Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

Malvandi, Amir Mohammad; Canclini, L.; Alliaj, Anxhela; Magni, Paolo; Zambón, Alberto; Catapano, Alberico L.

doi:10.1080/14712598.2020.1801628

Cited by 2 publications

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References 120 publications

(114 reference statements)

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“…LDL clearance from the circulation primarily occurs in the liver through the LDL receptor (LDLR) pathway [3]. PCSK9 promotes intracellular LDLR degradation, leading to fewer LDLRs on the cell membrane and decreased LDL uptake [4]. PCSK9 inhibition with monoclonal antibodies lowers LDL-C levels by ∼60%, resulting in a substantial reduction in cardiovascular risk [5].…”

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confidence: 99%

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

et al. 2021

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Background: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is key regulator of low-density lipoprotein (LDL) metabolism. A significant proportion of PCSK9 is believed to be associated with LDL in plasma as it circulates, although this finding is still a matter of debate. The purpose of this study was to establish an experimental method to investigate the presence of such an interaction in the bloodstream. Methods: We compared a number of well-established methods for lipoprotein (LP) isolation to clarify whether PCSK9 associates differently to circulating lipoproteins, such as KBr gradient ultracentrifugation, physical precipitation of ApoB-LPs, fast protein liquid chromatography (FPLC) and iodixanol gradient ultracentrifugation. Results: Our data show heterogeneity in PCSK9 association to lipoproteins according to the method used. Two methods, iodixanol ultracentrifugation and column chromatography, which did not involve precipitation or high salt concentration, consistently showed an interaction of PCSK9 with a subfraction of LDL that appeared to be more buoyant and have a lower size than average LDL. The percent of PCSK9 association ranged from 2 to 30% and did not appear to correlate to plasma or LDL cholesterol levels. Conclusions: The association of PCSK9 to LDL appeared to be sensitive to high salt concentrations. FPLC and iodixanol gradient ultracentrifugation appeared to be the most suitable methods for the study of this association.

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confidence: 99%

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

et al. 2021

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“…6 Disease-specific drug databases are now available to correlate alterations in metabolite profiles, levels, and ratios with treatment options. 7 Such approaches are not routinely applied to rare diseases, [8][9][10] in which a diagnosis may not adequately inform treatment options. Furthermore, therapy is often limited to palliative care and pain management.…”

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A case of personalized and precision medicine: Pharmacometabolomic applications to rare cancer, microbiological investigation, and therapy

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Malvandi

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Advances in metabolomics, together with consolidated genetic approaches, have opened the way for investigating the health of patients using a large number of molecules simultaneously, thus providing firm scientific evidence for personalized medicine and consequent interventions. Metabolomics is an ideal approach for investigating specific biochemical alterations occurring in rare clinical situations, such as those caused by rare associations between comorbidities and immunosuppression. Methods Metabolomic database matching enables clear identification of molecular factors associated with a metabolic disorder and can provide a rationale for elaborating personalized therapeutic protocols. Mass spectrometry (MS) forms the basis of metabolomics and uses mass‐to‐charge ratios for metabolite identification. Here, we used an MS–based approach to diagnose and develop treatment options in the clinical case of a patient afflicted with a rare disease further complicated by immunosuppression. The patient's data were analyzed using proprietary databases, and a personalized and efficient therapeutic protocol was consequently elaborated. Results The patient exhibited significant alterations in homocysteine:methionine and homocysteine:thiodiglycol acid plasma concentration ratios, and these were associated with low immune system function. This led to cysteine concentration deficiency causing extreme oxidative stress. Plasmatic thioglycolic acid concentrations were initially altered and were used for therapeutic follow‐up and to evaluate cysteine levels. Conclusions An MS–based pharmacometabolomics approach was used to define a personalized protocol in a clinical case of rare peritoneal carcinosis with confounding immunosuppression. This personalized protocol reduced both oxidative stress and resistance to antibiotics and antiviral drugs.

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Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

Cited by 2 publications

References 120 publications

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

A case of personalized and precision medicine: Pharmacometabolomic applications to rare cancer, microbiological investigation, and therapy

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