Unravelling the health effects of fasting : a long road from obesity treatment to healthy life span increase and improved cognition

In recent years a revival of interest has emerged in the health benefits of intermittent fasting and long-term fasting, as well as of other related nutritional strategies. In addition to meal size and composition a new focus on time and frequency of meals has gained attention. The present review will investigate the effects of the main forms of fasting, activating the metabolic switch from glucose to fat and ketones (G-to-K), starting 12-16 h after cessation or strong reduction of food intake. During fasting the deactivation of mTOR regulated nutrient signalling pathways and activation of the AMP protein kinase trigger cell repair and inhibit anabolic processes. Clinical and animal studies have clearly indicated that modulating diet and meal frequency, as well as application of fasting patterns, e.g. intermittent fasting, periodic fasting, or long-term fasting are part of a new lifestyle approach leading to increased life and health span, enhanced intrinsic defences against oxidative and metabolic stresses, improved cognition, as well as a decrease in cardiovascular risk in both obese and non-obese subjects. Finally, in order to better understand the mechanisms beyond fasting-related changes, human studies as well as non-human models closer to human physiology may offer useful clue

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

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

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

PCSK9 induces a pro-inflammatory response in macrophages

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250\u2009\uf7\u20092.5\u2009\ub5g/ml) of human recombinant PCSK9 (hPCSK9). After 24\u2009h incubation with 2.5\u2009\ub5g/ml PCSK9, a significant induction of IL-1\u3b2, IL-6, TNF-\u3b1, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-\u3b1 (2.4\u2009\ub1\u20090.5 fold) and IL-1\u3b2 (8.6\u2009\ub1\u20091.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-\u3b1 mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3\u2009\ub1\u20091.6 fold vs 31.1\u2009\ub1\u20096.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-\u3b1 plasma levels of healthy adult subjects (males 533, females 537) was observed (B\u2009=\u20098.73, 95%CI 7.54\u2009\uf7\u20099.93, p\u2009<\u20090.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer&#8217;s Disease

Alzheimer\u2019s disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment

Adipokines and Sexual Hormones Associated with the Components of the Metabolic Syndrome in Pharmacologically Untreated Subjects: Data from the Brisighella Heart Study

We evaluated the association of the sex hormone pattern and the serum level of the main adipokines to metabolic syndrome (MS) and its components in 199 pharmacologically untreated subjects. Men and women included in the age-class subgroups were matched for body mass index, waist circumference, blood pressure, heart rate, fasting plasma glucose, and plasma lipids. Men without MS had significantly lower leptin/adiponectin ratio than men with MS. Women without MS had lower leptin and leptin/adiponectin ratio than women with MS but had significantly higher adiponectin, estrone, and dehydroepiandrosterone levels. In men, the leptin/adiponectin ratio is the main factor associated to MS diagnosis (OR: 3.36, 95% CI 1.40–8.08), while in women adiponectin alone appears to be a protective factor (OR: 0.87, 95% CI 0.79–0.95). In conclusion, in a sample of pharmacologically untreated subjects, leptin/adiponectin ratio seems to be the factor more strongly associated to MS and its components

Body composition and metabolic changes during a 520\u2011day mission simulation to Mars

Purpose The \u201cMars-500 project\u201d allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. Methods The \u201cMars-500 project\u201d consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27\u201338 years). Results During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period ( 12 9.2 and 12 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved ( 12 47%) 60 days after hatch closure, remaining at this nadir ( 12 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. Conclusions Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement

Hdl in covid-19 patients: Evidence from an italian cross-sectional study

A number of studies have highlighted important alterations of the lipid profile in COVID-19 patients. Besides the well-known atheroprotective function, HDL displays anti-inflammatory, anti-oxidative, and anti-infectious properties. The aim of this retrospective study was to assess the HDL anti-inflammatory and antioxidant features, by evaluation of HDL-associated Serum amyloid A (SAA) enrichment and HDL-paraoxonase 1 (PON-1) activity, in a cohort of COVID-19 patients hospitalized at the Cardiorespiratory COVID-19 Unit of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan. COVID-19 patients reached very low levels of HDL-c (mean ± SD: 27.1 ± 9.7 mg/dL) with a marked rise in TG (mean ± SD: 165.9 ± 62.5 mg/dL). Compared to matched-controls, SAA levels were significantly raised in COVID-19 patients at admission. There were no significant differences in the SAA amount between 83 alive and 22 dead patients for all-cause in-hospital mortality. Similar findings were reached in the case of PON-1 activity, with no differences between alive and dead patients for all-cause in-hospital mortality. In conclusion, although not related to the prediction of in-hospital mortality, reduction in HDL-c and the enrichment of SAA in HDL are a mirror of SARS-CoV-2 positivity even at the very early stages of the infection

PCSK9 induces a pro-inflammatory response in macrophages.

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250\u2009\uf7\u20092.5\u2009\ub5g/ml) of human recombinant PCSK9 (hPCSK9). After 24\u2009h incubation with 2.5\u2009\ub5g/ml PCSK9, a significant induction of IL-1\u3b2, IL-6, TNF-\u3b1, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-\u3b1 (2.4\u2009\ub1\u20090.5 fold) and IL-1\u3b2 (8.6\u2009\ub1\u20091.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-\u3b1 mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3\u2009\ub1\u20091.6 fold vs 31.1\u2009\ub1\u20096.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-\u3b1 plasma levels of healthy adult subjects (males 533, females 537) was observed (B\u2009=\u20098.73, 95%CI 7.54\u2009\uf7\u20099.93, p\u2009&lt;\u20090.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR