Effects of L- and D-REKR amino acid-containing peptides on HIV and SIV envelope glycoprotein precursor maturation and HIV and SIV replication.

The aim of the present study was to evaluate the capacity of synthetic l- and d-peptides encompassing the HIV-1(BRU) gp160 REKR cleavage site to interfere with HIV and simian immuno-deficiency virus (SIV) replication and maturation of the envelope glycoprotein (Env) precursors. To facilitate their penetration into cells, a decanoyl (dec) group was added at the N-terminus. The sequences synthesized included dec5d or dec5l (decREKRV), dec9d or dec9l (decRVVQREKRV) and dec14d or dec14l (TKAKRRVVQREKRV). The peptide dec14d was also prepared with a chloromethane (cmk) group as C-terminus. Because l-peptides exhibit significant cytotoxicity starting at 35 microM, further characterization was conducted mostly with d-peptides, which exhibited no cytotoxicity at concentrations higher than 70 microM. The data show that only dec14d and dec14dcmk could inhibit HIV-1(BRU), HIV-2(ROD) and SIV(mac251) replication and their syncytium-inducing capacities. Whereas peptides dec5d and dec9d were inactive, dec14dcmk was at least twice as active as peptide dec14d. At the molecular level, our data show a direct correlation between anti-viral activity and the ability of the peptides to interfere with maturation of the Env precursors. Furthermore, we show that when tested in vitro the dec14d peptide inhibited PC7 with an inhibition constant K(i)=4.6 microM, whereas the peptide dec14l preferentially inhibited furin with a K(i)=28 microM. The fact that PC7 and furin are the major prohormone convertases reported to be expressed in T4 lymphocytes, the principal cell targets of HIV, suggests that they are involved in the maturation of HIV and SIV Env precursors

Pre-operative levels of angiopoietin protein-like 3 (ANGPTL3) in women diagnosed with high-grade serous carcinoma of the ovary

Abstract Cancer cells need constant supplies of lipids to survive and grow. Lipid dependence has been observed in various types of cancer, including high-grade serous ovarian carcinomas (HGSOC), which is a lethal form of gynecological malignancy. ANGPTL3, PCSK9, and Apo CIII are pivotal lipid-modulating factors, and therapeutic antibodies have been developed against each one (Evinacumab, Evolocumab and Volanesorsen, respectively). The roles -if any- of ANGPTL3, PCSK9, and Apo CIII in HGSOC are unclear. Moreover, levels of these lipid-modulating factors have never been reported before in HGSOC. In this study, circulating levels of ANGPTL3, PCSK9, and Apo CIII, along with lipid profiles, are examined to verify whether one or many of these lipid-regulating factors are associated with HGSOC. Methods ELISA kits were used to measure ANGPTL3, PCSK9 and Apo CIII levels in plasma samples from 31 women with HGSOC and 40 women with benign ovarian lesions (BOL) before treatment and surgery. A Roche Modular analytical platform measured lipid panels, Apo B and Lp(a) levels. Results ANGPTL3 levels were higher in women with HGSOC (84 ng/mL, SD: 29 ng/mL, n = 31) than in women with BOL (67 ng/mL, SD: 31 ng/mL, n = 40; HGSOC vs. BOL P = 0.019). Associations between the lipid panel and ANGPTL3, and the inverse relationship between HDL-cholesterol and triglycerides, were present in women with BOL but not with HGSOC. PCSK9 and Apo CIII were not associated with HGSOC. Conclusions In this cohort of 71 women, ANGPTL3 levels were increased in HGSOC patients. The presence of HGSOC disrupted the classic inverse relationship between HDL and triglycerides, as well as the association between the lipid panel and ANGPTL3. These associations were only maintained in cancer-free women. Given the availability of Evinacumab, a therapeutic antibody against ANGPTL3, the current finding prompts an assessment of whether ANGPTL3 inhibition has therapeutic potential in HGSOC

Additional file 1 of Pre-operative levels of angiopoietin protein-like 3 (ANGPTL3) in women diagnosed with high-grade serous carcinoma of the ovary

Additional file 1: Fig. S1. Flow chart of analyses performed on the study population. Fig. S2. Pairwise Spearman’s partial correlation analyses between all variables, with age-adjustment. Partial correlations based on age-adjustment are presented for (A) benign ovarian lesions (BOL), (B) high-grade serous ovarian carcinoma (HGSOC) and (C) the entire cohort (overall). Correlation coefficients (rho) are displayed in each matrix lower half-panel with color hues indicative of relationship strength (see rho coefficient scale). Correlation significance is expressed in upper half-panel (ns: non-significant, *: P < 0.05; **: P < 0.01; ***: P < 0.001; ****: P < 0.000 1). Fig. S3. CA125 and HE4 plasma levels between BOL and HGSOC. Significant level increase of tumor markers CA125 (BOL: n = 40, HGSOC: n = 31, P = 1.4E-7) and HE4 (BOL: n = 38, HGSOC: n = 23, P = 2.2E-7) was found in HGSOC compared to BOL. ****: P < 0.000 1

Variation in serum PCSK9 (proprotein convertase subtilisin/kexin type 9), cardiovascular disease risk, and an investigation of potential unanticipated effects of PCSK9 inhibition

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce serum LDL (low-density lipoprotein) cholesterol (LDL-C) by increasing uptake in the liver. Although some long-term trials have evaluated their safety, broad investigations of outcomes over the lifetime, leveraging genetic variation in serum PCSK9, have seldomly been conducted. We investigated effects of these variants on a range of outcomes to explore unanticipated effects of long-term PCSK9 inhibition

Variation in serum PCSK9 (proprotein convertase subtilisin/kexin type 9), cardiovascular disease risk, and an investigation of potential unanticipated effects of PCSK9 inhibition

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce serum LDL (low-density lipoprotein) cholesterol (LDL-C) by increasing uptake in the liver. Although some long-term trials have evaluated their safety, broad investigations of outcomes over the lifetime, leveraging genetic variation in serum PCSK9, have seldomly been conducted. We investigated effects of these variants on a range of outcomes to explore unanticipated effects of long-term PCSK9 inhibition