Squalene monooxygenase – a target for hypercholesterolemic therapy

2011 ◽  
Vol 392 (12) ◽  
pp. 1053-1075 ◽  
Author(s):  
Agnieszka Belter ◽  
Miroslawa Skupinska ◽  
Malgorzata Giel-Pietraszuk ◽  
Tomasz Grabarkiewicz ◽  
Leszek Rychlewski ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Clinical Evidence ◽  
Cholesterol Biosynthesis ◽  
Cardiovascular Prevention ◽  
Cost Effective ◽  
Clinical Use ◽  
Cellular Cholesterol ◽  
Squalene Monooxygenase ◽  
Hypolipidemic Drugs ◽  
Hypocholesterolemic Agents

Abstract Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes’ inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both sufficient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

scholarly journals Pleiotropic effects of niacin: Current possibilities for its clinical use

2016 ◽  
Vol 66 (4) ◽  
pp. 449-469 ◽  
Author(s):  
Miroslav Zeman ◽  
Marek Vecka ◽  
František Perlík ◽  
Barbora Staňková ◽  
Robert Hromádka ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cardiovascular Events ◽  
Pleiotropic Effects ◽  
Clinical Use ◽  
Specific Receptor ◽  
Hypolipidemic Drug ◽  
Major Cardiovascular Events ◽  
Future Clinical Practice ◽  
Hypolipidemic Drugs ◽  
Progression Of Atherosclerosis

Abstract Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin’s role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.

scholarly journals Viperin inhibits cholesterol biosynthesis and interacts with enzymes in the cholesterol biosynthetic pathway

2021 ◽  
Author(s):  
Timothy J. Grunkemeyer ◽  
Soumi Ghosh ◽  
Ayesha M. Patel ◽  
Keerthi Sajja ◽  
James Windak ◽  
...  
Keyword(s):  
Specific Activity ◽  
Cholesterol Biosynthesis ◽  
Hek293t Cell ◽  
Inhibitory Protein ◽  
Cellular Cholesterol ◽  
Enveloped Viruses ◽  
Cholesterol Levels ◽  
Squalene Monooxygenase ◽  
Lanosterol Synthase ◽  
Er Membrane

AbstractMany enveloped viruses bud from cholesterol-rich lipid rafts on the cell membrane. Depleting cellular cholesterol impedes this process and results in viral particles with reduced viability. Viperin (virus inhibitory protein endoplasmic reticulum-associated, interferon-induced) is an ER membrane-associated enzyme that when expressed in response to viral infections exerts broad-ranging antiviral effects, including inhibiting the budding of some enveloped viruses. Here we have investigated the effect of viperin expression on cholesterol biosynthesis. We found that viperin expression reduces cholesterol levels by 20 – 30 % in HEK293T cells. A proteomic screen of the viperin interactome identified several cholesterol biosynthetic enzymes among the top hits. The two most highly enriched proteins were lanosterol synthase and squalene monooxygenase, enzymes that catalyze key steps establishing the sterol carbon skeleton. Co-immunoprecipitation experiments established that viperin, lanosterol synthase and squalene monooxygenase form a complex at the ER membrane. Co-expression of viperin was found to significantly inhibit the specific activity of lanosterol synthase in HEK293T cell lysates. Co-expression of viperin had no effect on the specific activity of squalene monooxygenase, but reduced its expression levels in the cells by approximately 30 %. Despite these inhibitory effects, co-expression of either LS or SM failed to reverse the viperin-induced depletion of cellular cholesterol levels in HEK293T cells. Our results establish a clear link between the down-regulation of cholesterol biosynthesis and viperin, although at this point the effect cannot be unambiguously attributed interactions between viperin and a specific biosynthetic enzyme.

The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy “In Vivo” in the Differential Diagnosis of Alzheimer’s Dementia

2019 ◽  
Vol 16 (7) ◽  
pp. 587-595 ◽  
Author(s):  
Roberto Santangelo ◽  
Alessandro Dell'Edera ◽  
Arianna Sala ◽  
Giordano Cecchetti ◽  
Federico Masserini ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Clinical Diagnosis ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Cost Effective ◽  
Daily Clinical Practice ◽  
Different Types ◽  
Experimental Trials ◽  
Csf Findings

Background: The incoming disease-modifying therapies against Alzheimer’s disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption. Methods: We measured CSF AD biomarkers’ concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings. Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy. Conclusions: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

scholarly journals Antiplatelet Agents for Cancer Prevention: Current Evidences and Continuing Controversies

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1639 ◽  
Author(s):  
Corinne Frere ◽  
Manon Lejeune ◽  
Pierre Kubicek ◽  
Dorothée Faille ◽  
Zora Marjanovic ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Task Force ◽  
Cardiovascular Prevention ◽  
Antiplatelet Agents ◽  
Mortality Data ◽  
Low Dose Aspirin ◽  
The Us ◽  
Secondary Analyses ◽  
Prevention Trials ◽  
Related Mortality

Over the past two decades, aspirin has emerged as a promising chemoprotective agent to prevent colorectal cancer (CRC). In 2016, the mounting evidence supporting its chemoprotective effect, from both basic science and clinical research, led the US Preventive Services Task Force to recommend regular use of low-dose aspirin in some subgroups of patients for whom the benefits are deemed to outweigh the risks. In contrast, data on the chemoprotective effect of aspirin against other cancers are less clear and remain controversial. Most data come from secondary analyses of cardiovascular prevention trials, with only a limited number reporting cancer outcomes as a prespecified endpoint, and overall unclear findings. Moreover, the potential chemoprotective effect of aspirin against other cancers has been recently questioned with the publication of 3 long-awaited trials of aspirin in the primary prevention of cardiovascular diseases reporting no benefit of aspirin on overall cancer incidence and cancer-related mortality. Data on the chemoprotective effects of other antiplatelet agents remain scarce and inconclusive, and further research to examine their benefit are warranted. In this narrative review, we summarize current clinical evidence and continuing controversies on the potential chemoprotective properties of antiplatelet agents against cancer.

Proton Therapy in Clinical Practice: Current Clinical Evidence

2007 ◽  
Vol 25 (8) ◽  
pp. 965-970 ◽  
Author(s):  
Michael Brada ◽  
Madelon Pijls-Johannesma ◽  
Dirk De Ruysscher
Keyword(s):  
Clinical Practice ◽  
Proton Therapy ◽  
Clinical Evidence

scholarly journals Production of β-Lactamase Inhibitors by Streptomyces Species

Antibiotics ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 61 ◽  
Author(s):  
Daniela Viana Marques ◽  
Suellen Machado ◽  
Valéria Ebinuma ◽  
Carolina Duarte ◽  
Attilio Converti ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cost Effective ◽  
Multidrug Resistant ◽  
Bacterial Strains ◽  
Streptomyces Species ◽  
Innovative Strategies ◽  
New Antibiotics ◽  
Microbial Products ◽  
Type Strains ◽  
Streptomyces Genus

β-Lactamase inhibitors have emerged as an effective alternative to reduce the effects of resistance against β-lactam antibiotics. The Streptomyces genus is known for being an exceptional natural source of antimicrobials and β-lactamase inhibitors such as clavulanic acid, which is largely applied in clinical practice. To protect against the increasing prevalence of multidrug-resistant bacterial strains, new antibiotics and β-lactamase inhibitors need to be discovered and developed. This review will cover an update about the main β-lactamase inhibitors producers belonging to the Streptomyces genus; advanced methods, such as genetic and metabolic engineering, to enhance inhibitor production compared with wild-type strains; and fermentation and purification processes. Moreover, clinical practice and commercial issues are discussed. The commitment of companies and governments to develop innovative strategies and methods to improve the access to new, efficient, and potentially cost-effective microbial products to combat the antimicrobial resistance is also highlighted.

scholarly journals Current Practice in Preoperative Virtual and Physical Simulation in Neurosurgery

2020 ◽  
Vol 7 (1) ◽  
pp. 7 ◽  
Author(s):  
Elisa Mussi ◽  
Federico Mussa ◽  
Chiara Santarelli ◽  
Mirko Scagnet ◽  
Francesca Uccheddu ◽  
...  
Keyword(s):  
Clinical Practice ◽  
3D Printing ◽  
Surgical Planning ◽  
Physical Simulation ◽  
Planning Process ◽  
Preoperative Planning ◽  
Cost Effective ◽  
Patient Specific ◽  
Anatomical Models ◽  
Standard Clinical Practice

In brain tumor surgery, an appropriate and careful surgical planning process is crucial for surgeons and can determine the success or failure of the surgery. A deep comprehension of spatial relationships between tumor borders and surrounding healthy tissues enables accurate surgical planning that leads to the identification of the optimal and patient-specific surgical strategy. A physical replica of the region of interest is a valuable aid for preoperative planning and simulation, allowing the physician to directly handle the patient’s anatomy and easily study the volumes involved in the surgery. In the literature, different anatomical models, produced with 3D technologies, are reported and several methodologies were proposed. Many of them share the idea that the employment of 3D printing technologies to produce anatomical models can be introduced into standard clinical practice since 3D printing is now considered to be a mature technology. Therefore, the main aim of the paper is to take into account the literature best practices and to describe the current workflow and methodology used to standardize the pre-operative virtual and physical simulation in neurosurgery. The main aim is also to introduce these practices and standards to neurosurgeons and clinical engineers interested in learning and implementing cost-effective in-house preoperative surgical planning processes. To assess the validity of the proposed scheme, four clinical cases of preoperative planning of brain cancer surgery are reported and discussed. Our preliminary results showed that the proposed methodology can be applied effectively in the neurosurgical clinical practice both in terms of affordability and in terms of simulation realism and efficacy.

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