The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A

Peer reviewedPublisher PD

Apoptosis of Platelets Inhibited By Herba Sarcandrae Extract through the Mitochondria Pathway

The purpose of the present study is to decode the underlying mechanism of Herba Sarcandrae that indicated antipurpuric effect and to unveil one of its primary components, flavonoids, which play an important role. An immune mediated bone marrow failure (BMF) model in mouse was established by infusion thymus suspension cells after radiation in vivo. Platelets isolated in vitro were prepared from normal mice and BMF mice, respectively. The expressions of PS, P-selectin, PAC-1, Bax, Bad, Bid, and caspase-9 were examined by flow cytometry, and alteration of morphology of platelets under different conditions was observed. Our results indicated that the number of platelets was increased by addition of total flavonoids, and some of apoptotic markers such as Bax, Bad, Bid, and Caspase-9 were downregulated. In addition, the phosphatidylserine (PS) exposure on platelets was inhibited by total flavonoids, and the expressions of PAC-1 and P-selectin were decreased. In conclusion, it is suggested that the total flavonoids of Herba Sarcandrae may inhibit the excessive platelet apoptosis through mitochondrial pathway. In addition, activation of platelets may be also involved in mediating apoptosis of platelets

Effect of Yi Gong San Decoction on Iron Homeostasis in a Mouse Model of Acute Inflammation

We investigated the effect of Yi Gong San (YGS) decoction on iron homeostasis and the possible underlying mechanisms in a mouse model of acute inflammation in this study. Our findings suggest that YGS regulates iron homeostasis by downregulating the level of HAMP mRNA, which may depend on regulation of the IL-6/STAT3 or BMP/HJV/SMAD pathway during acute inflammation

Residual Risk of Trimethylamine‐N‐Oxide and Choline for Stroke Recurrence in Patients With Intensive Secondary Therapy

Background Trimethylamine N‐oxide (TMAO) contributes to cardiovascular disease through its prothrombotic, proatherothrombotic, and proinflammatory effects. We aimed to evaluate whether residual risk of recurrent stroke of TMAO and its precursor choline remain among patients who received dual‐antiplatelet therapy and intensive lipid‐lowering therapy and with a low inflammation level (high‐sensitivity C‐reactive protein <2 mg/L on admission). Methods and Results Patients with ischemic stroke or transient ischemic attack were enrolled from the CNSR‐III (Third China National Stroke Registry) in China. Plasma TMAO and choline concentrations at baseline were measured in 9793 participants using liquid chromatography–mass spectrometry. The primary outcome was a new stroke within 1 year. Multivariable‐adjusted hazard ratios were calculated using Cox regression models to investigate the associations of TMAO and choline with stroke recurrence. Among all patients, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke (adjusted hazard ratios, 1.28 [95% CI, 1.12–1.45]; and 1.50 [95% CI, 1.32–1.71], respectively). Moreover, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke among patients who received dual‐antiplatelet therapy (1.65 [95% CI, 1.28–2.13]; and 1.70 [95% CI, 1.32–2.19], respectively), intensive lipid‐lowering therapy (1.49 [95% CI, 1.15–1.94]; and 1.49 [95% CI, 1.15–1.92], respectively), with high‐sensitivity C‐reactive protein <2 mg/L (1.39 [95% CI, 1.14–1.69]; and 1.88 [95% CI, 1.53–2.30], respectively), and concurrently received dual‐antiplatelet therapy, intensive lipid‐lowering therapy and with high‐sensitivity C‐reactive protein <2 mg/L (3.57 [95% CI, 1.73–7.38]; and 2.19 [95% CI, 1.16–4.16], respectively). Conclusions TMAO and choline were risk factors for recurrent stroke independent of dual‐antiplatelet therapy, intensive lipid‐lowering therapy at discharge, and low inflammation on admission

Endogenous cholesterol ester hydroperoxides modulate cholesterol levels and inhibit cholesterol uptake in hepatocytes and macrophages

Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD. Keywords: Cholesterol/metabolism, LDL oxidation, Lipidomics, CVD, Cholesterol ester hydroperoxides, Cholesterol uptake, Lipid peroxidation, LXR, LDL