Mateusz Maligłówka

Bio: Mateusz Maligłówka is an academic researcher from Medical University of Silesia. The author has contributed to research in topics: Medicine & PCSK9. The author has an hindex of 2, co-authored 4 publications receiving 5 citations.

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders.

Abstract: Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

Insight into the Evolving Role of PCSK9

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

Endocrine diseases as causes of secondary hyperlipidemia

Abstract: Cardiovascular diseases are among the leading causes of increased morbidity and mortality in developed and developing countries. One of the most important risk factors responsible for atherosclerosis and subsequent cardiovascular diseases is hyperlipidaemia. Currently, hyperlipidaemias are divided into several clinical entities. The greatest risk is associated with hypercholesterolaemia. As a result, modern guidelines for the treatment and prevention of atherosclerosis focus predominantly on the reduction of LDL-cholesterol. Hypertriglyceridaemia and atherogenic dyslipidaemia, which are responsible for a less significant increase in the cardiovascular risk, are nowadays secondary targets of the treatment. During the work-up for hyperlipidaemia one of the essential actions is the exclusion of secondary causes of the lipid abnormalities. Those include, among others, endocrine diseases, diabetes, drugs, nephrotic syndrome, and pregnancy. Data regarding the impact of endocrine disease and diabetes on the lipid profile are scattered. In this review, the authors aimed to perform a thorough analysis of the available publications regarding the topic and the preparation of a comprehensive review dealing with the incidence, clinical features, and the therapy of hyperlipidaemias in patients with endocrine disease.

Pleiotropic Effects of PCSK-9 Inhibitors

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a group of drugs whose main mechanism of action is binding to the PCSK-9 molecule, which reduces the degradation of the low-density lipoprotein receptor (LDL-R) and, hence, increases the uptake of low-density lipoprotein cholesterol (LDLc) from the bloodstream as well as reducing its concentration. The effectiveness of three monoclonal antibodies, namely, alirocumab (human IgG1/κ monoclonal antibody, genetically engineered in Chinese hamster ovary cells), evolocumab (the first fully human monoclonal antibody), and bococizumab (humanized mouse antibody), in inhibiting the action of PCSK-9 and reducing LDLc levels has been confirmed. The first two, after clinical trials, were approved by the Food and Drug Administration (FDA) and are used primarily in the treatment of autosomal familial hypercholesterolemia and in cases of statin intolerance. They are currently used both as monotherapy and in combination with statins and ezetimibe to intensify therapy and achieve therapeutic goals following the American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines. However, the lipid-lowering effect is not the only effect of action described by researchers that PCSK-9 inhibitors have. This paper is a review of the literature describing the pleiotropic effects of PCSK-9 inhibitors, which belong to a group of drugs that are being increasingly used, especially when standard lipid-lowering therapy fails. The article focuses on activities other than lipid-lowering, such as the anti-atherosclerotic effect and stabilization of atherosclerotic plaque, the anti-aggregation effect, the anticoagulant effect, the antineoplastic effect, and the ability to influence the course of bacterial infections. In this publication, we try to systematically review the current scientific data, both from our own scientific work and knowledge from international publications.

The consequences of PCSK9 inhibition in selected tissues

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of nine members of the proprotein convertase family. These serine proteases play a pivotal role in the post-translational modification of proteins and the activation of hormones, enzymes, transcription factors and growth factors. As a result, they participate in many physiological processes like embryogenesis, activity of central nervous system and lipid metabolism. Scientific studies show that the family of convertases is also involved in the pathogenesis of viral and bacterial infections, osteoporosis, hyperglycaemia, cardiovascular diseases, neurodegenerative disorders and cancer. The inhibition of PCSK9 by two currently approved for use monoclonal antibodies (alirocumab, evolocumab) slows down the degradation of low-density lipoprotein cholesterol receptors (LDLRs). This leads to increased density of LDLRs on the surface of hepatocytes, resulting in decreased level of low-density lipoprotein cholesterol (LDL-C) in the bloodstream, which is connected with the reduction of cardiovascular risk. PCSK9 inhibitors (PCSK9i) were created for the patients who could not achieve appropriate level of LDL-C using current statin and ezetimibe therapy. It seems that high therapeutic efficacy of PCSK9i will make them more common in the clinical use. The pleiotropic effects of previously mentioned lipid-lowering therapies were the reasons for literature review of possible positive and negative effects of PCSK9 inhibition beyond cholesterol metabolism.

Dyslipidemia in age-related macular degeneration

Abstract: Lipid-rich drusen are the sine qua non of age-related macular degeneration (AMD), the leading cause of blindness in older adults in the developed world. Efforts directed at uncovering effective therapeutic strategies have led to the hypothesis that altered lipid metabolism may play a pathogenic role in AMD. This hypothesis is supported by the fact that: (1) drusen, the hallmark histopathologic feature of AMD, are composed of lipids, (2) polymorphisms of genes involved in lipid homeostasis are associated with increased odds of AMD, (3) metabolomics studies show that patients with AMD have alterations in metabolites from lipid pathways, and (4) alterations in serum lipid profiles as a reflection of systemic dyslipidemia are associated with AMD. There is strong evidence that statins, which are well described for treating dyslipidemia and reducing risk associated with cardiovascular disease, may have a role for treating certain cohorts of AMD patients, but this has yet to be conclusively proven. Of interest, the specific changes in serum lipoprotein profiles associated with decreased cardiovascular risk (i.e., high HDL levels) have been shown in some studies to be associated with increased risk of AMD. In this review, we highlight the evidence that supports a role for altered lipid metabolism in AMD and provide our perspective regarding the remaining questions that need to be addressed before lipid-based therapies can emerge for specific cohorts of AMD patients.摘要: 富含脂质的玻璃疣是年龄相关性黄斑变性 (AMD) 的重要特征, AMD是发达国家老年人失明的主要原因。为发现有效的治疗策略提出了一个假说, 即脂质代谢的改变可能在AMD中起致病作用。这一假说目前有以下事实支持: (1) 作为AMD标志性组织病理学特征的玻璃疣是由脂质组成, (2) 参与脂质稳态的基因多态性与AMD的患病几率增加有关, (3) 代谢组学研究表明AMD患者的脂质代谢产物发生了改变, 以及4) 反映全身性血脂异常的血脂谱变化与AMD有关。有强有力的证据表明, 他汀类药物可能在治疗某些AMD患者的队列中发挥作用, 但这一观点尚未得到确凿的证明, 且他汀类药物在治疗血脂异常和降低与心血管疾病相关的风险方面得到了证实。有趣的是, 一些研究表明, 血清脂蛋白谱中与心血管风险降低 (即高密度脂蛋白水平) 相关的特定变化与AMD风险增加有关。在这篇综述中, 我们强调了支持脂质代谢改变在AMD中作用的证据, 并就AMD患者特定队列中在脂质治疗前需要解决的问题提出了我们的观点。.

PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis

Abstract: The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of the optimal PCSK9 agents targeting PCSK9 for secondary prevention in patients with high-risk of cardiovascular events is lacking. Therefore, this study was conducted to evaluate the benefit and safety of different types of PCSK9 inhibitors.Several databases including Cochrane Central, Ovid Medline, and Ovid Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration of PCSK9 inhibitors with placebo or ezetimibe for secondary prevention of cardiovascular events in patients with statin-background therapy were identified. The primary efficacy outcome was all-cause mortality. The primary safety outcome was serious adverse events.Overall, nine trials totaling 54,311 patients were identified. Three types of PCSK9 inhibitors were evaluated. The use of alirocumab was associated with reductions in all-cause mortality compared with control (RR 0.83, 95% CrI 0.72-0.95). Moreover, evolocumab was associated with increased all-cause mortality compared with alirocumab (RR 1.26, 95% CrI 1.04-1.52). We also found alirocumab was associated with decreased risk of serious adverse events (RR 0.94, 95% CrI 0.90-0.99).In consideration of the fact that both PCSK9 monoclonal antibody and inclisiran enable patients to achieve recommended LDL-C target, the findings in this meta-analysis suggest that alirocumab might provide the optimal benefits regarding all-cause mortality with relatively lower SAE risks, and evolocumab might provide the optimal benefits regarding myocardial infarction for secondary prevention in patients with high-risk of cardiovascular events. Further head-to-head trials with longer follow-up and high methodologic quality are warranted to help inform subsequent guidelines for the management of these patients.

Mechanism of Astragalus membranaceus Alleviating Acquired Hyperlipidemia Induced by High-Fat Diet through Regulating Lipid Metabolism

Abstract: Astragalus membranaceus (AM) is a food and medicinal homologous plant. The current research is aimed to investigate the beneficial effects and mechanisms of AM in treating acquired hyperlipidemia. The network pharmacology and bioinformatics analysis results showed 481 AM-related targets and 474 acquired hyperlipidemia-associated targets, and 101 candidate targets were obtained through the intersection, mainly enriched in endocrine resistance, AGE-RAGE in diabetic complications and p53 signaling pathways. Quercetin, kaempferol, calycosin, formononetin and isorhamnetin were determined as the candidate active components of AM in the treatment of acquired hyperlipidemia. Moreover, key targets of AM, namely, AKT serine/threonine kinase 1 (AKT1), vascular endothelial growth factor A (VEGFA), cyclin D1 (CCND1) and estrogen receptor 1 (ESR1), were screened out, which were closely related to adipogenesis, fatty acid metabolism and bile acid metabolism. The subsequent animal experiments showed that AM extract treatment improved the lipid profiles of the high-fat diet (HFD)-fed mice by reducing lipogenesis and increasing lipolysis and lipid β-oxidation, which were associated with the downregulating of AKT1 and CCND1, and the upregulating of VEGFA and ESR1 in liver and adipose tissue. Overall, AM alleviated acquired hyperlipidemia through regulating lipid metabolism, and AKT1, VEGFA, CCND1 and ESR1 might be the key targets.

Inclisiran-Silencing the Cholesterol, Speaking up the Prognosis.

Abstract: The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%-20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.