The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (ß = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

Challenges and pitfalls in the development of liposomal delivery systems for cancer therapy.

Despite considerable advances in the application of liposomal drug delivery systems in cancer treatment, the clinical application of liposomal formulations has been limited by many factors. It seems that there is a wide gap between results of experimental studies and clinical application of liposomes. In this review, we discuss barriers which limit the translation of liposomal delivery systems in cancer therapy. The main focus of this review will be on differences between preclinical and clinical studies and potential approaches to overcome the main pitfalls in the clinical application of liposomal delivery systems.

Antibody-drug conjugates for lung cancer in the era of personalized oncology.

With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer.

Effects of statins on the biological features of mesenchymal stem cells and therapeutic implications.

Statins are well-known lipid-lowering drugs. The pleiotropic effects of statins have brought about some beneficial effects on improving the therapeutic outcomes of cell therapy and tissue engineering approaches. In this review, the impact of statins on mesenchymal stem cell behaviors including differentiation, apoptosis, proliferation, migration, and angiogenesis, as well as molecular pathways which are responsible for such phenomena, are discussed. A better understanding of pathways and mechanisms of statin-mediated effects on mesenchymal stem cells will pave the way for the expansion of statin applications. Furthermore, since designing a suitable carrier for statins is required to maintain a sufficient dose of active statins at the desired site of the body, different systems for local delivery of statins are also reviewed.

The Multifaceted Actions of Curcumin in Obesity.

Obesity remains a pervasive health concern worldwide with concomitant comorbidities such as cardiovascular diseases, diabetes, inflammation, and other metabolic disorders. A wealth of data validates dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity to slow the obesity development. Recently, the advent of phytochemicals such as curcumin, the active ingredient in turmeric, has attracted considerable research interest in tracking down their possible effects in protection against obesity and obesity-related comorbidities. According to the existing literature, curcumin may regulate lipid metabolism and suppress chronic inflammation interacting with white adipose tissue, which plays a central role in the complications associated with obesity. Curcumin also inhibits the differentiation of adipocyte and improves antioxidant properties. In the present review, we sought to deliberate the possible effects of curcumin in downregulating obesity and curtailing the adverse health effects of obesity.

Enzymes involved in tumor-driven angiogenesis: A valuable target for anticancer therapy.

Angiogenesis plays a pivotal role in cancer progression and is required for tissue invasion and metastasis. Starting with Folkman's initial observations in 1971, basic research continued to shed new molecular insight into this multifaceted process, leading to the development of several anti-angiogenic drugs. To date, anti-vascular endothelial growth factor monoclonal antibodies, such as bevacizumab and ramucirumab, and receptor tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, regorafenib and axitinib) have had a profound impact on the way we treat patients with advanced cancer, providing in some cases unprecedented clinical benefit. The molecular mechanisms underlying tumor-driven angiogenesis have been explored extensively and have unveiled a number of potential clinically relevant targets, including several novel enzymes. In this review, we summarized the current strategies to target tumor-driven angiogenesis through the inhibition of relevant and selected classes of enzymes involved in this process.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

The role of phosphatidylserine recognition receptors in multiple biological functions.

Apoptotic cells are rapidly engulfed and degraded by phagocytes through efferocytosis. Efferocytosis is a highly regulated process. It is triggered upon the activation of caspase-dependent apoptosis, which in turn promotes the expression of "eat me" signals on the surface of dying cells and the release of soluble "find me" signals for the recruitment of phagocytes. To date, many "eat me" signals have been recognized, including phosphatidylserine (PS), intercellular adhesion molecule-3, carbohydrates (e.g., amino sugars, mannose) and calreticulin. Among them, PS is the most studied one. PS recognition receptors are different functionally active receptors expressed by phagocytes. Various PS recognition receptors with different structure, cell type expression, and ability to bind to PS have been recognized. Although PS recognition receptors do not fall into a single classification or family of proteins due to their structural differences, they all share the common ability to activate downstream signaling pathways leading to the production of anti-inflammatory mediators. In this review, available evidence regarding molecular mechanisms underlying PS recognition receptor-regulated clearance of apoptotic cells is discussed. In addition, some efferocytosis-independent biological functions of PS recognition receptors are reviewed.

Resolution of Inflammation in Neurodegenerative Diseases: The Role of Resolvins.

Acute inflammation has been described as a reactive dynamic process, promoted by the secretion of proinflammatory mediators, including lipid molecules like leukotrienes and prostaglandins, and counterbalanced by proresolving mediators including omega-3 polyunsaturated fatty-acid- (PUFA-) derived molecules. The switch from the initiation to the resolution phase of acute inflammatory response is crucial for tissue homeostasis, whereas the failure to resolve early inflammation by specialized proresolving mediators leads to chronic inflammation and tissue damage. Among PUFA-derived proresolving mediators, different eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives have been described, namely, resolvins (resolution phase interaction products), which exert their anti-inflammatory and immune-regulatory activities through specific G-protein-coupled receptors. In recent years, compelling evidence has shown that impairment of resolution of inflammation is a crucial pathogenic hallmark in different neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. This review summarizes current knowledge on the role of resolvins in resolution of inflammation and highlights available evidence showing the neuroprotective potential of EPA- and DHA-derived resolvins (E-series and D-series resolvins, respectively) in neurodegenerative diseases.

In silico evidence of direct interaction between statins and ß-amyloid.

INTRODUCTION: Aggregation of amyloid-ß (Aß) peptides represents a crucial step in the pathogenesis of Alzheimer disease (AD). Compelling evidence from preclinical studies has established that statins may reduce amyloidogenesis and Aß-mediated neurodegeneration, supporting a potential role of statin treatment in the prevention of AD. Different statins have been shown to interfere indirectly with Aß production and clearance through either cholesterol-dependent or cholesterol-independent mechanisms. However, whether there may be a direct interaction between statins and Aß metabolism is still unclear. MATERIALS AND METHODS: To test the possible direct interaction between statins and Aß, we performed an in silico study by testing the orientation of different ligands, including statins and sulindac (the standard ligand of Aß), in the Aß active site using molecular operating environment (MOE) software. RESULTS: Docking experiments showed that all the tested statins could directly interact with Aß protofibrils. Among statins, pitavastatin had the strongest interaction with Aß (pki = 7.66), followed by atorvastatin (pk i = 7.63), rosuvastatin (pk i = 6.99), fluvastatin (pk i = 6.96), pravastatin (pk i = 6.46), lovastatin (pk i = 6.37), and simvastatin (pk i = 5.90). According to the above-mentioned results, pitavastatin, atorvastatin, rosuvastatin, and fluvastatin had a stronger binding to Aß compared with the standard ligand sulindac (pk i = 6.62). CONCLUSION: This study showed a direct interaction between statins and Aß protofibrils, which may underlie the protective role of this widely used class of drugs against amyloidogenesis and Aß-mediated neurodegeneration.

Efferocytosis: molecular mechanisms and pathophysiological perspectives.

During the life of a human being, several tons of apoptotic cells and debris are produced. These apoptotic particles should be cleared quickly and accurately from the body, as they may lose their membrane integrity with the probability of leakage of cytotoxic materials and other intracellular antigens into the environment. The action of removing apoptotic particles occurs by a process called efferocytosis. Efferocytosis is a highly regulated balance among a set of find-me, eat-me and don't-eat-me signals. Efferocytosis is accompanied by a suppression of the immune system that can explain its negative role in cancer. Additionally, defects in this process can lead to different diseases. In this review, we aim to describe the mechanism of efferocytosis and evaluate its association with the development of autoimmune diseases, airway inflammation, atherosclerosis and cancer to open a new window for the treatment of these diseases.

A review of gene- and cell-based therapies for familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic autosomal dominant disorder caused by an impaired receptor-mediated low-density lipoprotein (LDL) removal from the circulation, mainly due to disruptive autosomal co-dominant mutations in the LDL receptor (LDLr) gene, but also less frequently in the apolipoprotein B100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. A rare form of autosomal recessive FH has been also described due to LDLr adaptor protein 1 (LDLRAP1) gene mutations. FH is characterized by very high levels of plasma LDL cholesterol associated with the high incidence of premature atherosclerotic cardiovascular disease (CVD). Despite heterozygous FH (HeFH) patients are still poorly recognized and treated, there is today a large availability of drugs (i.e., statins, ezetimibe and PCSK9 inhibitors) allowing theoretically the normalization of plasma LDL cholesterol levels in this population. Homozygous FH patients (HoFH) have a more severe form of FH, characterized by low responsiveness to the conventional lipid-lowering treatment and often associated with unfavorable prognosis in the young age. Inspired by promising outcomes obtained by orthotopic liver transplantation (OLT), scientists are investigating the possibility of correcting the defective LDLr in these patients by using gene therapy approaches to achieve a novel therapeutic solution with high efficiency. In this article, we tried to review the in vitro, ex vivo, and in vivo attempts conducted to correct FH-causing LDLr gene mutations by using different methods of gene delivery, gene editing, and stem cell manipulation. We also discussed some clinical trials performed in this context.

The regulation and importance of monocyte chemoattractant protein-1.

PURPOSE OF REVIEW: Monocyte chemoattractant protein (MCP)-1, a chemokine regulating monocyte chemotaxis and T-lymphocyte differentiation by binding to the CC chemokine receptor 2 (CCR2), plays a crucial role in the pathogenesis of inflammatory diseases, atherosclerosis and cancer. This review summarizes the current knowledge on the regulation and importance of the MCP-1/CCR2 axis, focusing on the therapeutic potential of its inhibition. RECENT FINDINGS: Differential modulation of MCP-1 and CCR2 lead to downstream activation pathways, pathogenetic to differing disease conditions characterized by dysregulated monocyte/macrophage tissue recruitment. Pharmacological targeting of the MCP-1/CCR2 axis has led to selective MCP-1/CCR2 antagonists that have now entered phase I/II clinical trials for the treatment of inflammatory diseases, atherosclerosis and cancer. The pleiotropic nonselective MCP-1/CCR2 inhibition by current pharmacological agents is thought to contribute to their anti-inflammatory and antiatherosclerotic effects that is also seen for nutraceutical compounds such as curcumin. SUMMARY: MCP-1 has a critical role in regulating chemotaxis both in health and disease, with increasing interest in its pharmacological inhibition. However, the therapeutic efficacy and safety of targeting the MCP-1/CCR2 axis is still in evolution.

Cholesterol-Lowering Nutraceuticals Affecting Vascular Function and Cardiovascular Disease Risk.

PURPOSE OF REVIEW: The aim of this review is to provide an update on the effects of the dietary supplementation with cholesterol-lowering nutraceuticals and nutraceutical combinations affecting vascular function and CV risk in clinical interventional studies. RECENT FINDINGS: Current evidence supports the mild-to-moderate cholesterol-lowering efficacy of red yeast rice, berberine, plant sterols, fibers, and some nutraceutical combinations whereas data on the individual cholesterol-lowering action of other nutraceuticals are either less striking or even inconclusive. There is also promising evidence on the vascular protective effects of some of the aforementioned nutraceuticals. However, except for red yeast rice, clinical interventional studies have not investigated their impact on CV outcomes. Evidence of both cholesterol-lowering and vascular protection is a prerogative of few single nutraceuticals and nutraceutical combinations, which may support their clinical use; however, caution on their uncontrolled adoption is necessary as they are freely available on the market and, therefore, subject to potential misuse.

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism.

From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV-mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.

PCSK9 at the crossroad of cholesterol metabolism and immune function during infections.

Sepsis, a complex and dynamic syndrome resulting from microbial invasion and immune system dysregulation, is associated with an increased mortality, reaching up to 35% worldwide. Cholesterol metabolism is often disturbed during sepsis, with low plasma cholesterol levels being associated with poor prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the low-density lipoprotein receptor (LDLR), thus regulating intracellular and plasma cholesterol levels. PCSK9 is often upregulated during sepsis and might have a detrimental effect on immune host response and survival. Accordingly, PCSK9 reduces lipopolysaccharide uptake and clearance by human hepatocytes. Moreover, PCSK9 upregulation exacerbates organ dysfunction and tissue inflammation during sepsis, whereas a protective effect of PCSK9 deficiency has been documented in septic patients. Although a possible detrimental impact of PCSK9 on survival has been described, some beneficial effects of PCSK9 on immune response may be hypothesized. First, PCSK9 is associated with increased plasma cholesterol levels, which might be protective during sepsis. Second, PCSK9, by stimulating LDLR degradation and inhibiting reverse cholesterol transport (RCT), might promote preferential cholesterol accumulation in macrophages and other immune cells; these events might improve lipid raft composition and augment toll-like receptor function thus supporting inflammatory response. Hence, a more clear definition of the role of PCSK9 in septic states might provide additional insight in the understanding of the sepsis-associated immune dysregulation and enhance therapeutic outcomes.

Statins, haemostatic factors and thrombotic risk.

PURPOSE OF REVIEW: Statins reduce cholesterol synthesis and promote low-density lipoprotein clearance from circulation. Beyond their cholesterol-lowering action, statins may interfere with haemostasis. This review aims to provide an update on the impact of statin treatment on markers of haemostasis and platelet function and on thrombosis-related outcomes. RECENT FINDINGS: Different coagulation factors are modulated by statins, leading to inhibition of coagulation and increased fibrinolysis. Also, an impact of statins on platelet function has been documented. From a clinical perspective, several observational studies have revealed a reduced incidence of venous thromboembolism in patients receiving statins, which has been argued in some available studies and meta-analyses. Furthermore, a beneficial effect of early statin initiation following acute coronary syndrome for short-term prevention of thrombosis-related events has been documented, but the available data are still not consistent. SUMMARY: Although statins influence the levels of a multitude of haemostatic factors in an antithrombotic direction, data supporting their use for venous thromboembolism prevention are not consistent, and the impact of statins on early vascular events following acute coronary syndrome is still debated. Whether the robust long-term beneficial effects of statins in reducing cardiovascular risk may be also explained by persistent changes in haemostatic factors needs further exploration.

Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial loss of integrity.

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein whose ancestral useful properties have been gradually obscured by its adverse pro-atherogenic and pro-thrombotic effects, that culminate into an increased risk of ischemic cardiovascular events. Although plasma Lp(a) levels are largely determined on a genetic basis, multiple factors have been reported to interfere with its plasma levels. Inflammation is one of these factors and it is believed to promote pro-atherogenic and pro-thrombotic changes leading to increased cardiovascular disease risk. The influence of inflammation on plasma Lp(a) levels is variable, with studies reporting either increased, reduced or unchanged Lp(a) expression and plasma concentrations following exposure to pro-inflammatory stimuli. The complex association between inflammation and Lp(a) is further amplified by additional findings showing that Lp(a) may promote the expression of a plethora of pro-inflammatory cytokines and induces the endothelium to switch into an activated status which results in adhesion molecules expression and inflammatory cells invasion into the arterial wall. In this picture, it emerges that increased plasma Lp(a) levels and inflammation may coexist and their coexistence may exert a deleterious impact on endothelial integrity both at a functional and structural level. Also, the detrimental duet of inflammation and Lp(a) may interfere with the physiological endothelial repair response, thus further amplifying endothelial loss of integrity and protective functions. A fundamental understanding of the interaction between Lp(a) and inflammation is critical for our comprehension of the mechanisms leading to the derangement of endothelial homeostasis and vascular dysfunction.

Effect of orlistat on plasma lipids and body weight: A systematic review and meta-analysis of 33 randomized controlled trials.

Orlistat, an inhibitor of intestinal lipase, promotes body weight reduction. The lipid-lowering efficacy of orlistat is controversial and the effect of orlistat-induced body weight reduction on lipid changes has not been explored in meta-regression analyses. A systematic literature search was conducted to identify randomized controlled trials investigating the efficacy of orlistat on plasma total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides and lipoprotein(a) levels. Thirty-three studies were included in the meta-analysis (5522 and 4210 participants in the orlistat therapy and control groups, respectively). Orlistat reduced body weight (weighted mean difference: -2.12, p <0.001), total-cholesterol (weighted mean difference: -0.30mmol/L, p <0.001), low-density lipoprotein cholesterol (weighted mean difference: -0.27mmol/L, p <0.001), high-density lipoprotein cholesterol (weighted mean difference: -0.034mmol/L, p <0.001) and triglyceride (weighted mean difference: -0.09mmol/L, p <0.001) concentrations, while no effect on lipoprotein(a) was observed. Total- and low-density lipoprotein cholesterol-lowering were associated negatively with duration of orlistat treatment and positively with body weight changes. In conclusion, Orlistat treatment slightly reduces cholesterol and triglyceride levels, but not lipoprotein(a) levels. Total- and low-density lipoprotein cholesterol levels reductions are more consistent in patients with greater body weight reduction and shorter duration of orlistat treatment.

The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta-analysis of randomized controlled trials.

Dyslipidemia and hyperglycemia are associated with an increased risk of ischemic cardiovascular disease. Positive effects of a nutraceutical combination comprising red yeast rice, berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid (NComb) on plasma lipid and glucose levels have been reported in some but not all clinical trials. To address this inconsistency, we tried to estimate the size of lipid- and glucose-lowering effects of NComb through a systematic review and meta-analysis of randomized controlled trials. A systematic literature search in PubMed-Medline, SCOPUS and Google Scholar databases was conducted to identify randomized controlled trials investigating the effects of NComb on plasma lipids and glucose levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid and glucose levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma lipid and glucose levels. Fourteen trials (1670 subjects in the NComb arm and 1489 subjects in the control arm) met the eligibility criteria for lipid analysis and 10 trials (1014 subjects in the NComb arm and 962 subjects in the control arm) for glucose analysis. Overall, WMDs were significant for the impact of NComb supplementation on plasma levels of total cholesterol (-26.15mg/dL, p<0.001), LDL-cholesterol (-23.85mg/dL, p<0.001), HDL-cholesterol (2.53mg/dL, p<0.001), triglycerides (-13.83mg/dL, p<0.001) and glucose (-2.59mg/dL, p=0.010). NComb-induced amelioration of lipid profile was not affected by duration of supplementation nor by baseline lipid levels; conversely, a greater glucose-lowering effect of NComb was found with higher baseline glucose levels and longer durations of supplementation. In conclusion, the present results suggest that NComb supplementation is associated with improvement of lipid and glucose profile. Short-term beneficial effects of NComb supplementation appear to be maintained in the long term.