Silvia Marchianò

Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants. Methods and Results From the historical cohort of the Brisighella Heart Study, after exclusion of active smokers, participants in secondary prevention for cardiovascular disease, and patients in treatment with statins or vasodilating agents, we selected 227 premenopausal women and 193 age‐matched men and 460 postmenopausal women and 416 age‐matched men. In these participants, we evaluated the correlation between PCSK9 plasma circulating levels and pulse wave velocity. Postmenopausal women showed higher PCSK9 levels (309.9±84.1 ng/mL) compared with the other groups (P<0.001). Older men had significant higher levels than younger men (283.2±75.6 versus 260.9±80.4 ng/mL; P=0.008). In the whole sample, pulse wave velocity was predicted mainly by age (B=0.116, 95% CI 0.96–0.127, P<0.001), PCSK9 (B=0.014, 95% CI 0.011–0.016, P<0.001), and serum uric acid (B=0.313, 95% CI 0.024–0.391, P=0.026). Physical activity, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and estimated glomerular filtration rate were not associated with pulse wave velocity (P>0.05).By considering the subgroups described, age and PCSK9 levels were mainly associated with pulse wave velocity, which also correlated with serum uric acid in postmenopausal women. Conclusions In the Brisighella Heart Study cohort, circulating PCSK9 is significantly related to arterial stiffness, independent of sex and menopausal status in women.

In vitro anticancer activity evaluation of new cationic platinum(II) complexes based on imidazole moiety

The development and the synthesis of cationic platinum(II) complexes were realized and their cytotoxic activity was tested on triple negative breast cancer MDA-MB-231 cell line and in two cell lines poorly responsive to cisplatin (DLD-1 and MCF-7). The complex 2c resulted the most potent cytotoxic agent in MDA-MB-231 (IC50=61.9µM) and more effective than cisplatin on both DLD-1 (IC50=57.4µM) and MCF-7 (IC50=79.9µM) cell lines. 2c showed different cellular uptake and pharmacodynamic properties than cisplatin, interfering with the progression of the M phase of the cell cycle. Thus, 2c represents a lead compound of a new class of cytotoxic agents with promising antitumor activity.

Development of poly(lactide‐co‐glycolide) nanoparticles functionalized with a mitochondria penetrating peptide

The development of mitochondria‐targeting cell permeable vectors represents a promising therapeutic approach for several diseases, such as cancer and oxidative pathologies. Nevertheless, access to mitochondria can be difficult. A new hybrid material composed by poly(lactide‐co‐glycolide) (PLGA) functionalized with a 6‐mer mitochondria penetrating peptide (MPP), consisting in alternating arginine and unnatural cyclohexylalanine, was developed. Circular dichroism, FT‐IR and DSC studies indicated that the conjugation of the peptide with the polymer led to the obtainment of a more rigid material with respect to both PLGA and MPP as such. In particular, a conformational rearrangement to a helical structure was observed for MPP. MPP–PLGA conjugates were used for the preparation of nanoparticles that showed no cytotoxicity in MTT assay, suggesting their putative use for future studies on mitochondria targeting. Copyright

A field-based disparity analysis of new 1,2,5-oxadiazole derivatives endowed with antiproliferative activity

A series of 1,2,5‐oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT‐116 cancer cell line. The field‐based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure–activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.

Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9

Background A beneficial effect on cardiovascular risk may be obtained by improving lipid-related serum lipoprotein functions such as high-density lipoproteins (HDLs) cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) and by reducing proprotein convertase subtilisin kexin type 9 (PCSK9), independently of lipoprotein concentrations. Aim We aimed to evaluate the effect of an innovative nutraceutical (NUT) combination containing red yeast rice (monacolin K 3.3 mg), berberine 531.25 mg and leaf extract of Morus alba 200 mg (LopiGLIK®), on HDL-CEC, serum CLC and on circulating PCSK9 levels. Materials and methods Twenty three dyslipidemic subjects were treated for 4 weeks with the above NUT combination. HDL-CEC was measured using specific cell-based radioisotopic assays; serum CLC and PCSK9 concentrations were measured fluorimetrically and by enzyme-linked immunosorbent assay, respectively. Results The NUT combination significantly reduced plasma level of the total cholesterol and low-density lipoprotein cholesterol (−9.8% and −12.6%, respectively). Despite no changes in HDL-cholesterol, the NUT combination improved total HDL-CEC in 83% of the patients, by an average of 16%, as a consequence of the increase mainly of the ATP-binding cassette A1-mediated CEC (+28.5%). The NUT combination significantly reduced serum CLC (−11.4%) while it did not change PCSK9 plasma levels (312.9±69.4 ng/mL vs 334.8±103.5 mg/L, before and after treatment, respectively). Conclusion The present NUT combination improves the serum lipoprotein functional profile providing complementary beneficial effects, without any detrimental increase of PCSK9 plasma levels.

Geranylgeraniol prevents the simvastatin-induced PCSK9 expression: Role of the small G protein Rac1

&NA; Statins are known to increase the plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) through the activation of the sterol responsive element binding protein (SREBP) pathway due to the inhibition of cholesterol biosynthesis. In the present study, we explore a possible role of the prenylated proteins on the statin‐mediated PCSK9 induction in Caco‐2 cells. Simvastatin (40 &mgr;M) induced both PCSK9 mRNA (10.7 ± 3.2 fold) and protein (2.2 ± 0.3 fold), after 24 h incubation. The induction of PCSK9 mRNA was partially, but significantly, prevented by the co‐incubation with mevalonate (MVA), farnesol (FOH) and geranylgeraniol (GGOH), while a complete prevention was observed on secreted PCSK9, evaluated by ELISA assay. Under the same experimental conditions, MVA, GGOH, but not FOH, prevented the activation of the PCSK9 promoter by simvastatin in a SRE‐dependent manner. Simvastatin reduced by −35.7 ± 15.2% the Rac1‐GTP levels, while no changes were observed on RhoA‐ and Cdc42‐GTP. This effect was prevented by MVA and GGOH. A Rac inhibitor, and N17Rac1 dominant negative mutant, significantly induced PCSK9 levels, and a suppression of Rac1 expression by siRNA, counteract the effect of simvastatin on the induction of PCSK9 mRNA. Finally, simvastatin, and Rac inhibitor inhibited the nuclear translocation of STAT3 and its knock‐down by siRNA increased significantly the susceptibility of Caco‐2 to simvastatin on PCSK9 expression. Taken together, the present study reveal a direct role of Rac1 on simvastatin‐mediated PCSK9 expression via the reduction of STAT3 nuclear translocation. Graphical abstract Figure. No caption available.