PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology.
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ABSTRACT:
SUBMITTER: Sundararaman SS
PROVIDER: S-EPMC8301306 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Review novel insights into the biology of proprotein convertase subtilisin/kexin 9 (PCSK9) that may explain the extreme efficiency of PCSK9 inhibition and the unexpected metabolic effects resulting from PCSK9 monoclonal antibody therapy, and may identify additional patients as target of therapy.For over 20 years, the practical knowledge of cholesterol metabolism has centered around cellular mechanisms, and around the idea that statin therapy is the essential step to control metabolic abnormalities for cardiovascular risk management. This view has been embraced by the recent AHA/ACC guidelines, but is being challenged by recent studies including nonstatin medications and by the development of a new class of cholesterol-lowering agents that seems destined to early US Food and Drug Administration approval. The discovery of PCSK9 - a circulating protein that regulates hepatic low-density lipoprotein (LDL) receptor and serum LDL cholesterol levels - has led to a race for its therapeutic inhibition. Recent findings on PCSK9 regulation and pleiotropic effects will help identify additional patient groups likely to benefit from the inhibitory therapy and unravel the full potential of PCSK9 inhibition therapy.Injectable human monoclonal antibodies to block the interaction between PCSK9 and LDL receptor are demonstrating extraordinary efficacy (LDL reductions of up to 70%) and almost the absence of any side-effects. A more moderate effect is seen on other lipoprotein parameters, with the exception of lipoprotein(a) levels. We describe mechanisms that can explain the effect on lipoprotein(a), predict a potential effect on postprandial triglyderides, and suggest a new category of patients for anti-PCSK9 therapy.
| S-EPMC4384821 | biostudies-other
Project description:MotivationThe availability of large-scale curated protein interaction datasets has given rise to the opportunity to investigate higher level organization and modularity within the protein-protein interaction (PPI) network using graph theoretic analysis. Despite the recent progress, systems level analysis of high-throughput PPIs remains a daunting task because of the amount of data they present. In this article, we propose a novel PPI network decomposition algorithm called FACETS in order to make sense of the deluge of interaction data using Gene Ontology (GO) annotations. FACETS finds not just a single functional decomposition of the PPI network, but a multi-faceted atlas of functional decompositions that portray alternative perspectives of the functional landscape of the underlying PPI network. Each facet in the atlas represents a distinct interpretation of how the network can be functionally decomposed and organized. Our algorithm maximizes interpretative value of the atlas by optimizing inter-facet orthogonality and intra-facet cluster modularity.ResultsWe tested our algorithm on the global networks from IntAct, and compared it with gold standard datasets from MIPS and KEGG. We demonstrated the performance of FACETS. We also performed a case study that illustrates the utility of our approach.Supplementary informationSupplementary data are available at the Bioinformatics online.AvailabilityOur software is available freely for non-commercial purposes from: http://www.cais.ntu.edu.sg/~assourav/Facets/
| S-EPMC3467740 | biostudies-literature
Project description:One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.
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Project description:Synthetic biology has played a major role in engineering microbial cell factories to convert plant biomass (lignocellulose) to fuels and bioproducts by fermentation. However, the final product yield is limited by inhibition of microbial growth and fermentation by toxic phenolic compounds generated during lignocellulosic pre-treatment and hydrolysis. Advances in the development of systems biology technologies (genomics, transcriptomics, proteomics, metabolomics) have rapidly resulted in large datasets which are necessary to obtain a holistic understanding of complex biological processes underlying phenolic compound toxicity. Here, we review and compare different systems biology tools that have been utilized to identify molecular mechanisms that modulate phenolic compound toxicity in Saccharomyces cerevisiae. By focusing on and comparing functional genomics and transcriptomics approaches we identify common mechanisms potentially underlying phenolic toxicity. Additionally, we discuss possible ways by which integration of data obtained across multiple unbiased approaches can result in new avenues to develop yeast strains with a significant improvement in tolerance to phenolic fermentation inhibitors.
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Project description:Background and aimsThe new coronavirus disease (COVID-19) is a systemic disease. Mounting evidence depict signs and symptoms involving multiple organs, most of which supported by pathological data. A plausible link to these manifestations is vascular and endothelial dysfunction/damage. However, much of the current knowledge relies on opinion and incipient evidence. We aim to objectively appraise current evidence on the association between COVID-19 and vascular disease, specifically endotheliitis and vasculitis.MethodsTwo researchers independently entered the search terms COVID-19 OR SARS-CoV-2 AND vasculitis, endotheliitis OR endothelium in the following online platforms: MedRxiv and LitCovid (PubMed). The search period was set from November 1, 2019 to August 28, 2020. Manuscripts with unavailable full texts, not in English, mainly on pre-clinical data, presenting only study designs or not directly related to the topics of this review were excluded. Retrospective and prospective studies, especially longitudinal ones, were given priority to the purpose of this review. Since there was paucity of prospective controlled evidence, case reports/series were also considered.ResultsA total of 318 manuscripts were initially found. Sixty-seven (21%) were excluded: 59 (18.5%) met exclusion criteria and 8 (2.5%) were duplicates. One hundred and forty-two manuscripts (44,6%) did not provide original data and were also excluded: 35 (11%) were comments, 108 (33.9%) reviews; 1 (0.3%) position paper. One hundred and seven (33.6%) studies were considered for the present scoping review: 81 (25,5%) case reports/series; 18 (5.7%) prospective; 8 (2.5%) retrospective. Viral inclusions in endothelial cells, mononuclear cell infiltrates in the intima of small vessels and markers of endothelial cell apoptosis were demonstrated. Specificities of COVID-19 may lead to diverse vascular manifestations in different levels of the vascular bed.ConclusionsEvidence indicates that COVID-19 targets vasculature and endothelium. However, high quality data is still lacking and studies with prospective designs and appropriately matched controls are needed.
| S-EPMC7883684 | biostudies-literature
Project description:Cardiovascular diseases (CVD) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, sPCSK9 correlated positively with increasing age and the development of cardiovascular dysfunction. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats suggesting that PCSK9 plays an important role in cardiovascular aging.
2023-08-09 | GSE225859 | GEO
Project description:The mechano-bactericidal activity of nanostructured surfaces has become the focus of intensive research toward the development of a new generation of antibacterial surfaces, particularly in the current era of emerging antibiotic resistance. This work demonstrates the effects of an incremental increase of nanopillar height on nanostructure-induced bacterial cell death. We propose that the mechanical lysis of bacterial cells can be influenced by the degree of elasticity and clustering of highly ordered silicon nanopillar arrays. Herein, silicon nanopillar arrays with diameter 35 nm, periodicity 90 nm and increasing heights of 220, 360, and 420 nm were fabricated using deep UV immersion lithography. Nanoarrays of 360-nm-height pillars exhibited the highest degree of bactericidal activity toward both Gram stain-negative Pseudomonas aeruginosa and Gram stain-positive Staphylococcus aureus bacteria, inducing 95 ± 5% and 83 ± 12% cell death, respectively. At heights of 360 nm, increased nanopillar elasticity contributes to the onset of pillar deformation in response to bacterial adhesion to the surface. Theoretical analyses of pillar elasticity confirm that deflection, deformation force, and mechanical energies are more significant for the substrata possessing more flexible pillars. Increased storage and release of mechanical energy may explain the enhanced bactericidal action of these nanopillar arrays toward bacterial cells contacting the surface; however, with further increase of nanopillar height (420 nm), the forces (and tensions) can be partially compensated by irreversible interpillar adhesion that reduces their bactericidal effect. These findings can be used to inform the design of next-generation mechano-responsive surfaces with tuneable bactericidal characteristics for antimicrobial surface technologies.
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Project description:The transcription factor Gata3 is crucial for the development of several tissues and cell lineages both during development as well as postnatally. This importance is apparent from the early embryonic lethality following germline Gata3 deletion, with embryos displaying a number of phenotypes, and from the fact that Gata3 has been implicated in several cancer types. It often acts at the level of stem and progenitor cells in which it controls the expression of key lineage-determining factors as well as cell cycle genes, thus being one of the main drivers of cell fate choice and tissue morphogenesis. Gata3 is involved at various stages of haematopoiesis both in the adult as well as during development. This review summarizes the various contributions of Gata3 to haematopoiesis with a particular focus on the emergence of the first haematopoietic stem cells in the embryo-a process that appears to be influenced by Gata3 at various levels, thus highlighting the complex nature of Gata3 action.
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Project description:Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit y+LAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management.Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n?=?9), gastrointestinal disorders (n?=?2), cytopenia (n?=?6), hyperammonemia (n?=?10) with acute encephalopathy (n?=?4) or developmental disability (n?=?3), and proteinuria (n?=?1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p?=?0.08; logrank, p?=?0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p?=?0.16).As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.
| S-EPMC5217205 | biostudies-literature
Project description:Purpose of reviewSince the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL-cholesterol (LDLc). Accordingly, inhibitors of PCSK9, including monoclonal antibodies blocking its circulating activity and siRNA silencers of its hepatic expression, are now used in clinics worldwide to treat hypercholesterolemia patients effectively and safely in combination with statins and/or ezetimibe. These powerful treatments reduce the incidence of atherosclerosis by at least 20%. Since 2008, novel targets of PCSK9 began to be defined, thereby expanding its roles beyond LDLc regulation into the realm of inflammation, pathogen infections and cellular proliferation in various cancers and associated metastases.Recent findingsSome pathogens such as dengue virus exploit the ability of PCSK9 to target the LDLR for degradation to enhance their ability to infect cells. Aside from increasing the degradation of the LDLR and its family members VLDLR, ApoER2 and LRP1, circulating PCSK9 also reduces the levels of other receptors such as CD36 (implicated in fatty acid uptake), oxidized LDLR receptor (that clears oxidized LDLc) as well as major histocompatibility class-I (MHC-I) receptors (implicated in the immune response to antigens). Thus, these novel targets provided links between PCSK9 and inflammation/atherosclerosis, viral infections and cancer/metastasis. The functional activities of PCSK9, accelerated the development of novel therapies to inhibit PCSK9 functions, including small molecular inhibitors, long-term vaccines, and possibly CRISPR-based silencing of hepatic expression of PCSK9. The future of inhibitors/silencers of PCSK9 function or expression looks bright, as these are expected to provide a modern armamentarium to treat various pathologies beyond hypercholesterolemia and its effects on atherosclerosis.
| S-EPMC9335453 | biostudies-literature