Lipoprotein(a) in atherosclerotic cardiovascular disease and proprotein convertase subtilisin/kexin-type 9 inhibitors.

High plasma lipoprotein(a) (Lp(a)) levels increase the cardiovascular risk in populations with atherosclerotic cardiovascular disease (ASCVD). Apolipoprotein (a) [apo(a)], a unique protein component of Lp(a), plays an important role in the pathogenesis of atherosclerosis. Statins, the primary medication in managing ASCVD, lower low-density lipoprotein cholesterol (LDL-C) but concurrently elevate plasma Lp(a) levels, contributing to an increased residual cardiovascular risk. In turn, proprotein convertase subtilisin/kexin-type 9 (PCSK9) inhibitors, a novel class of LDL-C lowering drugs, effectively reduce plasma Lp(a) levels, which is believed to decrease residual cardiovascular risk. However, the mechanism by which PCSK9 inhibitors reduce Lp(a) levels remains unknown. In addition, there are some clinical limitations of PCSK9 inhibitors. Here, we systematically review the past, present, and prospects of studies pertaining to Lp(a), PCSK9 inhibitors, and ASCVD.

A Rare Case of Isolated Right Ventricular Non-compaction With the Novel TTN Mutation.

Isolated right ventricular non-compaction (RVNC) is rare yet life-threatening if left untreated, especially when accompanied by ventricular tachycardia. We describe a rare case of isolated RVNC, presenting as a prominent and excessive trabeculation of the right ventricle (RV), with an abnormal electrocardiogram. The transthoracic echocardiography, computed tomography, and ventricular angiography results clearly demonstrated an isolated spongy RV, both anatomically and functionally. Genetic testing identified a missense mutation of TTN. Combined, the diagnosis of RVNC was established. The subsequent combination of heart failure therapy, antiarrhythmic, and anticoagulation therapy were effective with a favorable outcome. This case report describes the possible etiology, manifestation, characteristic images, and problematic diagnostic criteria of the isolated RVNC. This case also emphasizes the necessity for comprehensive cardiac screening in familial cardiomyopathy.

Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine.

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.

Lipophilic Constituents in Salvia miltiorrhiza Inhibit Activation of the Hepatic Stellate Cells by Suppressing the JAK1/STAT3 Signaling Pathway: A Network Pharmacology Study and Experimental Validation.

Liver fibrosis is currently a global health challenge with no approved therapy, with the activation of hepatic stellate cells being a principal factor. Lipophilic constituents in Salvia miltiorrhiza (LS) have been reported to improve liver function and reduce the indicators of liver fibrosis for patients with chronic hepatitis B induced hepatic fibrosis. However, the pharmacological mechanisms of LS on liver fibrosis have not been clarified. In this study, 71 active compounds, 342 potential target proteins and 22 signaling pathways of LS were identified through a network pharmacology strategy. Through text mining and data analysis, the JAK1/STAT3 signaling pathway was representatively selected for further experimental validation. We firstly confirmed the protective effect of LS on liver fibrosis in vivo by animal experiments. Hepatic stellate cells, which proliferated and displayed a fibroblast-like morphology similar to activated primary stellate cells, were applied to evaluate its underlying mechanisms. The results showed that LS could inhibit the cell viability, promote the cell apoptosis, decrease the expression of liver fibrosis markers, and downregulate the JAK1/STAT3 signaling pathway. These results demonstrated that LS could exert anti-liver-fibrosis effects by inhibiting the activation of HSCs and regulating the JAK1/STAT3 signaling pathway, which is expected to benefit its clinical application.

Sesquiterpenoids from the roots of Daphne genkwa Siebold et Zucc. With potential anti-inflammatory activity.

Six undescribed sesquiterpenoids, including three acorane-type sesquiterpenoids (daphneaines A-C), three guaiane-type sesquiterpenoids (daphneaines E-G) and three known analogues were isolated from the roots of Daphne genkwa Siebold et Zucc. Their gross structures were elucidated by comprehensive spectroscopic analyses. The relative configurations of daphneaines A-C were determined by NOESY experiments. In addition, the relative configuration of daphneaine G was elucidated by performing a quantum chemical calculation of the NMR chemical shifts coupled with an advanced statistical procedure DP4+. The comparison of experimental and calculated electronic circular dichroism (ECD) data led to the establishment of the absolute configurations of daphneaines A-G. All isolates were tested for their inhibitory activity towards the LPS-induced NO production in RAW 264.7 macrophages, and daphneaine F showed inhibitory effect on NO production with an IC50 value of 35.68 ± 3.18 µM.