Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 384
Filtrar
1.
J Am Heart Assoc ; 10(22): e022077, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34743552

RESUMO

Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α-dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

2.
Exp Ther Med ; 22(5): 1256, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34603524

RESUMO

Mismatch between the titanium mesh cage and cervical geometries is an important factor that induces subsidence in anterior cervical corpectomy and fusion (ACCF). The aim of the present study was to construct a new quadrate anatomically adaptive titanium mesh cage (AA-TMC) that matches well with the cervical geometries and segmental alignment in one- and two-level ACCF. Computed tomography (CT) scans of 54 individuals were used to measure the cervical endplate geometries. X-rays of 74 young individuals were used to measure the intervertebral body angle (IBA) and intervertebral body height (IBH) of the surgical segments. The AA-TMC was designed based on these measured parameters. A total of 18 cervical cadaveric specimens underwent successive one- and two-level ACCF using the AA-TMC. Postoperatively, the specimens underwent CT scanning to assess the degree of matching of the TMC-endplate interface (TEI), IBA and IBH. A TEI interval <0.5 mm was considered well matching. In the sagittal plane, 93.8% of the inferior endplates were arched, whereas 94.8% of the superior endplates were flat. In the coronal plane, 82.9% of the inferior endplates and 93.8% of the superior endplates were flat. A total of 91.7 and 94.4% of the TEIs were well matched in one- and two-level ACCF, respectively. The postoperative IBA and IBH values were consistent with the values of young individuals. The AA-TMC achieved good matching with cervical geometries and segmental alignment in one- and two-level ACCF, and is proposed for use in ACCF to increase the contact at the TEI and achieve sufficient lordosis restoration.

3.
J BUON ; 26(4): 1691, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34565047

RESUMO

Retraction of "Acetylshikonin inhibits in vitro and in vivo tumorigenesis in cisplatin-resistant oral cancer cells by inducing autophagy, programmed cell death and targeting m-TOR/PI3K/Akt signalling pathway", by Peng Wang, Weiyue Gao, Yibin Wang, Jun Wang. JBUON 2019;24(5):2062-2067; PMID: 31786876 Following the publication of the above article, readers drew to our attention that part of the data was unreliable. We requested the authors to provide the raw data to prove the originality. Then the corresponding author contacted with our journal and stated below: Our group tried to repeat the results presented in this paper, but found that some data was not able to be reproducible. The authors then asked to retract this article. At the same time, our journal's investigation into this article also showed that part of the results in this article can not be supported by the data. Given above, we decided to retract this article. All the authors were informed of the retraction. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

4.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

6.
J Mol Cell Cardiol ; 161: 130-138, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34400182

RESUMO

BACKGROUND: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising tool for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes. OBJECTIVE: To improve the electrophysiological maturation of hiPSC-CMs. METHODS AND RESULTS: On day 16 of cardiac differentiation, hiPSC-CMs were treated with 100 nmol/L triiodothyronine (T3) and 1 µmol/L Dexamethasone (Dex) or vehicle for 14 days. On day 30, vehicle- and T3 + Dex-treated hiPSC-CMs were dissociated and replated either as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3 + Dex-treated hiPSC-CMs. Compared to vehicle, T3 + Dex-treated hiPSC-CMs had a slower spontaneous beating rate, more hyperpolarized resting membrane potential, faster maximal upstroke velocity, and shorter action potential duration. Changes in spontaneous activity and action potential were mediated by decreased hyperpolarization-activated current (If) and increased inward rectifier potassium currents (IK1), sodium currents (INa), and the rapidly and slowly activating delayed rectifier potassium currents (IKr and IKs, respectively). Furthermore, T3 + Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter action potential duration than the vehicle. Inhibition of IK1 by 100 µM BaCl2 significantly slowed conduction velocity and prolonged action potential duration in T3 + Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the importance of IK1 for conduction velocity and action potential duration. CONCLUSION: T3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.

8.
Nat Genet ; 53(8): 1250-1259, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267370

RESUMO

Tea is an important global beverage crop and is largely clonally propagated. Despite previous studies on the species, its genetic and evolutionary history deserves further research. Here, we present a haplotype-resolved assembly of an Oolong tea cultivar, Tieguanyin. Analysis of allele-specific expression suggests a potential mechanism in response to mutation load during long-term clonal propagation. Population genomic analysis using 190 Camellia accessions uncovered independent evolutionary histories and parallel domestication in two widely cultivated varieties, var. sinensis and var. assamica. It also revealed extensive intra- and interspecific introgressions contributing to genetic diversity in modern cultivars. Strong signatures of selection were associated with biosynthetic and metabolic pathways that contribute to flavor characteristics as well as genes likely involved in the Green Revolution in the tea industry. Our results offer genetic and molecular insights into the evolutionary history of Camellia sinensis and provide genomic resources to further facilitate gene editing to enhance desirable traits in tea crops.


Assuntos
Camellia sinensis/genética , Genoma de Planta , Haplótipos , Proteínas de Plantas/genética , Alelos , Evolução Biológica , Camellia sinensis/metabolismo , Produtos Agrícolas/genética , Domesticação , Regulação da Expressão Gênica de Plantas , Introgressão Genética , Variação Genética , Genética Populacional , Filogenia , Proteínas de Plantas/metabolismo , Polimorfismo de Nucleotídeo Único
9.
J Mol Cell Cardiol ; 160: 73-86, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34273410

RESUMO

The temporal nature of chromatin structural changes underpinning pathologic transcription are poorly understood. We measured chromatin accessibility and DNA methylation to study the contribution of chromatin remodeling at different stages of cardiac hypertrophy and failure. ATAC-seq and reduced representation bisulfite sequencing were performed in cardiac myocytes after transverse aortic constriction (TAC) or depletion of the chromatin structural protein CTCF. Early compensation to pressure overload showed changes in chromatin accessibility and DNA methylation preferentially localized to intergenic and intronic regions. Most methylation and accessibility changes observed in enhancers and promoters at the late phase (3 weeks after TAC) were established at an earlier time point (3 days after TAC), before heart failure manifests. Enhancers were paired with genes based on chromatin conformation capture data: while enhancer accessibility generally correlated with changes in gene expression, this feature, nor DNA methylation, was alone sufficient to predict transcription of all enhancer interacting genes. Enrichment of transcription factors and active histone marks at these regions suggests that enhancer activity coordinates with other epigenetic factors to determine gene transcription. In support of this hypothesis, ChIP-qPCR demonstrated increased enhancer and promoter occupancy of GATA4 and NKX2.5 at Itga9 and Nppa, respectively, concomitant with increased transcription of these genes in the diseased heart. Lastly, we demonstrate that accessibility and DNA methylation are imperfect predictors of chromatin structure at the scale of A/B compartmentalization-rather, accessibility, DNA methylation, transcription factors and other histone marks work within these domains to determine gene expression. These studies establish that chromatin reorganization during early compensation after pathologic stimuli is maintained into the later decompensatory phases of heart failure. The findings reveal the rules for how local chromatin features govern gene expression in the context of global genomic structure and identify chromatin remodeling events for therapeutic targeting in disease.

10.
Cell Signal ; 85: 110061, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34091011

RESUMO

Protein phosphorylation and dephosphorylation is central to signal transduction in nearly every aspect of cellular function, including cardiovascular regulation and diseases. While protein kinases are often regarded as the molecular drivers in cellular signaling with high specificity and tight regulation, dephosphorylation mediated by protein phosphatases is also gaining increasing appreciation as an important part of the signal transduction network essential for the robustness, specificity and homeostasis of cell signaling. Metal dependent protein phosphatases (PPM, also known as protein phosphatases type 2C, PP2C) belong to a highly conserved family of protein phosphatases with unique biochemical and molecular features. Accumulating evidence also indicates important and specific functions of individual PPM isoform in signaling and cellular processes, including proliferation, senescence, apoptosis and metabolism. At the physiological level, abnormal PPM expression and activity have been implicated in major human diseases, including cancer, neurological and cardiovascular disorders. Finally, inhibitors for some of the PPM members have been developed as a potential therapeutic strategy for human diseases. In this review, we will focus on the background information about the biochemical and molecular features of major PPM family members, with emphasis on their demonstrated or potential roles in cardiac pathophysiology. The current challenge and potential directions for future investigations will also be highlighted.

12.
JCI Insight ; 6(10)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34027891

RESUMO

Individuals with heart failure (HF) frequently present with comorbidities, including obesity, insulin resistance, hypertension, and dyslipidemia. Many patients with HF experience cardiogenic dementia, yet the pathophysiology of this disease remains poorly understood. Using a swine model of cardiometabolic HF (Western diet+aortic banding; WD-AB), we tested the hypothesis that WD-AB would promote a multidementia phenotype involving cerebrovascular dysfunction alongside evidence of Alzheimer's disease (AD) pathology. The results provide evidence of cerebrovascular insufficiency coupled with neuroinflammation and amyloidosis in swine with experimental cardiometabolic HF. Although cardiac ejection fraction was normal, indices of arterial compliance and cerebral blood flow were reduced, and cerebrovascular regulation was impaired in the WD-AB group. Cerebrovascular dysfunction occurred concomitantly with increased MAPK signaling and amyloidogenic processing (i.e., increased APP, BACE1, CTF, and Aß40 in the prefrontal cortex and hippocampus) in the WD-AB group. Transcriptomic profiles of the stellate ganglia revealed the WD-AB group displayed an enrichment of gene networks associated with MAPK/ERK signaling, AD, frontotemporal dementia, and a number of behavioral phenotypes implicated in cognitive impairment. These provide potentially novel evidence from a swine model that cerebrovascular and neuronal pathologies likely both contribute to the dementia profile in a setting of cardiometabolic HF.

13.
Cancer Res ; 81(12): 3174-3186, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33863779

RESUMO

Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC. SIGNIFICANCE: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK-p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.

14.
Comput Assist Surg (Abingdon) ; 26(1): 49-57, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33929922

RESUMO

PURPOSE: Due to the high perforation rate of cervical pedicle screw placement, we have designed four different types of rapid prototyping navigation templates to enhance the accuracy of cervical pedicle screw placement. METHODS: Fifteen human cadaveric cervical spines from C2 to C7 were randomly divided into five groups, with three specimens in each group. The diameter of pedicle screw used in this study was 3.5 mm. Groups 1-4 were assisted by the two-level template, one-level bilateral template, one-level unilateral template and one-level point-contact template, respectively. Group 5 was without any navigation template. After the surgery, the accuracy of screw placement in the five groups was evaluated using postoperative computed tomographic scans to observe whether the screw breached the pedicle cortex. RESULTS: A total of 180 pedicle screws were inserted without any accidents. The accuracy rate was 75%, 100%, 100%, 91.7%, and 63.9%, respectively, from Groups 1 to 5. All the template groups were significantly higher than Group 5, though the two-level navigation template group was significantly lower than the other three template groups. The operation time was 4.72 ± 0.28, 4.81 ± 0.29, 5.03 ± 0.35, 8.42 ± 0.36, and 10.05 ± 0.52 min, respectively, from Groups 1 to 5. The no template and point-contact procedures were significantly more time-consuming than the template procedures. CONCLUSION: This study demonstrated that four different design types of navigation templates achieved a higher accuracy in assisting cervical pedicle screw placement than no template insertion. However, the two-level template's accuracy was the lowest compared to the other three templates. Meanwhile, these templates avoided fluoroscopy during the surgery and decreased the operation time. It is always very challenging to translate cadaveric studies to clinical practice. Hence, the one-level bilateral, unilateral, and point-contact navigation templates designed by us need to be meticulously tested to verify their accuracy and safety.

15.
Chem Res Chin Univ ; : 1-7, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33814861

RESUMO

Both electrospinning apparatus and their commercial products are extending their applications in a wide variety of fields. However, very limited reports can be found about how to implement an energy-saving process and in turn to reduce the production cost. In this paper, a brand-new type of coaxial spinneret with a solid core and its electrospinning methods are developed. A novel sort of medicated Eudragit/lipid hybrid nanofibers are generated for providing a colon-targeted sustained release of aspirin. A series of characterizations demonstrates that the as-prepared hybrid nanofibers have a fine linear morphology with the aspirin/lipid separated from the matrix Eudragit to form many tiny islands. In vitro dissolution tests exhibit that the hybrid nanofibers are able to effectively prevent the release of aspirin under an acid condition (8.7%±3.4% for the first two hours), whereas prolong the drug release time period under a neutral condition(99.7±4.2% at the seventh hour). The energy-saving mechanism is discussed in detail. The prepared aspirin-loaded hybrid nanofibers can be further transferred into an oral dosage form for potential application in countering COVID-19 in the future.

18.
Biomater Sci ; 9(11): 3968-3978, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33666216

RESUMO

Nanoparticle-mediated photothermal therapy (PTT) has shown promising capability for tumor therapy through the high local temperature at the tumor site generated by a photothermal agent (PTA) under visible or near-infrared (NIR) irradiation. Improving the accumulation of PTA at the tumor site is crucial to achieving effective photothermal treatment. Here, we developed temperature-activatable engineered neutrophils (Ne) by combining indocyanine green (ICG)-loaded magnetic silica NIR-sensitive nanoparticles (NSNP), which provide the potential for dual-targeted photothermal therapy. The combined effect of neutrophil targeting and magnetic targeting increased the accumulation of PTA at the tumor site. According to magnetic resonance imaging (MRI), the retention of intravenous injected NSNP-incorporated neutrophils within the tumor site was markedly augmented as compared to free NSNP. Furthermore, when irradiated by NIR, NSNP could cause a high local temperature at the tumor site and the thermal stimulation of neutrophils. The heat can kill tumor cells directly, and also lead to the death of neutrophils, upon which active substances with tumor-killing efficacy will be released to kill residual tumor cells and thus reduce tumor recurrence. Thereby, our therapy achieved the elimination of malignancy in the mouse model of the pancreatic tumor without recurrence. Given that all materials used in this system have been approved for use in humans, the transition of this treatment method to clinical application is plausible.


Assuntos
Hipertermia Induzida , Nanopartículas , Ferro , Imageamento por Ressonância Magnética , Neutrófilos , Fototerapia , Terapia Fototérmica
19.
Med (N Y) ; 2(4): 435-447.e4, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33521746

RESUMO

Background: To develop a sensitive risk score predicting the risk of mortality in patients with coronavirus disease 2019 (COVID-19) using complete blood count (CBC). Methods: We performed a retrospective cohort study from a total of 13,138 inpatients with COVID-19 in Hubei, China, and Milan, Italy. Among them, 9,810 patients with ≥2 CBC records from Hubei were assigned to the training cohort. CBC parameters were analyzed as potential predictors for all-cause mortality and were selected by the generalized linear mixed model (GLMM). Findings: Five risk factors were derived to construct a composite score (PAWNN score) using the Cox regression model, including platelet counts, age, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio. The PAWNN score showed good accuracy for predicting mortality in 10-fold cross-validation (AUROCs 0.92-0.93) and subsets with different quartile intervals of follow-up and preexisting diseases. The performance of the score was further validated in 2,949 patients with only 1 CBC record from the Hubei cohort (AUROC 0.97) and 227 patients from the Italian cohort (AUROC 0.80). The latent Markov model (LMM) demonstrated that the PAWNN score has good prediction power for transition probabilities between different latent conditions. Conclusions: The PAWNN score is a simple and accurate risk assessment tool that can predict the mortality for COVID-19 patients during their entire hospitalization. This tool can assist clinicians in prioritizing medical treatment of COVID-19 patients. Funding: This work was supported by National Key R&D Program of China (2016YFF0101504, 2016YFF0101505, 2020YFC2004702, 2020YFC0845500), the Key R&D Program of Guangdong Province (2020B1111330003), and the medical flight plan of Wuhan University (TFJH2018006).

20.
Curr Drug Deliv ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33588728

RESUMO

BACKGROUND: Electrospinning is developing rapidly from an earlier laboratory method into an industrial process. The clinical applications are approached in various ways through electrospun medicated nanofibers. The fast-dissolving oral drug delivery system (DDS) among them is one of the most promising routes in the near future for commercial applications. METHODS: Related papers are investigated, including the latest research results, on electrospun nanofiber-based fast-dissolution DDSs. RESULTS: Several relative topics have been concluded: 1) the development of electrospinning, ranging from 1-fluid blending to multi-fluid process and potential applications in the formation of medicated nanofibers involving poorly water-soluble drugs; 2) Selection of appropriate polymer matrices and drug carriers for filament formation; 3) Types of poorly water-soluble drugs ideal for fast oral delivery; 4) The methods for evaluating fast-dissolving nanofibers; 5) The mechanisms that promote the fast dissolution of poorly water-soluble drugs by electrospun nanofibers; 6) the important issues for further development of electrospun medicated nanofibers as oral fast-dissolving drug delivery systems. Conclusions & Perspectives: The unique properties of electrospun-medicated nanofibers can be used as oral fast dissolving DDSs of poorly water-soluble drugs. However, some significant issues need to be investigated, such as scalable productions and solid dosage form conversions.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...