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Pharmaceutics
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Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human...
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Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 10520

Special Issue Editor

Dr. Giulio Preta

E-Mail Website
Guest Editor
Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio 7, LT-10257 Vilnius, Lithuania
Interests: lipid rafts; cholesterol homeostasis; membrane organization; statins; membrane-lipid therapy

Special Issue Information

Dear Colleagues,

Statins reduce cholesterol levels through the inhibition of 3-hydroxy-methylglutaryl CoA reductase and are worldwide used for the prevention of cardiovascular diseases. However, statins are also associated with several beneficial effects, which are independent from the cholesterol-lowering properties and are generally referred to as pleiotropic effects. During clinical trials of statins, anti-inflammatory, antioxidant, immunomodulatory and anti-proliferative properties have been observed. The discovery of these pleiotropic effects has led to additional investigations that aim to enhance the use of statins for the treatment of different diseases ranging from prevention of bacterial/viral infection to cancer therapy. This Special Issue welcomes studies showing that statins might have important roles in diseases that are not mediated by their cholesterol-lowering effect. Novel findings on lipid-independent effects of statins would open the road for new therapeutic approaches, catching the attention of researchers and clinicians across the globe.

Dr. Giulio Preta
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • statins
  • pleiotropic effects
  • cholesterol
  • inflammation
  • immunotherapy
  • antioxidants

Published Papers (5 papers)

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Editorial

Jump to: Research, Review

3 pages, 2761 KiB  
Editorial
Role of Lactone and Acid Forms in the Pleiotropic Effects of Statins
by Giulio Preta
Pharmaceutics 2022, 14(9), 1899; https://doi.org/10.3390/pharmaceutics14091899 - 08 Sep 2022
Cited by 1 | Viewed by 1464
Abstract
Statins are a class of drugs used worldwide to lower low-density lipoprotein cholesterol [...] Full article
(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)
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Research

Jump to: Editorial, Review

26 pages, 8048 KiB  
Article
Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study
by Doaa I. Mohamed, Dalia Alaa El-Din Aly El-Waseef, Enas S. Nabih, Omnyah A. El-Kharashi, Hanaa F. Abd El-Kareem, Hebatallah H. Abo Nahas, Basel A. Abdel-Wahab, Yosra A. Helmy, Samar Zuhair Alshawwa and Essa M. Saied
Pharmaceutics 2022, 14(3), 529; https://doi.org/10.3390/pharmaceutics14030529 - 27 Feb 2022
Cited by 24 | Viewed by 2710
Abstract
Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins [...] Read more.
Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins on cognitive function is still not fully understood. In the present study, we have investigated the molecular and microscopic basis of cognitive impairment induced by alcohol and/or Atorvastatin (ATOR) administration to male Wistar albino rats and explored the possible protective effect of acetylsalicylic acid (ASA). The biochemical analysis indicated that either alcohol or ATOR or together in combination produced a significant increase in the nucleotide-binding domain–like receptor 3 (NLRP3), interleukin-1β (IL-1β) miRNA155 expression levels in the frontal cortex of the brain tissue. The histological and morphometric analysis showed signs of degeneration in the neurons and the glial cells with aggregations of inflammatory cells and a decrease in the mean thickness of the frontal cortex. Immunohistochemical analysis showed a significant increase in the caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex. Interestingly, administration of ASA reversed the deleterious effect of the alcohol and ATOR intake and improved the cognitive function as indicated by biochemical and histological analysis. ASA significantly decreased the expression levels of miRNA155, NLRP3, and IL1B, and produced a significant decrease in caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex with a reduction in the process of neuroinflammation and neuronal damage. To further investigate these findings, we have performed an extensive molecular docking study to investigate the binding affinity of ASA to the binding pockets of the NLRP3 protein. Our results indicated that ASA has high binding scores toward the active sites of the NLRP3 NACHT domain with the ability to bind to the NLRP3 pockets by a set of hydrophilic and hydrophobic interactions. Taken together, the present study highlights the protective pharmacological effect of ASA to attenuate the deleterious effect of alcohol intake and long term ATOR therapy on the cognitive function via targeting miRNA155 and NLRP3 proteins. Full article
(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)
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18 pages, 4296 KiB  
Article
Pleiotropic Long-Term Effects of Atorvastatin on Posttraumatic Joint Contracture in a Rat Model
by Erik Wegner, Ekaterina Slotina, Tim Mickan, Sebastian Truffel, Charlotte Arand, Daniel Wagner, Ulrike Ritz, Pol M. Rommens, Erol Gercek, Philipp Drees and Andreas Baranowski
Pharmaceutics 2022, 14(3), 523; https://doi.org/10.3390/pharmaceutics14030523 - 26 Feb 2022
Cited by 3 | Viewed by 1441
Abstract
The antifibrotic effect of atorvastatin has already been demonstrated in several organ systems. In the present study, a rat model was used to investigate the effect of atorvastatin on posttraumatic joint contracture. Forty-eight Sprague Dawley rats were equally randomized into an atorvastatin group [...] Read more.
The antifibrotic effect of atorvastatin has already been demonstrated in several organ systems. In the present study, a rat model was used to investigate the effect of atorvastatin on posttraumatic joint contracture. Forty-eight Sprague Dawley rats were equally randomized into an atorvastatin group and a control group. After initial joint trauma, knee joints were immobilized for intervals of 2 weeks (n = 16) or 4 weeks (n = 16) or immobilized for 4 weeks with subsequent remobilization for another 4 weeks (n = 16). Starting from the day of surgery, animals received either atorvastatin or placebo daily. After euthanasia at week 2, 4 or 8, joint contracture was determined, histological examinations were performed, and gene expression was assessed. The results suggest that the joint contracture was primarily arthrogenic. Atorvastatin failed to significantly affect contracture formation and showed a reduction in myofibroblast numbers to 98 ± 58 (control: 319 ± 113, p < 0.01) and a reduction in joint capsule collagen to 60 ± 8% (control: 73 ± 9%, p < 0.05) at week 2. Gene expression of α-smooth muscle actin (α-SMA), collagen type I, transforming growth factor β1 (TGF-β1) and interleukin-6 (IL-6) was not significantly affected by atorvastatin. Atorvastatin decreases myofibroblast number and collagen deposition but does not result in an improvement in joint mobility. Full article
(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)
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8 pages, 870 KiB  
Communication
Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis
by Karen Claesen, Lynn Roth, Joachim C. Mertens, Karlijn Hermans, Yani Sim and Dirk Hendriks
Pharmaceutics 2021, 13(10), 1731; https://doi.org/10.3390/pharmaceutics13101731 - 19 Oct 2021
Cited by 2 | Viewed by 1692
Abstract
Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 [...] Read more.
Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−), a model of advanced atherosclerosis, statins do not lower cholesterol. Consequently, studying cholesterol-independent effects of statins can be achieved more straightforwardly in these mice. Female ApoE −/−Fbn1C1039G+/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided into a WD group (receiving WD only) and a WD + atorvastatin group (receiving 10 mg/kg/day atorvastatin +WD) group. After 15 weeks, blood was collected from the retro-orbital plexus, and the mice were sacrificed. Total plasma cholesterol and C-reactive protein (CRP) were measured with commercially available kits. Plasma proCPU levels were determined with an activity-based assay. Total plasma cholesterol levels were not significantly different between both groups, while proCPU levels were significantly lower in the WD + atorvastatin group. Interestingly proCPU levels correlated with CRP and circulating monocytes. In conclusion, our results confirm that atorvastatin downregulates proCPU levels in ApoE−/−Fbn1C1039G+/− mice on a WD, and evidence was provided that this downregulation is a pleiotropic effect of atorvastatin treatment. Full article
(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)
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Review

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17 pages, 1873 KiB  
Review
Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus
by Melissa D. Evans and Susan A. McDowell
Pharmaceutics 2021, 13(12), 2047; https://doi.org/10.3390/pharmaceutics13122047 - 30 Nov 2021
Cited by 3 | Viewed by 2212
Abstract
An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects [...] Read more.
An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection. Full article
(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)
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