Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9.

Annexin A2 (AnxA2) was reported to be an extracellular endogenous inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9) activity on cell-surface LDL receptor degradation. In this study, we investigated the effect of silencing the expression of AnxA2 and PCSK9 in HepG2 and Huh7 cells to better define the role of AnxA2 in PCSK9 regulation. AnxA2 knockdown in Huh7 cells significantly increased PCSK9 protein levels as opposed to AnxA2 knockdown in HepG2 cells.

The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells.

The proprotein convertases (PCs) play an important role in protein precursor activation through processing at paired basic residues. However, significant substrate cleavage redundancy has been reported between PCs. The question remains whether specific PC inhibitors can be designed.

Molecular Validation of PACE4 as a Target in Prostate Cancer.

Prostate cancer remains the single most prevalent cancer in men. Standard therapies are still limited and include androgen ablation that initially causes tumor regression. However, tumor cells eventually relapse and develop into a hormone-refractory prostate cancer.

Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity.

Angiopoietin-like protein 4 (ANGPTL4) has been associated with a variety of diseases. It is known as an endogenous inhibitor of lipoprotein lipase (LPL), and it modulates lipid deposition and energy homeostasis. ANGPTL4 is cleaved by unidentified protease(s), and the biological importance of this cleavage event is not fully understood with respect to its inhibitory effect on LPL activity.

Selective and potent furin inhibitors protect cells from anthrax without significant toxicity.

Furin and related proprotein convertases cleave the multibasic motifs R-X-R/K/X-R in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides. Furin is present both in the intracellular secretory pathway and at the cell surface. Intracellular furin processes its multiple normal cellular targets in the Golgi and secretory vesicle compartments while cell-surface furin appears to be essential only for the processing of certain pathogenic proteins and, importantly, anthrax.

Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.

Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer, and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporating decarboxylated arginine mimetics in the P1 position of substrate analogue peptidic inhibitors, we could identify highly potent furin inhibitors.

Regulation of C/EBPdelta-dependent transactivation by histone deacetylases in intestinal epithelial cells.

The C/EBPdelta transcription factor is involved in the positive regulation of the intestinal epithelial cell acute phase response. C/EBPdelta regulation by histone deacetylases (HDACs) during the course of inflammation remains to be determined. Our aim was to examine the effect of HDACs on C/EBPdelta-dependent regulation of haptoglobin, an acute phase protein induced in intestinal epithelial cells in response to pro-inflammatory cytokines.

Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.

Objective: To reassess the comparative efficacy of vancomycin versus metronidazole in the treatment of Clostridium difficile-associated disease (CDAD) after the emergence in 2003 of the hypervirulent NAP1/027 strain.

Methods: A retrospective cohort study was conducted in a tertiary-care Canadian hospital among 1,616 patients treated initially with metronidazole (N=1,360), vancomycin (N=219), or both (N=37), between 1991 and 2006, and followed for 60 days after diagnosis. Primary outcome was severe/complicated CDAD (SC-CDAD) defined as any of: (a) death within 30 days, (b) septic shock, (c) megacolon, (d) perforation, or (e) emergency colectomy.

Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada.

Background: During an epidemic of Clostridium difficile-associated disease (CDAD) caused by a strain that is a hyper-producer of toxins A and B, the frequency of a first recurrence after metronidazole treatment of the initial episode doubled in 2003-2004, compared with 1991-2002.

Methods: To examine whether administration of metronidazole as treatment for a first recurrence of CDAD remained appropriate, we reviewed data for patients with CDAD diagnosed in a hospital in Quebec, Canada, during 1991-2005, who experienced a first recurrence. The frequency of a second recurrence within 60 days after the first one was measured using Kaplan-Meier analysis.