Alirocumab: PCSK9 inhibitor for LDL cholesterol reduction.

The proof of concept that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition affects cholesterol levels was first established after the demonstration that PCSK9 loss-of-function mutations result in a significant drop in circulating LDL cholesterol levels. Subsequent studies revealed that PCSK9 binds the epidermal growth factor precursor homology domain-A on the surface LDL Receptor (LDLR) and directs LDLR and PCSK9 for lysosomal degradation. Alirocumab (also known as SAR236553/REGN727) is a monoclonal antibody that binds circulating PCSK9 and blocks its interactions with surface LDLR.

Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians.

Aims: Why South Asians are at increased risk of premature atherosclerotic cardiovascular diseases compared with other ethnic groups is not fully understood. Atherogenic dyslipoproteinemia - hypertriglyceridemia, elevated numbers of low-density lipoprotein (LDL) particles and low high-density lipoprotein cholesterol (HDL-C) - is more common in South Asians but the mechanisms responsible have not been explicated. Here we examined whether the circulating lipid transfer protein, cholesteryl ester transfer protein (CETP), plays a role in the pathogenesis of the atherogenic dyslipoproteinemia among South Asians.

Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9.

Objectives: In this study, our goal was to determine if human resistin plays a role in regulating the uptake of atherogenic low-density lipoproteins in human hepatocytes.

Background: Serum levels of resistin, an adipose tissue-derived adipokine, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular diseases. However, the function of resistin in humans is enigmatic.

Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling.

Rationale: Obese individuals are at high risk for developing atherosclerosis primarily attributable to elevated plasma concentrations of apolipoprotein (apo)B-containing particles, including very-low-density lipoprotein (VLDL). Plasma levels of the adipose tissue adipokine resistin are increased in human obesity, and resistin expression is positively correlated with coronary atherosclerosis and VLDL levels.

Objective: We sought to determine for the first time whether resistin directly stimulates human hepatocyte production of apoB-containing particles and to elucidate the mechanisms responsible.

Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms.

Parasites from the protozoan phylum Apicomplexa are responsible for diseases, such as malaria, toxoplasmosis and cryptosporidiosis, all of which have significantly higher rates of mortality and morbidity in economically underdeveloped regions of the world. Advances in vaccine development and drug discovery are urgently needed to control these diseases and can be facilitated by production of purified recombinant proteins from Apicomplexan genomes and determination of their 3D structures. To date, both heterologous expression and crystallization of Apicomplexan proteins have seen only limited success.