The combined effects of low-molecular-weight fucoidan (LMF) and fucoxanthin (Fx) in terms of antihyperglycemic, antihyperlipidemic, and hepatoprotective activities were investigated in a mouse model ...of type II diabetes. The intake of LMF, Fx, and LMF + Fx lowered the blood sugar and fasting blood sugar levels, and increased serum adiponectin levels. The significant decrease in urinary sugar was only observed in LMF + Fx supplementation. LMF and Fx had ameliorating effects on the hepatic tissue of db/db mice by increasing hepatic glycogen and antioxidative enzymes, and LMF was more effective than Fx at improving hepatic glucose metabolism. As for glucose and lipid metabolism in the adipose tissue, the expression of insulin receptor substrate (IRS)-1, glucose transporter (GLUT), peroxisome proliferator-activated receptor gamma (PPARγ), and uncoupling protein (UCP)-1 mRNAs in the adipose tissue of diabetic mice was significantly upregulated by Fx and LMF + Fx, and levels of inflammatory adipocytokines, such as adiponectin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were significantly modulated only by LMF + Fx supplementation. The efficacy of LMF + Fx supplementation on the decrease in urinary sugar and on glucose and lipid metabolism in the white adipose tissue of db/db mice was better than that of Fx or LMF alone, indicating the occurrence of a synergistic effect of LMF and Fx.
Many genetic diseases are caused by single-nucleotide polymorphisms. Base editors can correct these mutations at single-nucleotide resolution, but until recently, only allowed for transition edits, ...addressing four out of twelve possible DNA base substitutions. Here, we develop a class of C:G to G:C Base Editors to create single-base genomic transversions in human cells. Our C:G to G:C Base Editors consist of a nickase-Cas9 fused to a cytidine deaminase and base excision repair proteins. Characterization of >30 base editor candidates reveal that they predominantly perform C:G to G:C editing (up to 90% purity), with rAPOBEC-nCas9-rXRCC1 being the most efficient (mean 15.4% and up to 37% without selection). C:G to G:C Base Editors target cytidine in WCW, ACC or GCT sequence contexts and within a precise three-nucleotide window of the target protospacer. We further target genes linked to dyslipidemia, hypertrophic cardiomyopathy, and deafness, showing the therapeutic potential of these base editors in interrogating and correcting human genetic diseases.
•Six chitosans with molecular weights ranging from 3.3 to 300kDa were prepared.•Combined effects of chitosan MW, temperature, pH on bacterial growth were studied.•The pH effects on water solubility ...and zeta potential of chitosans were examined.•Positive correlation between chitosan ZP and antibacterial activity was obtained.
Six chitosans with molecular weights (MWs) of 300, 156, 72.1, 29.2, 7.1, and 3.3kDa were prepared by cellulase degradation of chitosan (300kDa) and ultrafiltration techniques. We examined the correlation between activity against Escherichia coli and Staphylococcus aureus and chitosan MW, and provided the underlying explanation. In acidic pH conditions, the chitosan activity increased with increasing MW, irrespective of the temperature and bacteria tested. However, at neutral pH, chitosan activity increased as the MW decreased, and little activity was observed for chitosans with MW >29.2kDa. At pH 5.0 and 6.0, chitosans exhibited good water solubility and zeta potential (ZP) decreased with the MW, whereas the solubility and ZP of the chitosans decreased with increasing MW at pH 7.0. Particularly, low solubility and negative ZP values were determined for chitosans with MW >29.2kDa, which may explain the loss of their antibacterial activity at pH 7.0.
Heart failure due to diastolic dysfunction exacts a major economic, morbidity and mortality burden in the United States. Therapeutic agents to improve diastolic dysfunction are limited. It was ...recently found that Dynamin related protein 1 (Drp1) mediates mitochondrial fission during ischemia/reperfusion (I/R) injury, whereas inhibition of Drp1 decreases myocardial infarct size. We hypothesized that Dynasore, a small noncompetitive dynamin GTPase inhibitor, could have beneficial effects on cardiac physiology during I/R injury.
In Langendorff perfused mouse hearts subjected to I/R (30 minutes of global ischemia followed by 1 hour of reperfusion), pretreatment with 1 µM Dynasore prevented I/R induced elevation of left ventricular end diastolic pressure (LVEDP), indicating a significant and specific lusitropic effect. Dynasore also decreased cardiac troponin I efflux during reperfusion and reduced infarct size. In cultured adult mouse cardiomyocytes subjected to oxidative stress, Dynasore increased cardiomyocyte survival and viability identified by trypan blue exclusion assay and reduced cellular Adenosine triphosphate(ATP) depletion. Moreover, in cultured cells, Dynasore pretreatment protected mitochondrial fragmentation induced by oxidative stress.
Dynasore protects cardiac lusitropy and limits cell damage through a mechanism that maintains mitochondrial morphology and intracellular ATP in stressed cells. Mitochondrial protection through an agent such as Dynasore can have clinical benefit by positively influencing the energetics of diastolic dysfunction.
A variety of studies carried out using either human subjects or laboratory animals suggest that vitamin D and its analogues possess important beneficial activity in the cardiovascular system. Using ...Cre-Lox technology we have selectively deleted the vitamin D receptor (VDR) gene in the cardiac myocyte in an effort to better understand the role of vitamin D in regulating myocyte structure and function.
Targeted deletion of the exon 4 coding sequence in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following a 7-day infusion of isoproterenol. There was no increase in interstitial fibrosis. These knockout mice demonstrated a reduction in end-diastolic and end-systolic volume by echocardiography, activation of the fetal gene program (ie, increased atrial natriuretic peptide and alpha skeletal actin gene expression), and increased expression of modulatory calcineurin inhibitory protein 1 (MCIP1), a direct downstream target of calcineurin/nuclear factor of activated T cell signaling. Treatment of neonatal cardiomyocytes with 1,25-dihydroxyvitamin D partially reduced isoproterenol-induced MCIP1 mRNA and protein levels and MCIP1 gene promoter activity.
Collectively, these studies demonstrate that the vitamin D-VDR signaling system possesses direct, antihypertrophic activity in the heart. This appears to involve, at least in part, suppression of the prohypertrophic calcineurin/NFAT/MCIP1 pathway. These studies identify a potential mechanism to account for the reported beneficial effects of vitamin D in the cardiovascular system.
BaTiO3‐based compounds are recognized as the most common dielectric material used in multilayer ceramic capacitors (MLCCs), among which, BaTiO3‐BiMeO3 is extensively investigated to improve the ...thermal stability and extend the service life of MLCCs, which are strongly dependent on the conductivity at high temperatures. Despite numerous efforts have been made, the mechanism of oxygen vacancy conduction, which makes the major contributions to the conduction mechanism of BaTiO3‐based compounds at high temperatures below 450°C, is still unclear. In this paper, BaTiO3, 0.88BaTiO3‐0.12Bi(Zn2/3Nb1/3)O3, 0.88BaTiO3‐0.12Bi(Mg2/3Nb1/3)O3, and 0.88BaTiO3‐0.12Bi(Mg2/3Ta1/3)O3 ceramics have been prepared by solid‐state reaction method, and their electrical and dielectric properties have been studied in detail. Meanwhile, first principles were applied to study the mechanisms of the increase of electrical resistivity and the decrease of dielectric loss. It is found that B‐site dopants (Zn, Mg, Nb, and Ta) are effective in reducing the conductivity by inhibiting the migration of oxygen vacancies, which is a kinetics process with an increase of energy barrier. Notably, the greater ability of Zn to inhibit oxygen vacancies migration is a combination of thermodynamics (a strong ability to trap oxygen vacancies) and kinetics (an effect of block the migrating defects in the lattice). This work reveals a new insight into the mechanism of oxygen vacancies migration in BaTiO3‐based perovskite compounds, which makes BaTiO3‐BiMeO3 prospective in designing efficient and durable medium‐temperature solid oxide capacitor devices.
The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty ...liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.
Liver function is routinely assessed in clinical practice as liver function tests provide sensitive indicators of hepatocellular injury. However, the prognostic value of enzymes that indicate hepatic ...injury has never been systematically investigated in lymphoma, including diffuse large B-cell lymphoma (DLBCL).
This study examined the prognostic value of baseline aspartic transaminase (AST) in DLBCL patients. The association between AST and clinical features was analyzed in 179 DLBCL patients treated from 2006 to 2016. All enrolled patients were treated with R-CHOP or R-CHOP-like chemotherapy. Log-rank test, univariable analysis, and subgroup analysis were performed to evaluate the impact of AST on survival.
AST 33.3 U/L was considered to be the optimal threshold value for predicting prognosis. A higher AST level was associated with advanced stage (P = 0.001), poorer performance status (P = 0.014), elevated lactate dehydrogenase level (P < 0.0001), presence of B symptoms (P = 0.001), high-risk International Prognostic Index (IPI, IPI 3-5) (P = 0.002), non-germinal center B-cell subtypes (P = 0.038), hepatitis B virus surface antigen positivity (P = 0.045) and more extra nodal involvement (ENI, ENI ≥ 2) (P = 0.027). Patients with a higher AST level had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P < 0.001). Subgroup analysis indicated that higher AST levels have poorer prognostic values in patients without B symptoms and LDH positive groups.
A pretreatment AST level is associated with OS in DLBCL patients treated with R-CHOP or similar chemotherapy regimens. A high pretreatment AST level might be a reliable prognostic factor for predicting a dismal outcome in DLBCL patients. Serum AST levels may be investigated for use as an easily determinable, inexpensive biomarker for risk assessment in patients with DLBCL.
Growth and expansion of ventricular chambers is essential during heart development and is achieved by proliferation of cardiac progenitors. Adult cardiomyocytes, by contrast, achieve growth through ...hypertrophy rather than hyperplasia. Although epicardial-derived signals may contribute to the proliferative process in myocytes, the factors and cell types responsible for development of the ventricular myocardial thickness are unclear. Using a coculture system, we found that embryonic cardiac fibroblasts induced proliferation of cardiomyocytes, in contrast to adult cardiac fibroblasts that promoted myocyte hypertrophy. We identified fibronectin, collagen, and heparin-binding EGF-like growth factor as embryonic cardiac fibroblast-specific signals that collaboratively promoted cardiomyocyte proliferation in a paracrine fashion. Myocardial β1-integrin was required for this proliferative response, and ventricular cardiomyocyte-specific deletion of β1-integrin in mice resulted in reduced myocardial proliferation and impaired ventricular compaction. These findings reveal a previously unrecognized paracrine function of embryonic cardiac fibroblasts in regulating cardiomyocyte proliferation.
A combination strategy involving the use of a hard template and a biomass material was employed to prepare carbon sphere–intercalated porous carbon with a hierarchical structure for application in a ...high-performance supercapacitor. The preparation of the microporous activated carbon first involved the carbonization and chemical activation of golden shower tree seeds and potassium ferrate. The activated carbon was then modulated through anchoring with hard-template-derived mesoporous carbon spheres (HMCSs). The obtained porous carbon had a high surface area (1446 m2 g−1), a high pore volume (1.29 cm3 g−1), a low proportion of micropores (Smicro/SBET = 8.4 %), and mesopores, indicating the successful development of carbon sphere–intercalated heterostructural architectures. It displayed a specific capacitance (154 F g−1 at a scan rate of 5 mV s−1) in 6 M KOH aqueous electrolyte. Considering the pore structure, this study employed the LiPF6 electrolyte, which has a larger ionic size, in assembling a supercapacitor. The device exhibited excellent capacitive properties, with a peak energy density of 19.16 mWh cm−3 and a peak power density of 3.25 W cm−3.
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•The hard-template derived mesoporous carbon spheres (HMCSs) anchored biomass-derived activated carbon has been synthesized.•The superior electrochemical performance is ascribed to the well-constructed micro–mesoporous structure.•The reported sphere-intercalated porous carbon has hierarchical structure and will be a promising electrode materials.
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