Naturally Occurring PCSK9 Inhibitors

Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described

Changes in the atmospheric circulation conditions and regional climatic characteristics in two remote regions since the mid-20th century

A meridional Northern Hemisphere (NH) circulation epoch, which began in 1957, is marked by changes in the temperature and precipitation regimes over southwest Russia and central USA depending on the occurrence of NH atmospheric circulation regimes. A classification scheme proposed in 1968, and studied later put forth 13 NH circulation types, fitting more broadly into four groups, two of which are more zonal type flows and two of which are more meridional flows. Using the results of a previous study that showed four distinct sub-periods during the 1957-2017 epoch, the temperature and precipitation regimes of both regions were studied across all seasons in order to characterize modern day climate variability and their suitability for vegetation growth. Then the Hydrologic Coefficient, which combined the temperature and precipitation variables, was briefly studied. The most optimal conditions for vegetation growth, positive temperature and precipitation anomalies, were noted during the period 1970-1980 for southwest Russia, which was dominated by an increasingly more zonal flow regime in the Belgorod region and NH in general. For the central USA, the HTC showed more ideal conditions for agriculture in recent years due to favorable precipitation occurrence. In southwest Russia, variable precipitation regimes were noted during the meridional flow periods, and with the increase in temperature (since 1998), these can adversely affect the hydrothermal characteristics of the growing season. Finally, a comparison of the 13 NH circulation types with several teleconnection indexes demonstrated the robustness of the NH flow regime classification scheme used here

In-Vivo Expansion of T Regulatory Cells by Rapamycin in a Calcineurin-Inhibitor Free GVHD Prophylaxis in Unmanipulated Haploidentical Stem Cell Transplantation (SCT)

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From lipoprotein apheresis to proprotein convertase subtilisin/kexin type 9 inhibitors: Impact on low-density lipoprotein cholesterol and C-reactive protein levels in cardiovascular disease patients

In this observational study, we compared the effect of lipoprotein apheresis and evolocumab or alirocumab on levels of lipoprotein cholesterol, triglycerides and inflammatory markers (C reactive protein and interleukin 6) in cardiovascular patients (n1\u204449). Patients were monitored during the last year of lipoprotein apheresis followed by six months of treatment with proprotein convertase subtilisin/kexin type 9 inhibitors. The biochemical parameters were determined pre- and post- every apheresis procedure for 12 months and then after one, three and six months of treatment with evolocumab (140mg every two weeks [Q2W]) or alirocumab (75mg or 150mg every two weeks [Q2W]). Lipoprotein apheresis significantly reduced low-density lipoprotein cholesterol levels from 138 32 mg/dl to 4616mg/dl (p<0.001), with an inter-apheresis level of 11426mg/dl. Lipoprotein(a) was also reduced from a median of 42 mg/dl to 17 mg/dl (p < 0.01). Upon anti-proprotein convertase subtilisin/kexin type 9 therapy, low-density lipoprotein cholesterol levels were similar to post-apheresis (59 25, 41 22 and 42 21mg/dl at one, three and six months, respectively) as well as those of lipoprotein(a) (18 mg/dl). However, an opposite effect was observed on high- density lipoprotein cholesterol levels: \u201316.0% from pre- to post-apheresis and \ufe34.0% between pre-apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors. Apheresis significantly reduced high-sensitivity C-reactive pro- tein levels (1.5 1.2 mg/l pre-apheresis to 0.6 0.6 mg/l post-apheresis), while no changes were found upon proprotein convertase subtilisin/kexin type 9 mAbs administration. In conclusion, our study demonstrated that, by switching from lipoprotein apheresis to anti-proprotein convertase subtilisin/kexin type 9 therapies, patients reached similar low-density lipoprotein cholesterol and lipoprotein(a) levels, increased those of high-density lipoprotein cholesterol, and showed no changes on high-sensitivity C-reactive protein

Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: new therapeutic approaches for the treatment of atherogenic dyslipidemia

Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile

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

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\ua0\u3bcM) induced both PCSK9 mRNA (10.7\ua0\ub1\ua03.2 fold) and protein (2.2\ua0\ub1\ua00.3 fold), after 24\ua0h 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 1235.7\ua0\ub1\ua015.2% 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

PCSK9 Levels Are Raised in Chronic HCV Patients with Hepatocellular Carcinoma

Background: Since emerging evidence suggests a protective role of proprotein convertase subtilisin/kexin type 9 (PCSK9) on hepatitis C virus (HCV) infection, the aim of the present study was to evaluate the correlation between PCSK9 and HCV infection in hepatocellular carcinoma (HCC) patients. Methods: In this retrospective study, PCSK9 levels were evaluated by ELISA, in plasma samples from control (n = 24) and 178 patients diagnosed for HCC, cirrhosis, or chronic hepatitis, either positive or negative for HCV. Results: HCV positive patients (HCV+) presented with higher PCSK9 levels compared to HCV negative individuals (HCV-), 325.2 \ub1 117.7 ng/mL and 256.7 \ub1 139.5 ng/mL, respectively. This difference was maintained in the presence of HCC, although this disease significantly reduced PCSK9 levels. By univariate analysis, a positive correlation between PCSK9 and HCV viral titer was found, being G2 genotype the most-potent inducer of PCSK9 among other genotypes. This induction was not associated with changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). A negative correlation was also found between PCSK9 levels and liver impairment, assessed by Model for End-Stage Liver Disease (MELD). Finally, a multivariate correlation analysis corrected for age, TC, LDL-C, and sex, demonstrated, in the whole cohort, a positive association between PCSK9 and HCV and a negative with HCC. Conclusions: taken together, our study reveals that HCV raised PCSK9 in both the presence and absence of HCC

Impact of bariatric surgery-induced weight loss on circulating PCSK9 levels in obese patients

Background and aims: To investigate the effect of obesity and bariatric-induced weight loss on circulating levels of proprotein convertase subtilisin/kexin 9 (PCSK9) in severely obese patients. Methods and results: In this non-randomized interventional study, we enrolled 36 severely obese patients (BMI 43.7 \ub1 5.6 kg/m2), of which 20 underwent bariatric surgery, and 12 nonobese healthy controls. An oral glucose tolerance test (75-g OGTT) was performed in 31 of these obese patients at baseline (T0) and in 14 patients at 6 months after bariatric surgery (T6) to assess plasma glucose, insulin and PCSK9 levels. Plasma PCSK9 levels were also measured in 18 of these obese patients at T0 during a 2-h hyperinsulinemic-euglycemic clamp (HEC). At T0, PCSK9 levels were higher in obese patients than in controls (274.6 \ub1 76.7 ng/mL vs. 201.4 \ub1 53.3 ng/mL) and dropped after bariatric surgery (T6; 205.5 \ub1 51.7 ng/mL) along with BMI (from 44.1 \ub1 5.9 kg/m2 to 33.1 \ub1 5.6 kg/m2). At T6, there was also a decrease in plasma glucose (T0 vs. T6: 6.0 \ub1 1.8 vs. 5.0 \ub1 0.5 mmol/L) and insulin (15.7 \ub1 8.3 vs. 5.4 \ub1 2.1 mU/L) levels. At T0, plasma PCSK9 levels decreased during OGTT in obese patients, reaching a nadir of 262.0 \ub1 61.4 ng/mL at 120 min with a hyperinsulinemic peak of 75.1 \ub1 40.0 mU/L, at 60 min. Similarly, at T0 insulin infusion during 2-h HEC acutely reduced plasma PCSK9 levels in obese patients. The aforementioned OGTT-induced changes in plasma PCSK9 levels were not observed neither in nonobese healthy controls nor in obese patients after bariatric-surgery weight loss. Conclusions: These results suggest a pivotal role of adipose tissue and insulin resistance on PCSK9 homeostasis in severely obese patients

Identification of patients with defects in the globin genes:a case report

INTRODUCTION: hemoglobinopathies constitute a major health problem worldwide. These disorders are characterized by a clinical and hematological phenotypic heterogeneity. The increase of HbA2 is an invaluable hematological marker of the beta-thalassemia heterozygosis and of double heterozygosis for the alleles of delta and alpha globin genes or for the alleles of delta and beta globin genes which can cause the increase of HbA2 up to normal or borderline values. CASE REPORT: we report the case of a 30-year-old woman (first pregnant) who was admitted to our Unit at 12 weeks for a screening for thalassemia. The outcomes of the biochemical and haematological exams (MCV, MCH, HbA2, HbF) highlighted that the patient was a carrier of a beta-thalassemic trait. Molecular analysis of the beta globin genes highlighted a β(0)39C>T heterozygous mutation. Biochemical and hematological parameters of the husband (MCV, MCH, HbA2, HbF) were normal except for the level of HbA2 (3,6%). The molecular analysis of the beta globin genes highlighted a IVS2 nt844 C>G heterozygous mutation. Furthermore, the heterozygous mutation δ(+)cod.27G>T was detected in his δ globin gene. For this reason, he was diagnosed a δ+β Thal. CONCLUSIONS: the aim of this paper is to highlight that biochemical diagnosis could not exhaustive and a molecular diagnostic widening is required to detect the genetic deficiency causing the thalassemic trait