (p = 0.048). Besides, the remission rate was higher in the TWG + ARB group than in the ARB group among patients who were positive for anti-phospholipase A2 receptor (PLA2R) antibodies (65.4% vs. 21.4%, p = 0.02). CONCLUSIONS: These data demonstrate that TWG may be a promising treatment for PMN patients with sub-nephrotic proteinuria, whether anti-PLA2R antibody is positive or negative.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Glomerulonefrite Membranosa/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Proteinúria/tratamento farmacológico , Tripterygium , Adulto , Autoanticorpos/sangue , China , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Imunossupressores , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/isolamento & purificação , Modelos de Riscos Proporcionais , Receptores da Fosfolipase A2/imunologia , Indução de Remissão , Estudos Retrospectivos
10.
Front Cardiovasc Med ; 8: 585691, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732733

RESUMO

Enhancer of zeste 2 (EZH2) governs gene reprogramming during cardiac hypertrophy through epigenetic remodeling, a process regulated by numerous non-coding RNAs (ncRNAs). However, the dynamic interaction between EZH2 and ncRNAs upon hypertrophic stimulation remains elusive. Here we performed an unbiased profiling for EZH2-associated ncRNAs in mouse hearts treated with Angiotensin II (AngII) at different time points (0, 4, and 24 h). The interactions between EZH2 and long ncRNAs (lncRNAs), Chaer, Mirt1, Hotair, and H19, were validated by PCR. RIP-seq analysis identified a total of 126 ncRNAs to be significantly associated with EZH2. These ncRNAs covers all five categories including intergenic, antisense, intron-related, promoter-related and both antisense and promoter-related. According to their changing patterns after AngII treatment, these ncRNAs were clustered into four groups, constantly enhanced, transiently enhanced, constantly suppressed and transiently suppressed. Structural prediction showed that EZH2 bound to hairpin motifs in ncRNAs including snoRNAs. Interaction strength prediction and RNA pull-down assay confirmed the direct interaction between EZH2 and Snora33. Interestingly, two antisense lncRNAs of Malat1, Gm20417, and Gm37376, displayed different binding patterns from their host gene after AngII treatment, suggesting a crucial role of this genomic locus in modulating EZH2 behavior. Our findings reveal the profile of EZH2-associated ncRNAs upon hypertrophic stimulation, and imply a dynamic regulation of EZH2 function in cardiac hypertrophy.

11.
Int Q Community Health Educ ; 41(3): 309-314, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32631151

RESUMO

Though many community cardiopulmonary resuscitation (CPR) training classes are available throughout the United States, disparities exist in training and receipt of bystander CPR for Chinese immigrants with limited English proficiency. To increase the number of persons prepared to respond to a cardiac emergency, a Chinese language CPR training program was offered in the community in collaboration with the Stanford Department of Community Partnership. Program leaders imported the American Heart Association approved Chinese version of Heartsaver® for Adult CPR and AED from the China Mainland to make the training accessible to Chinese immigrants with LEP. In 2018, two CPR training events were conducted with 47 participants. All participants successfully demonstrated bystander (hands-only) CPR skills with 91% of participants reporting confidence and 97% willingness to perform CPR. As the first known CPR class offered in the Chinese language in the San Francisco Bay Area using official AHA products, this project provides valuable information regarding community interest and feasibility for expanding this educational program.


Assuntos
Reanimação Cardiopulmonar , Emigrantes e Imigrantes , Adulto , China , Humanos , Idioma , São Francisco , Estados Unidos
12.
Acta Pharm Sin B ; 10(11): 2156-2170, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33304783

RESUMO

Macrophages have a leading position in the tumor microenvironment (TME) which paves the way to carcinogenesis. Initially, monocytes and macrophages are recruited to the sites where the tumor develops. Under the guidance of different microenvironmental signals, macrophages would polarize into two functional phenotypes, named as classically activated macrophages (M1) and alternatively activated macrophages (M2). Contrary to the anti-tumor effect of M1, M2 exerts anti-inflammatory and tumorigenic characters. In progressive tumor, M2 tumor-associated macrophages (TAMs) are in the majority, being vital regulators reacting upon TME. This review elaborates on the role of TAMs in tumor progression. Furthermore, prospective macrophage-focused therapeutic strategies, including drugs not only in clinical trials but also at primary research stages, are summarized followed by a discussion about their clinical application values. Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.

13.
ACS Appl Mater Interfaces ; 12(52): 57798-57809, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33325679

RESUMO

Metastasis is the primary cause of death for most cancer patients, in which tumor-associated macrophages (TAMs) are involved through several mechanisms. While hitherto there is still a lack of study on exclusive elimination of TAMs to inhibit metastasis due to the difficulties in specific targeting of TAMs, we construct an extra- and intracellular stepwise-responsive delivery system p-(aminomethyl)benzoic acid (PAMB)/doxorubicin (DOX) to achieve specific TAM depletion for the first time, thereby preventing tumor metastasis. Once accumulated into the tumor, PAMB/DOX would stepwise responsively (hypoxia and reactive oxygen species (ROS) responsively) disintegrate to expose the TAM-targeting ligand and release DOX sequentially, which depletes TAMs effectively in vivo. Owing to the inhibition of extracellular matrix (ECM) degradation, neovascularization, and tumor invasion contributed by TAM depletion, lung metastasis was successfully inhibited. Furthermore, PAMB/DOX showed efficient inhibition against tumor growth as well as spontaneous metastasis formation when combined with additional chemotherapy, representing a safe and efficient nanoplatform to modulate the adverse tumor microenvironment via TAM elimination.


Assuntos
Portadores de Fármacos/química , Espaço Extracelular/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Nanoestruturas/química , Macrófagos Associados a Tumor/efeitos dos fármacos , para-Aminobenzoatos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Espaço Extracelular/metabolismo , Espaço Intracelular/metabolismo , Camundongos , Metástase Neoplásica , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual , Hipóxia Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/patologia , para-Aminobenzoatos/farmacocinética
14.
Nanoscale Res Lett ; 15(1): 205, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146756

RESUMO

It is challenging to explore and prepare polyoxometalates-based nanomaterials (PNMs) with controllable morphologies and diversiform components. Herein, 3d-4f metals are introduced into isopolyoxometalates and Anderson-type polyoxometalates, CeCdW12 nanoflower and EuCrMo6 microflaky have been fabricated respectively. A series of control experiments are carried out to identify the impact factors on the rare morphologies in PNMs. Furthermore, upon excitation at 396 nm, the emission spectrum of EuCrMo6 displays five prominent f - f emitting peaks at 674, 685, 690, 707, and 734 nm that are assigned to Eu3+ 5D0 → 7FJ (J = 0, 1, 2, 3, 4) transitions. Meanwhile, the VSM results show that the Cr+3 ions in EuCrMo6 display anti-ferromagnetic interactions when the temperature is lower than - 17.54 K. After rising temperature, this material exhibits paramagnetic property. This work opens up strategies toward the brand new morphologies and components of PNMs, endowing this kind of material with new functions.

15.
STAR Protoc ; 1(1): 100004, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-33111066

RESUMO

Melanocytes, derived from neural crest cells, are involved in melanin production. This protocol describes a method to generate induced melanocytes (iMelanocytes) from human induced pluripotent stem cells (iPSCs) using a suspension culture system, which considerably improves the differentiation efficiency. The most critical parts of this protocol are the selection of a reliable iPSC line with strong potential to differentiate into melanocytes and their stemness maintenance. For complete information on the use and generation of this protocol, please refer to our Cell Reports article, Liu el al. (2019).

16.
Neurotoxicology ; 78: 163-169, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203791

RESUMO

Methamphetamine (METH) has been reported to induce endoplasmic reticulum (ER) stress and neuronal apoptosis in the central nervous system (CNS) during the development of addiction. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays an important role in inhibiting apoptosis and protects neurons from cytotoxicity through ER and mitochondria-mediated pathways. Our previous study has been reported that Trx-1 protects mice from METH-induced rewarding effect. However, whether Trx-1 plays the role in resisting METH injury is still unclear. Here, we aim to investigate whether Trx-1 participates in the regulation of METH-induced CNS injury via ER stress and mitochondria-mediated pathways. Our study first repeated the conditioned place preference expression induced by METH. Then we detected and found that METH increased the expression of N-methyl-d-asparate (NMDA) receptor subunit 2B (NR2B) and the level of glutamate (Glu) in the ventral tegmental area (VTA) and nucleus accumbens (NAc), while Trx-1 overexpression suppressed the increases. We further examined ER stress-related proteins and mitochondrial apoptosis pathway in the VTA and NAc, and found that METH increased the expressions of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Bax, as same time decreased the expressions of procaspase12, Bcl-2, and procaspase3, while Trx-1 overexpression blocked these changes. These results indicate that Trx-1 blocks METH-induced injury by suppressing ER stress and mitochondria-mediated apoptosis in the VTA and NAc via targeting glutamatergic system.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metanfetamina/toxicidade , Tiorredoxinas/metabolismo , Animais , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
17.
World J Stem Cells ; 12(1): 25-34, 2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110273

RESUMO

Human induced pluripotent stem cells (hiPSCs) are invaluable resources for producing high-quality differentiated cells in unlimited quantities for both basic research and clinical use. They are particularly useful for studying human disease mechanisms in vitro by making it possible to circumvent the ethical issues of human embryonic stem cell research. However, significant limitations exist when using conventional flat culturing methods especially concerning cell expansion, differentiation efficiency, stability maintenance and multicellular 3D structure establishment, differentiation prediction. Embryoid bodies (EBs), the multicellular aggregates spontaneously generated from iPSCs in the suspension system, might help to address these issues. Due to the unique microenvironment and cell communication in EB structure that a 2D culture system cannot achieve, EBs have been widely applied in hiPSC-derived differentiation and show significant advantages especially in scaling up culturing, differentiation efficiency enhancement, ex vivo simulation, and organoid establishment. EBs can potentially also be used in early prediction of iPSC differentiation capability. To improve the stability and feasibility of EB-mediated differentiation and generate high quality EBs, critical factors including iPSC pluripotency maintenance, generation of uniform morphology using micro-pattern 3D culture systems, proper cellular density inoculation, and EB size control are discussed on the basis of both published data and our own laboratory experiences. Collectively, the production of a large quantity of homogeneous EBs with high quality is important for the stability and feasibility of many PSCs related studies.

18.
Circulation ; 141(11): 916-930, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-31992066

RESUMO

BACKGROUND: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. METHODS: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. RESULTS: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. CONCLUSIONS: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.


Assuntos
Ceramidase Ácida/fisiologia , Terapia Genética , Hipóxia/metabolismo , Infarto do Miocárdio/metabolismo , RNA Mensageiro/uso terapêutico , Esfingolipídeos/metabolismo , Ceramidase Ácida/antagonistas & inibidores , Ceramidase Ácida/genética , Animais , Animais Recém-Nascidos , Apoptose , Ceramidas/metabolismo , Cicatriz/patologia , Corpos Embrioides , Indução Enzimática , Feminino , Humanos , Hipóxia/etiologia , Hipóxia/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamação , Masculino , Camundongos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Transfecção , Regulação para Cima
19.
Biomater Sci ; 8(1): 118-124, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777865

RESUMO

On account of the biological significance of self-assembling peptides in blocking the cellular mass exchange as well as impeding the formation for actin filaments resulting in program cell death, stimuli-responsive polypeptide nanoparticles have attracted more and more attention. In this work, we successfully fabricated doxorubicin-loaded polyethylene glycol-block-peptide (FFKY)-block-tetraphenylethylene (PEG-Pep-TPE/DOX) nanoparticles, where the aggregation-induced emission luminogens (AIEgen, TPE-CHO) can become a fluorescence resonance energy transfer (FRET) pair with the entrapped antitumor drug DOX to detect the release of drugs dynamically. This is the first successful attempt to detect and quantify the change of FRET signals in A549 cells via three methods to monitor the cellular uptake of nanoprobes and intracellular drug molecule release intuitively. As we proposed here, the combination of free DOX and the self-assembling peptide could achieve the synergistic anticancer efficacy. The multifunctional PEG-Pep-TPE/DOX nanoparticles may provide a new opportunity for combination cancer therapy and real-time detection of the drug release from stimuli-responsive nanomedicine.


Assuntos
Antineoplásicos/química , Doxorrubicina/química , Transferência Ressonante de Energia de Fluorescência/métodos , Nanopartículas/química , Peptídeos/química , Polietilenoglicóis/química , Estilbenos/química , Células A549 , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Glutationa/química , Humanos , Concentração de Íons de Hidrogênio , Substâncias Luminescentes/química , Nanopartículas/toxicidade
20.
Biomacromolecules ; 21(2): 444-453, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31851512

RESUMO

Self-assembled peptide nanofibers have been widely studied in cancer nanotherapeutics with their excellent biocompatibility and low toxicity of degradation products, showing the significant potential in inhibiting tumor progression. However, poor solubility prevents direct intravenous administration of nanofibers. Although water-soluble peptide precursors have been formed via the method of phosphorylation for intravenous administration, their opportunities for broad in vivo application are limited by the weak capacity of encapsulating drugs. Herein, we designed a novel restructured reduced glutathione (GSH)-responsive drug delivery system encapsulating doxorubicin for systemic administration, which achieved the intracellular restructuration from three-dimensional micelles into one-dimensional nanofibers. After a long blood circulation, micelles endocytosed by tumor cells could degrade in response to high GSH levels, achieving more release and accumulation of doxorubicin at desired sites. Further, the synergistic chemotherapy effects of self-assembled nanofibers were confirmed in both in vitro and in vivo experiments.


Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Glutationa/metabolismo , Nanofibras/química , Células A549 , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Glutationa/sangue , Células Endoteliais da Veia Umbilical Humana , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Micelas , Peptídeos/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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