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1.
Artigo em Inglês | MEDLINE | ID: mdl-34642871

RESUMO

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs with regulatory activity and regarded as new types of therapeutic targets in diseases such as cancers. By means of RNA-Seq technology, numerous cardiac circRNAs were discovered. Although some candidates were detected to involve in heart disease in murine model, relative low sequence conservation and expression level of their human homologs might result in an insignificant, even distinct effect in the human heart. Therefore, the therapeutic significance of circRNAs should be more strictly considered. It is also necessary to discuss which circRNA is suitable for being applied in heart disease treatment. Here, we are willing to introduce a ~ 1830 nt circular transcript generated from single exon of sodium/calcium exchanger 1 (ncx1) gene (also called solute carrier family 8 member A1, slc8a1), usually named circNCX1 or circSLC8A1, which is gradually coming into our view. circNCX1 is one of the most cardiac-enriched circRNAs. It is widely existent in vertebrate and relatively conserved, indicating its indispensability during the evolution of species. Indeed, circNCX1 was shown to involve in heart development by some expression analysis. It was further revealed that the dysregulation of circNCX1 is one of the key pathogeneses of heart diseases including ischemic cardiac injury and hypertrophic cardiomyopathy. To make the significance of circNCX1 in the heart clear, we comprehensively dissected circNCX1 in the aspects of its parental gene structure, conservation, biogenesis and expression profiles, function, molecular mechanisms, and clinical application in this review. New medicine or therapeutic schedules based on circNCX1 are expected in the future.

2.
Front Endocrinol (Lausanne) ; 12: 712855, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552558

RESUMO

Objective: To evaluate the association between neck circumference (NC) and hyperuricemia in women with polycystic ovary syndrome (PCOS). Methods: This is a cross-sectional study that recruited 601 women with PCOS from January 2018 to January 2021. PCOS was diagnosed according to the Rotterdam definition. Hyperuricemia was defined as serum uric acid level of at least 357 µmol/L. Results: PCOS females with hyperuricemia had significantly greater values of NC, body mass index (BMI), waist circumference (WC) and hip circumference (HC). NC was positively associated with serum uric acid levels, with a standardized regression coefficient of 0.34 after adjusting for confounding factors. Furthermore, logistic regression analysis showed that NC was significantly associated with an increased risk of hyperuricemia, with an adjusted odds ratio of 1.36. The associations between NC and serum uric acid levels were more considerable in those with medium/high BMI (BMI ≥ 21.63 kg/m2), all ranges of WC or medium/high HC (HC ≥ 90 cm). The optimal cut-off point of NC in predicting hyperuricemia was 32.0 cm (Youden index = 0.48), with the sensitivity and negative predictive value of 84.81% and 92.08%, respectively. Conclusions: NC was positively correlated with serum uric acid levels and the prevalence of hyperuricemia in women with PCOS. Therefore, we suggest NC as a simple, novel, and reliable anthropometric measure to be used in the routine clinical assessment of women with PCOS to screen those at high risk of hyperuricemia.

3.
Int Heart J ; 62(5): 1135-1144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34588407

RESUMO

Myocardial fibrosis is an important pathological phenomenon of cardiac remodeling that is induced by hypertension, myocardial ischemia, valvular heart disease, hypertrophic cardiomyopathy, and other heart diseases and can progress to heart failure. Urotensin II (UII) is regarded as a cardiovascular autacoid/hormone that is not only the most potent vasoconstrictor in mammals but also involved in cardiac remodeling. However, the molecular mechanisms responsible for UII-induced cardiac fibrosis have not yet been fully elucidated. Therefore, we aimed to investigate the effect of UII on myocardial fibrosis in cardiac hypertrophy and the mechanism of UII-induced cardiac fibrosis. Cardiac tissue from mice subjected to Transverse aortic constriction (TAC) was collected. Cardiac hypertrophy, myocardial fibrosis, and the expression of UII protein were assessed using echocardiography and pathological and molecular biological analyses. The effect of UII on fibrosis was evaluated in UII-treated mice and isolated rat primary cardiac fibroblasts, and the results indicated that UII induced significant myocardial fibrosis and increases in the proliferation and fibrotic responses both in mice and cultured fibroblasts. Mechanistically, UII treatment induced activation of the TGF-ß/Smad signaling pathway, which was suppressed by the UII receptor antagonist. In conclusion, UII plays critical roles in cardiac fibrosis by modulating the TGF-ß/Smads signaling pathway, which may be a promising therapeutic target in hypertrophic cardiomyopathy and related problems, such as cardiac remodeling and heart failure.

4.
Mol Neurodegener ; 16(1): 64, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526055

RESUMO

BACKGROUND: Human genetic association studies point to immune response and lipid metabolism, in addition to amyloid-beta (Aß) and tau, as major pathways in Alzheimer's disease (AD) etiology. Accumulating evidence suggests that chronic neuroinflammation, mainly mediated by microglia and astrocytes, plays a causative role in neurodegeneration in AD. Our group and others have reported early and dramatic losses of brain sulfatide in AD cases and animal models that are mediated by ApoE in an isoform-dependent manner and accelerated by Aß accumulation. To date, it remains unclear if changes in specific brain lipids are sufficient to drive AD-related pathology. METHODS: To study the consequences of CNS sulfatide deficiency and gain insights into the underlying mechanisms, we developed a novel mouse model of adult-onset myelin sulfatide deficiency, i.e., tamoxifen-inducible myelinating glia-specific cerebroside sulfotransferase (CST) conditional knockout mice (CSTfl/fl/Plp1-CreERT), took advantage of constitutive CST knockout mice (CST-/-), and generated CST/ApoE double knockout mice (CST-/-/ApoE-/-), and assessed these mice using a broad range of methodologies including lipidomics, RNA profiling, behavioral testing, PLX3397-mediated microglia depletion, mass spectrometry (MS) imaging, immunofluorescence, electron microscopy, and Western blot. RESULTS: We found that mild central nervous system (CNS) sulfatide losses within myelinating cells are sufficient to activate disease-associated microglia and astrocytes, and to increase the expression of AD risk genes (e.g., Apoe, Trem2, Cd33, and Mmp12), as well as previously established causal regulators of the immune/microglia network in late-onset AD (e.g., Tyrobp, Dock, and Fcerg1), leading to chronic AD-like neuroinflammation and mild cognitive impairment. Notably, neuroinflammation and mild cognitive impairment showed gender differences, being more pronounced in females than males. Subsequent mechanistic studies demonstrated that although CNS sulfatide losses led to ApoE upregulation, genetically-induced myelin sulfatide deficiency led to neuroinflammation independently of ApoE. These results, together with our previous studies (sulfatide deficiency in the context of AD is mediated by ApoE and accelerated by Aß accumulation) placed both Aß and ApoE upstream of sulfatide deficiency-induced neuroinflammation, and suggested a positive feedback loop where sulfatide losses may be amplified by increased ApoE expression. We also demonstrated that CNS sulfatide deficiency-induced astrogliosis and ApoE upregulation are not secondary to microgliosis, and that astrogliosis and microgliosis seem to be driven by activation of STAT3 and PU.1/Spi1 transcription factors, respectively. CONCLUSION: Our results strongly suggest that sulfatide deficiency is an important contributor and driver of neuroinflammation and mild cognitive impairment in AD pathology.

5.
Commun Biol ; 4(1): 1034, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465887

RESUMO

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10-10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10-9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10-8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.


Assuntos
COVID-19/etnologia , COVID-19/genética , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Humanos , Íntrons/genética , Polimorfismo de Nucleotídeo Único
6.
J Hazard Mater ; 416: 125829, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492790

RESUMO

Enhancing the performance of adsorbents to the utmost extent is an objective but challenging in applying adsorption technology to wastewater treatment. In this work, novel quaternary ammonium polymers (QAPs) with high density adsorption site (i.e., quaternized N, confirmed by FT-IR results) were designed and prepared for rapid selective removal of Cr(VI) from water. The results of EDS analysis indicated the maximum exposure rate of N on the surface of QAPs was as high as 86.1%, which almost doubled comparing to that of Cr(VI) ions imprinted polymers (Cr(VI)-IIP) (46.2%). Interestingly, the maximum adsorption capacity (211.8 mg/g) and initial adsorption rate (h0, 66.6 mg/ (g·min)) of QAPs (i.e., 5:1(TRIM)) for Cr(VI) are about 3.6 times and 4.9 times those of Cr(VI)-IIP (63.0 mg/g and 13.5 mg/(g·min)), respectively. Impressively, flow-through adsorption experiments demonstrated 5:1(TRIM) can completely remove 5 mg/L of Cr(VI) within five seconds. Additionally, 5:1(TRIM) exhibited a remarkable selectivity for Cr(VI) adsorption, and high purity (100%) of chromium can be readily obtained. The proposed idea of high exposure effect of the adsorption site can provide a valuable guidance for designing rapid selective adsorbents to remove and reclaim Cr(VI) from wastewater.


Assuntos
Compostos de Amônio , Poluentes Químicos da Água , Adsorção , Cromo/análise , Concentração de Íons de Hidrogênio , Cinética , Polímeros , Espectroscopia de Infravermelho com Transformada de Fourier , Poluentes Químicos da Água/análise
7.
Peptides ; 144: 170609, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34242679

RESUMO

Cell pyroptosis, a new type of programmed cell death, has been recently reported to play important roles in the development of cardiac remodeling. How cardiomyocyte pyroptosis is induced remains to be elucidated. Urotensin II (UII) has been known closely related to cardiac remodeling and the development of heart failure. Inhibition of UII receptors has been shown to be effective in the treatment of cardiac hypertrophy and remodeling. However, it is not clear whether UII might induce cardiomyocyte pyroptosis. We here examined the effect of UII treatment on pyroptosis in cultured cardiomyocytes. Treatment of cardiomyocyes of neonatal rats with UII (500 nmol/l) for 48 hours induced a significant pyroptosis as evidenced by not only increased cell death but also upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, IL-18 and gasdermin D (GMDSD)-N which are important markers for the identification of cell pyroptosis. All these pyroptosis responses induced by UII were abrogated by an inhibitor of NLRP3. Moreover, the antagonist of UII receptor, Urantide abolished UII- induced cardiomyocyte pyroptosis. Additionally, inhibition of calcineurin by cyclosporin A rather than that of CaMKII by KN93 suppressed the UII-upregulated expression levels of those pyroptosis markers. We therefore demonstrate that UII might induce cardiomyocyte pyroptosis through calcineurin.

8.
Biosci Biotechnol Biochem ; 85(8): 1873-1884, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34196365

RESUMO

Phospholipids reportedly alleviate drug-induced acute kidney injury. However, no study has compared the effect of phospholipids with different fatty acids and polar heads on drug-induced nephrotoxicity. In the present study, we aimed to compare the possible nephroprotection afforded by phosphatidylcholine and phosphatidylserine with different fatty acids in a mouse model of vancomycin-induced nephrotoxicity. Pretreatment with phospholipids rich in docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) doubled the survival time when compared with the model group. Moreover, phospholipids rich in DHA/EPA significantly reduced the serum levels of renal function biomarkers and ameliorated kidney pathologies. In terms of alleviating renal damage, no significant differences were observed between different polar heads in DHA-enriched phospholipids, while phosphatidylserine from soybean was better than phosphatidylcholine in mitigating renal injury. Furthermore, DHA/EPA-enriched phospholipids inhibited vancomycin-induced nephrotoxicity mainly by inhibiting apoptosis and oxidative stress. These results provide a scientific basis for phospholipids as potential ingredients to prevent acute kidney injury.

9.
Mikrochim Acta ; 188(8): 242, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34226955

RESUMO

In-depth study of cellular heterogeneity of rare cells (e.g. circulating tumour cells (CTCs) and circulating foetal cells (CFCs)) is greatly needed in disease management but has never been completely explored due to the current technological limitations. We have developed a retrieval method for single-cell detection using a static droplet array (SDA) device through liquid segmentation with almost no sample loss. We explored the potential of using SDA for low sample input and retrieving the cells of interest using everyday laboratory equipment for downstream molecular analysis. This single-cell isolation and retrieval method is low-cost, rapid and provides a solution to the remaining challenge for single rare cell detection. The entire process takes less than 15 min, is easy to fabricate and allows for on-chip analysis of cells in nanolitre droplets and retrieval of desired droplets. To validate the applicability of our device and method, we mimicked detection of single CTCs by isolating and retrieving single cells and perform real-time PCR on their mRNA contents.

10.
J Healthc Eng ; 2021: 9921094, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249297

RESUMO

AR technology, also known as AR or virtual reality, refers to a technology that combines and allows interaction of the virtual world on the display system with the real world through the position and angle of the camera video and image analysis technology. This technology is different from VR technology, and its characteristics can be easily explained as follows: when using AR technology, the user's eyes can see not only the real world but also the virtual world derived from the computer through things in the real world. At present, AR has been widely used in education, engineering, entertainment, and medical fields. In order to provide better perioperative care and bring patients a good nursing experience, this article mainly introduces the perioperative care of vascular decompression in the treatment of trigeminal neuralgia by augmented reality medical technology, in order to provide better care for patients with trigeminal neuralgia. This article proposes the perioperative nursing research method of vascular decompression for the treatment of trigeminal neuralgia under AR medical technology, including an overview of trigeminal neuralgia, perioperative related research, and AR medical technology algorithms, and designs related experiments to study whether AR medical technology can bring good news to nursing. Experimental results show that 96% of patients believe that with the enhancement of realistic medical technology, perioperative vascular decompression care for trigeminal neuralgia can help them recover faster and can be gradually popularized.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34292345

RESUMO

BACKGROUND: The deposition of ß-amyloid (Aß) in the brain is a biomarker of Alzheimer's disease (AD). Highly sensitive Aß positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD. AIM: To synthesize a new Aß tracer [18F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects. METHODS: [18F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [18F]DRKXH1 were investigated. Small-animal-PET was used for [18F]DRKXH1 and [18F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aß plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [18F]DRKXH1. RESULTS: The yield of [18F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/µmol. [18F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. The concentration of [18F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0-60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aß plaque-rich areas in the brain of AD transgenic mice. The DVR value of [18F]-DRKXH1 is higher than that of [18F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [18F]DRKXH1-labeled Aß plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake. CONCLUSIONS: [18F]DRKXH1 is an Aß tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.

12.
Mol Nutr Food Res ; 65(17): e2100009, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34219360

RESUMO

SCOPE: A growing number of studies have reported the effects of eicosapentaenoic acid (EPA) and terrestrial phospholipids on ameliorating mood disorders. Marine-derived EPA-enriched phospholipids (EPA-PL) exhibit the structural characteristics of EPA and phospholipids. However, the effect of dietary EPA-PL, and the differences between amphiphilic EPA-PL and lyophobic EPA on mood disorders had not been studied. METHODS AND RESULTS: A comparative investigation to determine the effects of dietary EPA-enriched ethyl ester (EPA-EE) and EPA-PL on improving depression- and anxiety-like behavior in a mouse model is performed, induced by 4 week chronic unpredictable mild stress (CUMS) coupled with lipopolysaccharide (LPS) challenge. It is found that dietary 4 week 0.6% (w/w) EPA-PL rescued depression- and anxiety-like behavior to a greater extent than did EPA-EE. Moreover, dietary EPA-PL significantly reduced the immobility time by 56.6%, close to the normal level, in forced swimming test, which revealed a reversal of depression-like behavior. Further studies revealed that dietary EPA-PL regulated immunity, monoamine systems, and the hypothalamic-pituitary-adrenal (HPA) axis by multi-target interactions, including inhibition of neuroinflammation and apoptosis. CONCLUSION: EPA-PL exerted superior effects to EPA-EE in alleviating depression- and anxiety-like behavior. The data suggest potential novel candidate or targeted dietary patterns to prevent and treat mood disorder.

13.
Lancet Digit Health ; 3(8): e486-e495, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325853

RESUMO

BACKGROUND: Medical artificial intelligence (AI) has entered the clinical implementation phase, although real-world performance of deep-learning systems (DLSs) for screening fundus disease remains unsatisfactory. Our study aimed to train a clinically applicable DLS for fundus diseases using data derived from the real world, and externally test the model using fundus photographs collected prospectively from the settings in which the model would most likely be adopted. METHODS: In this national real-world evidence study, we trained a DLS, the Comprehensive AI Retinal Expert (CARE) system, to identify the 14 most common retinal abnormalities using 207 228 colour fundus photographs derived from 16 clinical settings with different disease distributions. CARE was internally validated using 21 867 photographs and externally tested using 18 136 photographs prospectively collected from 35 real-world settings across China where CARE might be adopted, including eight tertiary hospitals, six community hospitals, and 21 physical examination centres. The performance of CARE was further compared with that of 16 ophthalmologists and tested using datasets with non-Chinese ethnicities and previously unused camera types. This study was registered with ClinicalTrials.gov, NCT04213430, and is currently closed. FINDINGS: The area under the receiver operating characteristic curve (AUC) in the internal validation set was 0·955 (SD 0·046). AUC values in the external test set were 0·965 (0·035) in tertiary hospitals, 0·983 (0·031) in community hospitals, and 0·953 (0·042) in physical examination centres. The performance of CARE was similar to that of ophthalmologists. Large variations in sensitivity were observed among the ophthalmologists in different regions and with varying experience. The system retained strong identification performance when tested using the non-Chinese dataset (AUC 0·960, 95% CI 0·957-0·964 in referable diabetic retinopathy). INTERPRETATION: Our DLS (CARE) showed satisfactory performance for screening multiple retinal abnormalities in real-world settings using prospectively collected fundus photographs, and so could allow the system to be implemented and adopted for clinical care. FUNDING: This study was funded by the National Key R&D Programme of China, the Science and Technology Planning Projects of Guangdong Province, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Fundamental Research Funds for the Central Universities. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Aprendizado Profundo , Sistemas Especialistas , Processamento de Imagem Assistida por Computador/métodos , Programas de Rastreamento/métodos , Modelos Biológicos , Retina , Doenças Retinianas/diagnóstico , Área Sob a Curva , Inteligência Artificial , Tecnologia Biomédica , China , Retinopatia Diabética/diagnóstico , Fundo de Olho , Humanos , Oftalmologistas , Fotografação , Curva ROC
14.
J Int Med Res ; 49(6): 3000605211028554, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34187209

RESUMO

OBJECTIVE: To assess the outcomes of traditional three-dimensional (3D) printing technology (TPT) versus mirror 3D printing technology (MTT) in treating isolated acetabular fractures (IAFs). METHODS: Consecutive patients with an IAF treated by either TPT or MTT at our tertiary medical centre from 2012 to 2018 were retrospectively reviewed. Follow-up was performed 1, 3, 6, and 12 months postoperatively and annually thereafter. The primary outcome was the Harris hip score (HHS), and the secondary outcomes were major intraoperative variables and key orthopaedic complications. RESULTS: One hundred fourteen eligible patients (114 hips) with an IAF (TPT, n = 56; MTT, n = 58) were evaluated. The median follow-up was 25 months (range, 21-28 months). At the last follow-up, the mean HHS was 82.46 ±14.70 for TPT and 86.30 ± 13.26 for MTT with a statistically significant difference. Significant differences were also detected in the major intraoperative variables (operation time, intraoperative blood loss, number of fluoroscopic screenings, and anatomical reduction number) and the major orthopaedic complications (loosening, implant failure, and heterotopic ossification). CONCLUSION: Compared with TPT, MTT tends to produce accurate IAF reduction and may result in better intraoperative variables and a lower rate of major orthopaedic complications.


Assuntos
Acetábulo , Artroplastia de Quadril , Acetábulo/diagnóstico por imagem , Acetábulo/cirurgia , Seguimentos , Humanos , Impressão Tridimensional , Estudos Retrospectivos , Resultado do Tratamento
15.
Basic Res Cardiol ; 116(1): 38, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34089101

RESUMO

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

16.
Curr Opin Biotechnol ; 71: 25-31, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34091124

RESUMO

Genetically modified organisms (GMOs) have emerged as an integral component of a sustainable bioeconomy, with an array of applications in agriculture, bioenergy, and biomedicine. However, the rapid development of GMOs and associated synthetic biology approaches raises a number of biosecurity concerns related to environmental escape of GMOs, detection thereof, and impact upon native ecosystems. A myriad of genetic safeguards have been deployed in diverse microbial hosts, ranging from classical auxotrophies to global genome recoding. However, to realize the full potential of microbes as biocatalytic platforms in the bioeconomy, a deeper understanding of the fundamental principles governing microbial responsiveness to biocontainment constraints, and interactivity of GMOs with the environment, is required. Herein, we review recent analytical biotechnological advances and strategies to assess biocontainment and microbial bioproductivity, as well as opportunities for predictive systems biodesigns towards securing a viable bioeconomy.

17.
J Nutr ; 151(8): 2206-2214, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-33978190

RESUMO

BACKGROUND: DHA (22:6n-3), a long-chain n-3 PUFA, is essential for normal brain development and function. Our previous study demonstrated that DHA significantly improves scopolamine-induced dementia. However, there are no reports on the relation between n-3 PUFA deficiency and scopolamine-induced cognitive impairment. OBJECTIVES: The aim of this study was to evaluate whether n-3 PUFA deficiency increases vulnerability to scopolamine-induced cognitive impairment. METHODS: Male and female C57BL/6 mice were mated and fed an n-3 PUFA-adequate [containing 2.88% α-linolenic acid (ALA; 18:3n-3)] or -deficient (containing 0.09% ALA) diet for 2 consecutive generations. The corresponding second-generation male offspring were kept on the same diet as their mothers after weaning, and were randomly assigned to 2 subgroups at 7 wk of age, in which they were intraperitoneally injected with saline [fed n-3 PUFA-adequate (Con) or -deficient (Def) diet] or scopolamine [5 mg/kg body weight; fed n-3 PUFA-adequate (Sco) or -deficient (Def + Sco) diet] once per day for 7 d before killing. Behavioral performance was analyzed using the Morris Water Maze test. Fatty acid composition, protein expression, and indicators of cholinergic and oxidative stress in the brain were measured. RESULTS: The Def group showed lower brain DHA (-63.7%, P ≤ 0.01) and higher n-6 PUFA (+65.5%, P ≤ 0.05) concentrations than the Con group. The Def + Sco group and the Sco group showed poorer spatial learning and memory (escape latency on the sixth day: +60.3% and +36.8%; platform crossings: -43.9% and -28.2%, respectively) and more obvious cholinergic dysfunction (acetylcholine: -47.6% and -27.7%, respectively), oxidative stress (glutathione peroxidase: -64.2% and -32.5%, respectively), apoptosis [B-cell lymphoma 2 (BCL2)-associated X protein/BCL2: +230.8% and +153.8%; phosphorylated P38/P38: +232% and +130%, phosphorylated c-Jun N-terminal kinase (JNK)/JNK: +104.5% and +58.8%, respectively], neuroinflammation (IL-1ß: +317.6% and +95%, respectively), and neurodevelopmental delay (brain-derived neurotrophic factor: -54.4% and -7.25%, respectively) than their corresponding saline-treated controls. CONCLUSIONS: Dietary n-3 PUFA deficiency significantly decreases brain DHA concentrations and increases vulnerability to scopolamine-induced cognitive impairment in C57BL/6 male mice.

18.
Health Aff (Millwood) ; 40(5): 745-753, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939502

RESUMO

Reducing postacute care in skilled nursing facilities (SNFs) in favor of home-based care is a leading cost-saving strategy in new payment models. Yet the extent to which SNF stays can be safely shortened remains unclear. We leveraged the exposure of fee-for-service Medicare beneficiaries without supplemental coverage to cost sharing after SNF benefit day 20 as a cause of shortened stays. Marked reductions in length-of-stay because of cost sharing shifted patients to home more than a week earlier than expected without cost sharing, producing a discharge spike. These reductions were not associated with clear evidence of compromised patient safety as measured by death, hospitalization for fall-related injuries, or all-cause hospitalization within nine days of the spike. Adverse consequences requiring hospitalization could not be excluded for a small proportion of shortened stays. These findings suggest potential for improving postacute care efficiency, as SNF stays may be unnecessarily long to ensure safety.


Assuntos
Instituições de Cuidados Especializados de Enfermagem , Cuidados Semi-Intensivos , Idoso , Humanos , Medicare , Alta do Paciente , Readmissão do Paciente , Estados Unidos
19.
Food Funct ; 12(11): 4887-4896, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-33977967

RESUMO

Compared with terrestrial organisms, the sterols in sea cucumber exhibit a sulfate group at the C-3 position. Our previous study demonstrated that dietary sterol sulfate was superior to phytosterol in alleviating metabolic syndrome by ameliorating inflammation and mediating cholesterol metabolism in high-fat-high-fructose diet mice, which indicated its potential anti-atherosclerosis bioactivity. In the present study, administration with sea cucumber-derived sterol sulfate (SCS) significantly decreased the cholesterol level in oleic acid/palmitic acid-treated HepG2 cells, while no significant changes were observed in the triacylglycerol level. RNA-seq analysis showed that the metabolic changes were mostly attributed to the steroid biosynthesis pathway. ApoE-/- mice were used as an atherosclerosis model to further investigate the regulation of SCS on cholesterol metabolism. The results showed that SCS supplementation dramatically reduced atherosclerotic lesions by 45% and serum low-density lipoprotein cholesterol levels by 59% compared with the model group. Dietary SCS inhibited hepatic cholesterol synthesis via downregulating SREBP-2 and HMGCR. Meanwhile, SCS administration increased cholesterol uptake via enhancing the expression of Vldlr and Ldlr. Noticeably, SCS supplementation altered bile acid profiles in the liver, serum, gallbladder and feces, which might cause the activation of FXR in the liver. These findings provided new evidence about the high bioactivity of sterols with the sulfate group on atherosclerosis.

20.
Chem Biodivers ; 18(5): e2100196, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33830612

RESUMO

Two unprecedented tetranorlanostane triterpenoids, poricolides A (1) and B (2), and two new lanostane triterpenoids, 3ß-acetoxy-24-methyllanosta-8,16,24(31)-trien-21-oic acid (3) and 3ß-acetoxylanosta-7,9(11),16,23-tetraen-21-oic acid (4), were isolated from the epidermis of Poria cocos. The structures of 1-4 were determined via analysis of 1 H-, 13 C-, and 2D-NMR, and HR-ESI-MS data, and the absolute configurations of 1 and 3 were established by single-crystal X-ray diffraction analysis. Compounds 1 and 2 were the first report of tetranorlanostane triterpenoid having a δ-lactone ring at C(17). Compounds 3 and 4 were rare lanostane triterpenoids having a double bond between C(16) and C(17). Compounds 1-4 exhibited potent antiproliferative effects against A549, SMMC-7721, MCF-7, and SW480 cancer cell lines with IC50 values from 16.19±0.38 to 27.74±1.12 µM.


Assuntos
Antineoplásicos/farmacologia , Epiderme/química , Triterpenos/farmacologia , Wolfiporia/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Triterpenos/química , Triterpenos/isolamento & purificação
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