Inflammation and microenvironment play a crucial role in muscle regeneration. IL (interleukin)-6, as a multifunctional cytokine is involved in the processes. However, the causative effect of IL-6 in ...muscle regeneration remains unclear. In a mouse model of cardiotoxin-induced muscle injury/regeneration, infiltrated monocytes/macrophages produce a high level of IL-6 started on 1 day (24 h) after injury. In IL-6 knock-out (−/−) mice, the muscle regeneration procedure was impaired along with decreased myogenic determination factor (MyoD) and myogenin mRNA level and increased interstitial fibrosis. The IL-6−/− mice exhibited less macrophage infiltration, lower inflammatory cytokine (IL-1β, inducible NO synthase, Transforming growth factor (TGF)-β1, and IL-10) and chemokine (CCL2, CCL3, and CCL5) expression, and inhibited myoblast proliferation. In vitro, IL-6 deficiency or Signal Transducer and Activator of Transcription 3 (STAT3) knockdown in activated macrophage attenuated the expression of CCL2, CCL3, but not CCL5, which resulted in less macrophage migration. Moreover, inflammatory macrophages promoted myoblast proliferation in an IL-6-dependent manner. Finally, adoptive transfer IL-6+/+ BM cells into IL-6−/− mice rescued the impaired regeneration with improved MyoD and myogenin expression. Taken together, IL-6 expression and the activated STAT3 signaling pathway in monocytes/macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration.
Background: Interleukin-6 (IL-6), as a multifunctional cytokine, was involved in the inflammation microenvironment of muscle regeneration.
Results: In mice lacking IL-6, less macrophage recruitment and decreased myoblast proliferation impairs muscle regeneration.
Conclusion: In monocytes/macrophages, activation of the IL-6/STAT3 pathway is critical to macrophage migration and myoblast proliferation during muscle regeneration.
Significance: IL-6/STAT3 pathway is essential for muscle regeneration.
This paper applies a novel nonparametric estimator to the modeling of auctions subject to shape restrictions. In particular, we employ a Bayesian estimator with a Gaussian process prior parameterized ...by a spectral representation. We use squared Gaussian processes to model the functional derivatives and therefore are able to impose global shape restrictions. Our first application is the estimation of a monotonically increasing bidding process of online auctions. The second application concerns the estimation of bidders’ risk-averse latent preferences in sealed-bid timber auctions. The results show that the shape-constrained estimator not only ensures the conformity with economic theories but also improves estimation precision.
To explore whether red yeast rice is a safe and effective alternative approach for dyslipidemia.
Pubmed, the Cochrane Library, EBSCO host, Chinese VIP Information (VIP), China National Knowledge ...Infrastructure (CNKI), Wanfang Databases were searched for appropriate articles. Randomized trials of RYR (not including Xuezhikang and Zhibituo) and placebo as control in patients with dyslipidemia were considered. Two authors read all papers and independently extracted all relevant information. The primary outcomes were serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The secondary outcomes were increased levels of alanine transaminase, aspartate aminotransferase, creatine kinase, creatinine and fasting blood glucose.
A total of 13 randomized, placebo-controlled trials containing 804 participants were analyzed. Red yeast rice exhibited significant lowering effects on serum TC WMD = -0.97 (95% CI: -1.13, -0.80) mmol/L, P<0.001, TG WMD = -0.23 (95% CI: -0.31, -0.14) mmol/L, P<0.001, and LDL-C WMD = -0.87 (95% CI: -1.03, -0.71) mmol/L, P<0.001 but no significant increasing effect on HDL-C WMD = 0.08 (95% CI: -0.02, 0.19) mmol/L, P = 0.11 compared with placebo. No serious side effects were reported in all trials.
The meta-analysis suggests that red yeast rice is an effective and relatively safe approach for dyslipidemia. However, further long-term, rigorously designed randomized controlled trials are still warranted before red yeast rice could be recommended to patients with dyslipidemia, especially as an alternative to statins.
We consider the problem of selecting the smoothing parameter by a data-driven method in adaptive testing of a parametric model against a nonparametric alternative model. Simulations show that our ...proposed procedure works well and outperforms existing approaches. We discuss extensions of our method to more general model specification testing problems including testing a parametric quantile function and testing nonparametric significance.
•We consider the problem of smoothing parameter selection in adaptive testing.•We combine the adaptive testing procedure with the LSCV method for a powerful test.•Simulations confirm that our proposed procedure outperforms the existing approaches.•Extensions to more general model specification testing problems are discussed.
Dissolved organic matter (DOM) greatly influences the transformation of nutrients and pollutants in the environment. To investigate the effects of pyrolysis temperatures on the composition and ...evolution of pyroligneous acid (PA)-derived DOM, DOM solutions extracted from a series of PA derived from eucalyptus at five pyrolysis temperature ranges (240–420 °C) were analysed with Fourier transform infrared spectroscopy, gas chromatography–mass spectroscopy, and fluorescence spectroscopy. Results showed that the dissolved organic carbon content sharply increased (p < 0.05) with an increase in pyrolysis temperature. Analysis of the dissolved organic matter composition showed that humic-acid-like substances (71.34–100%) dominated and other fluorescent components (i.e., fulvic-acid-like, soluble microbial by-products, and proteinlike substances) disappeared at high temperatures (>370 °C). The results of two-dimensional correlation spectroscopic analysis suggested that with increasing pyrolysis temperatures, the humic-acid-like substances became more sensitive than other fluorescent components. This study provides valuable information on the characteristic evolution of PA-derived DOM.
Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and ...premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies.
Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients.
Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients.
Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.
Familial hypercholesterolemia (FH) is a severe genetic hyperlipidemia characterized by increased levels of low-density lipoprotein cholesterol (LDL-C), leading to premature atherosclerosis. ...Angiopoietin-like protein (ANGPTL3) is a hepatocyte-specific protein that can be used to lower LDL in FH. However, it was unknown whether ANGPTL3 variants are present in FH patients. This study was performed to identify ANGPTL3 variants in unrelated Chinese Han patients with FH.
We screened 80 patients with FH (total cholesterol >7.8mmol/L, LDL-cholesterol >4.9mmol/L) and 77 controls using targeted next-generation sequencing (NGS) of six FH candidate genes (LDLR, ApoB100, PCSK9, ABCG5, ABCG8, and ANGPTL3). Candidate pathogenic variants identified by NGS were validated by Sanger sequencing. Mutant and wild-type plasmids containing the variant sequence were constructed and verified by Sanger sequencing. The gene expression profile was analyzed by an expression profile chip in transfected HepG2 cells using quantitative real-time (qRT)-PCR. We identified 41 variants in 28 FH patients, including two ANGPTL3 mutations: one exonic (c.A956G: p.K319R) and one in the untranslated region (c.*249G>A). Gene ontology analyses found that the cholesterol metabolic process and ANGPTL3 expression were significantly up-regulated in the ANGPTL3 K319R mutation group compared with the wild-type group. qRT-PCR findings were consistent with the expression profile analysis.
Rare ANGPTL3 variants were identified in Chinese patients with FH, including ANGPTL3: p.(Lys319Arg) which affected the expression of ANGPTL3 and the cholesterol metabolic process as determined by bioinformatics analysis.
Chinese Clinical Trial Registration (ChiCTR-ROC-17011027) http://www.chictr.org.cn/listbycreater.aspx.
Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence ...of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the in the ATP binding pocket form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.
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Background:
Diabetic cardiomyopathy (DCM), the main complication of diabetes mellitus, presents as cardiac dysfunction by ventricular remodeling. In addition, the inhibition of P2X7 purinergic ...receptors (P2X7R) alleviates cardiac fibrosis and apoptosis in Type 1 diabetes. However, whether exercise training improves cardiac remodeling by regulating P2X7R remains unknown.
Methods:
Db/db mice spontaneously induced with type 2 diabetes and high-fat diet (HFD) and mice with streptozotocin (STZ)-induced type 2 diabetes mice were treated by 12-week treadmill training. Cardiac functions were observed by two-dimensional echocardiography. Hematoxylin-eosin staining, Sirius red staining and transmission electron microscopy were respectively used to detect cardiac morphology, fibrosis and mitochondria. In addition, real-time polymerase chain reaction and Western Blot were used to detect mRNA and protein levels.
Results:
Studying the hearts of db/db mice and STZ-induced mice, we found that collagen deposition and the number of disordered cells significantly increased compared with the control group. However, exercise markedly reversed these changes, and the same tendency was observed in the expression of MMP9, COL-I, and TGF-β, which indicated cardiac fibrotic and hypertrophic markers, including ANP and MyHC expression. In addition, the increased Caspase-3 level and the ratio of Bax/Bcl2 were reduced by exercise training, and similar results were observed in the TUNEL test. Notably, the expression of P2X7R was greatly upregulated in the hearts of db/db mice and HFD + STZ-induced DM mice and downregulated by aerobic exercise. Moreover, we indicated that P2X7R knock out significantly reduced the collagen deposition and disordered cells in the DM group. Furthermore, the apoptosis levels and TUNEL analysis were greatly inhibited by exercise or in the P2X7R
−/−
group in DM. We found significant differences between the P2X7R
−/−
+ DM + EX group and DM + EX group in myocardial tissue apoptosis and fibrosis, in which the former is significantly milder. Moreover, compared with the P2X7R
−/−
+ DM group, the P2X7R
−/−
+ DM + EX group represented a lower level of cardiac fibrosis. The expression levels of TGF-β at the protein level and TGF-β and ANP at the genetic level were evidently decreased in the P2X7R
−/−
+ DM + EX group.
Conclusion:
Aerobic exercise reversed cardiac remodeling in diabetic mice at least partly through inhibiting P2X7R expression in cardiomyocytes.
(Jacq.) A.DC. root (PGR) flour is well known for its medical and edible values. In order to develop nutritionally fortified products, breads were prepared using wheat flour, partially replaced with ...PGR flour. The rheological properties and microstructure of dough and the physicochemical characterization of bread were investigated. Results showed that lower level of PGR addition (3 and 6 g/100 g) would improve the baking performance of breads, while the higher level of PGR addition (9 g/100 g) led to smaller specific volume (3.78 mL/g), increased hardness (7.5 ± 1.35 N), and unpalatable mouthfeel (21.8% of resilience and 92.6% of springiness) since its negative effect on the viscoelasticity and microstructure of dough. Moreover, sensory evaluation analysis also showed that the PGR3 and PGR6 breads exhibited a similar flavor to the control bread, but the 9 g/100 g addition of PGR provided bread with an unpleasant odor through its richer volatile components. As expected, the phenolic content and antioxidant capacity of bread increased significantly (
< 0.05) as PGR flour was added to the bread formulation. The total phenolic content (TPC) ranged from 14.23 to 22.36 g GAE/g; thus,
• and
•+ scavenging capacity increased from 10.44 and 10.06 μg Trolox/g to 14.69 and 15.12 μg Trolox/g, respectively. Therefore, our findings emphasized the feasibility of PGR flour partially replacing wheat flour in bread-making systems.
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