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Cells Apr 2023Oxysterols are oxidized cholesterol derivatives whose systemic levels are found elevated in pregnancy disorders such as gestational diabetes mellitus (GDM). Oxysterols...
Oxysterols are oxidized cholesterol derivatives whose systemic levels are found elevated in pregnancy disorders such as gestational diabetes mellitus (GDM). Oxysterols act through various cellular receptors and serve as a key metabolic signal, coordinating inflammation. GDM is a condition of low-grade chronic inflammation accompanied by altered inflammatory profiles in the mother, placenta and fetus. Higher levels of two oxysterols, namely 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), were observed in fetoplacental endothelial cells (fpEC) and cord blood of GDM offspring. In this study, we tested the effects of 7-ketoC and 7β-OHC on inflammation and investigated the underlying mechanisms involved. Primary fpEC in culture treated with 7-ketoC or 7β-OHC, induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling, which resulted in the expression of pro-inflammatory cytokines (IL-6, IL-8) and intercellular cell adhesion molecule-1 (ICAM-1). Liver-X receptor (LXR) activation is known to repress inflammation. Treatment with LXR synthetic agonist T0901317 dampened oxysterol-induced inflammatory responses. Probucol, an inhibitor of LXR target gene ATP-binding cassette transporter A-1 (ABCA-1), antagonized the protective effects of T0901317, suggesting a potential involvement of ABCA-1 in LXR-mediated repression of inflammatory signaling in fpEC. TLR-4 inhibitor Tak-242 attenuated pro-inflammatory signaling induced by oxysterols downstream of the TLR-4 inflammatory signaling cascade. Taken together, our findings suggest that 7-ketoC and 7β-OHC contribute to placental inflammation through the activation of TLR-4. Pharmacologic activation of LXR in fpEC decelerates its shift to a pro-inflammatory phenotype in the presence of oxysterols.
Topics: Humans; Female; Pregnancy; Oxysterols; Liver X Receptors; Endothelial Cells; Toll-Like Receptor 4; Placenta; Diabetes, Gestational; Inflammation
PubMed: 37190095
DOI: 10.3390/cells12081186 -
Translational Neurodegeneration Jan 2024Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative... (Review)
Review
Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.
Topics: Humans; Neurodegenerative Diseases; Probucol; Alzheimer Disease; Parkinson Disease; Blood-Brain Barrier
PubMed: 38247000
DOI: 10.1186/s40035-024-00398-w -
Biomedicine & Pharmacotherapy =... Dec 2021In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms.
BACKGROUND
In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms.
METHODS
D-galactose (100 mg/kg, once daily for 6 weeks) was subcutaneously injected to induce aging in mice. Then the mice were administered with probucol or vehicle once a day for 2 weeks. The hippocampus-related cognition was evaluated with Morris water maze test, novel object recognition test, and contextual fear conditioning test. Moreover, synaptic plasticity was assessed, and RNA-sequencing was applied to further explore the molecular mechanisms.
RESULTS
Aging mice induced by D-galactose showed conspicuous learning and memory impairment, which was significantly ameliorated by probucol. Meanwhile, probucol enhanced the spine density and dendritic branches, improved long-term potentiation, and increased the expression of PSD95 of aging mice. Probucol regulated 70 differentially expressed genes compared to D-galactose group, of which 38 genes were upregulated and 32 genes were downregulated. At last, RNA-sequencing results were verified by quantitative reverse transcription-polymerase chain reaction.
CONCLUSIONS
Probucol improved learning and memory in aging mice through enhancing synaptic plasticity and regulating gene expression, indicating the potential application of probucol to prevent and treat aging-related disorders.
Topics: Age Factors; Animals; Behavior, Animal; Cellular Senescence; Cognition; Cognitive Dysfunction; Cyclin-Dependent Kinase Inhibitor p16; Disease Models, Animal; Disks Large Homolog 4 Protein; Fear; Gene Expression Regulation; Hippocampus; Long-Term Potentiation; Male; Mice, Inbred C57BL; Morris Water Maze Test; Neurons; Nootropic Agents; Open Field Test; Probucol; Tumor Suppressor Protein p53; Mice
PubMed: 34634555
DOI: 10.1016/j.biopha.2021.112266 -
European Journal of Preventive... Oct 2020Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density... (Review)
Review
Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.
Topics: Biomarkers; Cholesterol, HDL; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipids
PubMed: 31060364
DOI: 10.1177/2047487319845314 -
Chonnam Medical Journal Sep 2017Delayed arterial healing at culprit sites after drug-eluting stent (DES) placement for acute myocardial infarction (AMI) is associated with increased risk of late stent... (Review)
Review
Delayed arterial healing at culprit sites after drug-eluting stent (DES) placement for acute myocardial infarction (AMI) is associated with increased risk of late stent thrombosis. The Korea Acute Myocardial Infarction Registry was established in commemoration of the 50 anniversary of Korea Circulation Society. Between November 2005 and December 2016, more than 62,000 patients were registered from 50 primary percutaneous coronary intervention (PCI) centers in Korea. DES in AMI may be safe and effective, however, there is concern about increased stent thrombosis after DES implantation in AMI patients, requiring longer-term dual anti-platelet therapy to reduce the risk of late stent thrombosis. Device innovation is needed to overcome issues such as stent thrombosis and restenosis by using new coating materials with biocompatible polymers, different coating methods using non-polymer techniques, bioabsorbable stents and pro-healing stents. In this review article, we describe the current usage of DES in AMI in Korea and introduce novel DES uses in development for patients with AMI. We have developed many types of DES in our research laboratory. Abciximab-coated stents inhibited platelet thrombi and restenosis. Furthermore, anti-oxidants (carvedilol, probucol and alpha-lipoic acid) were used for stent coating. Currently we are developing novel DESs using polymer-free and natural binding techniques, peptide coating stents, gene-and-drug delivery, bioabsorbable stents using 3D printing, endothelial progenitor cell capturing stents to promote reendothelialization and reduce stent thrombosis. New DESs in development may be safe and effective in preventing late stent thrombosis and restenosis in patients with AMI.
PubMed: 29026706
DOI: 10.4068/cmj.2017.53.3.187 -
International Journal of Molecular... May 2023CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research... (Review)
Review
CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being translated into practical and effective applications in the clinic.
Topics: Animals; Humans; Autoimmune Diseases; Autoimmunity; Autophagy; Lectins, C-Type; Monosaccharide Transport Proteins; Risk Factors
PubMed: 37175930
DOI: 10.3390/ijms24098224 -
PloS One 2015Restenosis after percutaneous coronary intervention (PCI) is a remained clinical problem which limits long-term success of PCI. Although there was recognition that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Restenosis after percutaneous coronary intervention (PCI) is a remained clinical problem which limits long-term success of PCI. Although there was recognition that probucol in treating restenosis after percutaneous transluminal coronary angioplasty, the efficacy of probucol on restenosis after stent-implantation is controversial. So this meta-analysis was conducted to investigate the association between probucol and late restenosis.
METHODS
Articles were assessed by four trained investigators, with divergences resolved by consensus. PubMed, EMBASE, ScienceDirect and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocated to treatment and a comparison of probucol-treated patients and control patients (not treated with lipid-lowering drug) undergoing PCI.
RESULTS
Fifteen studies with 859 subjects were analyzed. Major outcome, binary angiographic restenosis defined as >50% stenosis upon follow-up angiography, was significantly decreased with probucol treatment (RR = 0.59 [0.43, 0.80] among vessels, P = 0.0007; and RR = 0.52 [0.40, 0.68] among patients, P<0.00001). Probucol also increased the minimal luminal diameter (SMD = 0.45 [0.30, 0.61], P<0.00001) and decreased late loss upon follow-up after 6 months (SMD = -0.41 [-0.60, -0.22], P<0.0001). Moreover, there was a significantly lower incidence of major adverse cardiac events (MACE) in the probucol group than control group (RR = 0.69 [0.51, 0.93], P = 0.01).
CONCLUSION
Probucol is more than a lipid-lowering drug. It is also effective in reducing the risk of restenosis and incidence of MACE after PCI.
Topics: Anticholesteremic Agents; Cardiovascular Agents; Combined Modality Therapy; Coronary Disease; Humans; Percutaneous Coronary Intervention; Probucol; Treatment Outcome
PubMed: 25898372
DOI: 10.1371/journal.pone.0124021 -
European Journal of Pharmaceutics and... Jul 2022Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro...
Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
Topics: Administration, Oral; Atazanavir Sulfate; Hydrogen-Ion Concentration; Intestinal Absorption; Pharmaceutical Preparations; Probucol; Solubility
PubMed: 35605926
DOI: 10.1016/j.ejpb.2022.05.010 -
Cardiovascular Therapeutics Oct 2014Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, and its prevalence has increasing substantially over the last decades. Recent data... (Review)
Review
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, and its prevalence has increasing substantially over the last decades. Recent data suggest that there is an increased risk of AF among the patients with diabetes mellitus (DM). However, the potential molecular mechanisms regarding DM-related AF and diabetic atrial remodeling are not fully understood. In this comprehensive review, we would like to summarize the potential relationship between diabetes and atrial remodeling, including structural, electrical, and autonomic remodeling. Also, some upstream therapies, such as thiazolidinediones, probucol, ACEI/ARBs, may play an important role in the prevention and treatment of AF. Therefore, large prospective randomized, controlled trials and further experimental studies should be challengingly continued.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Atrial Remodeling; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Oxidative Stress; PPAR gamma; Probucol; Receptor for Advanced Glycation End Products; Receptors, Immunologic
PubMed: 25065462
DOI: 10.1111/1755-5922.12089 -
Journal of the American College of... Jul 2020
Topics: Drug-Eluting Stents; Humans; Percutaneous Coronary Intervention; Pharmaceutical Preparations; Polymers; Sirolimus
PubMed: 32646564
DOI: 10.1016/j.jacc.2020.05.050