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ObjectiveThis study aimed to assess the association between triglyceride-glucose (TyG) index/homeostasis model assessment-insulin resistance (HOMA-IR) within young adults and congestive heart failure (CHF), and to explore whether TyG index can replace HOMA-IR as a surrogate marker for IR in predicting the risk of CHF.MethodsA total of 4,992 participants between the ages of 18 and 30 years were enrolled from the Coronary Artery Risk Development in Young Adults (CARDIA) investigation [from 1985 to 1986 (year 0)]. A Cox proportional hazard regression analysis was conducted for assessing correlations between baseline TyG index/HOMA-IR and CHF events, together with the receiver operating characteristic (ROC) curve employed for scrutinizing TyG index/HOMA-IR and the risk of CHF.ResultsDuring the 31-year follow-up period, 64 (1.3%) of the 4,992 participants developed CHF. In multivariable Cox proportional hazards models, adjusted for confounding factors for CHF, an increased risk of CHF was associated with a per-unit increase in the TyG index [hazard ratio (HR) 2.8; 95% confidence interval (CI), 1.7–4.7] and HOMA-IR (HR 1.2; 95% CI, 1.1–1.3). A Kaplan–Meier curve analysis showed that participants in the TyG index and HOMA-IR index Q4 group had a higher risk of CHF than those in the Q1 group. The area under curve (AUC) for the TyG index and HOMA-IR consisted of 0.67 (95% CI, 0.6–0.742) and 0.675 (95% CI, 0.604–0.746), respectively. There were no significant differences between the TyG index and HOMA-IR for AUC (p = 0.986).ConclusionThe higher TyG index and HOMA-IR are independent risk factors for CHF. The TyG index can replace HOMA-IR in young adulthood as a surrogate marker for IR to predict the risk of CHF.

Ligustilide is a phenolic compound isolated from Asian plants of Umbelliferae family. This study was aimed at exploring the neuroprotective effects of Ligustilide from the perspective of endoplasmic reticulum stress (ERS) and autophagy. The Alzheimer's disease (AD) cell models were constructed by SH-SY5Y cell line, which was exposed to 20 μM Aβ25-35 . CCK-8 was used to evaluate the cell viability of Ligustilide on AD cell model. Hoechst staining and LysoTracker Red were used to test the cell apoptosis and Lysosome function, respectively. ERS in living cells were detected by Thioflavin T. The expression of autophagy-related proteins (LC3B-II/I, P62/SQSTM1, Beclin1, and Atg5), ERS marker proteins (PERK, GRP78, and CHOH), and apoptosis proteins (Bax, Bcl-2, and Caspase-12) were analyzed by Western blot analyses. Aβ25-35 could induce ERS and autophagy in a time-dependent manner in SH-SY5Y cells. We demonstrated that Ligustilide significantly decreased the rate of apoptosis, and improved the viability of cells. Simultaneously, Ligustilide effectively modulated ERS via inhibiting the over-activation of GRP78/PERK/CHOP signaling pathway. In addition, Ligustilide alleviated the accumulation of autophagy vacuoles, reduced the ratio of LC3B-II/I and the level of P62/SQSTM1. Ligustilide significantly up-regulated lysosomal acidity and the expression of Cathepsin D (CTSD). Ligustilide could rescue lysosomal function to promote autophagy flux and inhibit the over-activation of ERS. This finding may contribute to the development of new therapeutic strategies for AD.

Introduction: Cell senescence has been identified as an impact etiological factor in cardiovascular diseases, as well as calcific aortic valve disease (CAVD) . In our previous experiment results, We found that a large number of senescent aortic valve interstitial cells (AVIC) accumulated in the calcific aortic valve tissues, especially around the calcification sites. But the role and mechanism of cellular senescence in the development of calcified aortic stenosis have not been clarified. We hypothesized valvular interstitial cell senescence sensitize interstitial cell for osteogenic response through enhancing cell senescence associated epigenetic modification. Methods and Results: Representative immunofluorescence results of the clinical samples show that p16INK4A positive cells in the calcific aortic valve expressed more osteogenic associated factors, such as Runx2 and BMP2. And RAS system hyperactivation seemed to be an impact association with aortic valve calcification. Then we found Angiotensin II (1μM, 72h) chronic irritation induces valve interstitial cell senescence associated secretion phenotype (SASP) and activates osteogenic response through ERK1/2 and NF-κB pathway. ChIP-qPCR results demonstrated H3K9Me3 modifications on the promoters of Runx2, ACTA2(also known as α-SMA), IL-6, IL-8, MCP-1 were significantly decreased in angiotensin II pretreated AVIC. Blockage of angiotensin II and ABT-263 pretreatment inhibited valvular interstitial cell to convert into osteoblast-like phenotype induced by Angiotensin II, as well as attenuating senescence associated secretion phenotype factors yield. Blockage of angiotensin II receptor and p16 INK4A knockdown contributed to recover H3K9me3 modification on the promoters of those gene in angiotensin II pretreated AVIC through attenuating angiotensin II-induced ubiquitination degradation of SUV39H1. Conclusion: p16 INK4A mediated H3K9me3 decline sensitizes aortic valvular interstitial cell for osteogenic response, which impacts on aortic valve homeostasis and aortic valve calcification. Taken together, p16 INK4A positive senescent cells would be the potential target on prevention and treatment of calcific aortic valve disease.

The details of Toll-like receptor (TLR) 4 signaling affects protein succinylation in intracerebral hemorrhage (ICH) brains remains completely unclear. In this study, we constructed mice ICH models to investigate the changes in ICH-associated brain protein succinylation with the treatment of TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized a concentration of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase in 29 succinyllysine sites of 28 succinylated proteins and reduction of 24 succinyllysine sites on 23 succinylated proteins in ICH brains. Both the TAK242 treatment induced hypersuccinylated and hyposuccinylated proteins in ICH brains were mainly located in mitochondria and cytoplasm. GO analysis showed that TAK242 treatment induced changes in ICH-associated succinylated proteins were mostly located in synapse, membrane, vesicle, etc., and enriched in many processes, such as metabolism, synapse, myeline, etc.. KEGG analysis showed that TAK242 induced downregulation of succinylation was significantly linked to fatty acid metabolism and lysosome. Moreover, a combination analysis of our succinylproteomic data with previously published transcriptome data identified that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed into neurons, astrocytes and endothelial cells; and 7 and 3 of these succinylated proteins significantly high express in neurons and astrocytes, respectively. In conclusion, our analyses uncover a number of TLR4 signaling affected succinylation processes and pathways in mouse ICH brains and provide new insights for understanding ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

Autophagy serves an important role in amyloid-β (Aβ) metabolism and τ processing and clearance in Alzheimer's disease. The progression of Aβ plaque accumulation and hyperphosphorylation of τ proteins are enhanced by oxidative stress. A hydrogen peroxide (H2O2) injury cell model was established using SH-SY5Y cells. Cells were randomly divided into normal, H2O2 and chlorogenic acid (5-caffeoylquinic acid; CGA) groups. The influence of CGA on cell viability was evaluated using a Cell Counting Kit-8 assay and cell death was assessed using Hoechst 33342 nuclear staining. Autophagy induction and fusion of autophagic vacuoles assays were performed using monodansylcadaverine staining. Additionally, SH-SY5Y cells expressing Ad-mCherry-green fluorescent protein-LC3B were established to detect autophagic flow. LysoTracker Red staining was used to evaluate lysosome function and LysoSensor™ Green staining assays were used to assess lysosomal acidification. The results demonstrated that CGA decreased the apoptosis rate, increased cell viability and improved cell morphology in H2O2-treated SH-SY5Y cells. Furthermore, CGA alleviated the accumulation of autophagic vacuoles, reduced the LC3BII/I ratio and decreased P62 levels, resulting in increased autophagic flux. Additionally, CGA upregulated lysosome acidity and increased the expression levels of cathepsin D. Importantly, these effects of CGA on H2O2-treated SH-SY5Y cells were mediated via the mTOR-transcription factor EB signaling pathway. These results indicated that CGA protected cells against H2O2-induced oxidative damage via the upregulation of autophagosomes, which promoted autophagocytic degradation and increased autophagic flux.

Supplemental material, sj-docx-1-taj-10.1177_20406223211056730 for Efficacy and safety of antithrombotic therapy with non-vitamin K antagonist oral anticoagulants after transcatheter aortic valve replacement: a systematic review and meta-analysis by Qing An, Shuwen Su, Yan Tu, Lingfeng Gao, Gaopeng Xian, Yujia Bai, Qiong Zhan, Xingbo Xu, Dingli Xu and Qingchun Zeng in Therapeutic Advances in Chronic Disease

Increasing demand for DRAM scaling and high-bandwidth has driven DRAM technology to 3D/2.5D integration. With the innovative Hybrid Bonding technology, a new Stacked Embedded DRAM (SEDRAM) architecture was developed on LPDDR4/4X product. In this SEDRAM, a DRAM array wafer and logic wafer were fabricated separately and then face-to-face fusion connected through ultra-high-density, low-resistance Hybrid Bonding. By separating the control, I/O, DFT and periphery circuits to a logic die, SEDRAM offers a novel approach to DRAM product development and accomplishes an extremely high-bandwidth logic-to-memory interface speed of 34GBps per 1Gb with low power consumption as low as 0.88pJ/bit.