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Diabetes & Vascular Disease Research Jan 2019An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2... (Comparative Study)
Comparative Study
An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2 diabetes. Our previous studies demonstrated that selected anti-inflammatory/anti-oxidative agents can preserve the integrity of blood-brain barrier and prevent neuroinflammation in mouse models of dysfunctional blood-brain barrier. Therefore, we have tested whether the previously proven blood-brain barrier protective agent, probucol, can prevent blood-brain barrier breakdown and cognitive decline in a dietary-induced murine model of diabetic insulin resistance. After 6-month chronic ingestion of a diet high in fat and fructose, the mice became insulin resistant. The high-fat and high-fructose-fed mice showed significant cognitive decline assessed by Morris water maze, concomitant with significant elevations in cortical and hippocampal glial acidic fibrillary protein and Fluoro Jade-C staining, indicating heightened neuroinflammation and neurodegeneration, respectively. The integrity of blood-brain barrier in high-fat and high-fructose-fed mice was substantially compromised, and this showed a significant association with heightened neurodegeneration. Co-provision of probucol with high-fat and high-fructose diet completely prevented the cognitive decline and blood-brain barrier dysfunction. Similarly, metformin was able to restore the cognitive function in high-fat and high-fructose-fed mice, while its blood-brain barrier protective effects were modest. These data suggest that probucol may prevent cognitive decline induced by insulin resistance by preserving the integrity of blood-brain barrier, whereas metformin's neuroprotective effects may be mediated through a separate pathway.
Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Blood-Brain Barrier; Cerebral Cortex; Cognition; Cognition Disorders; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Fructose; Glial Fibrillary Acidic Protein; Hippocampus; Hypoglycemic Agents; Inflammation Mediators; Insulin Resistance; Male; Maze Learning; Metformin; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Probucol
PubMed: 30156119
DOI: 10.1177/1479164118795274 -
Drug Design, Development and Therapy 2015The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (I Kr), which is important for cardiac repolarization....
The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (I Kr), which is important for cardiac repolarization. Reduction of I hERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on I hERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.
Topics: Anticholesteremic Agents; Carbachol; Dose-Response Relationship, Drug; ERG1 Potassium Channel; Endosomal Sorting Complexes Required for Transport; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Immediate-Early Proteins; Long QT Syndrome; Nedd4 Ubiquitin Protein Ligases; Phosphorylation; Probucol; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 26229434
DOI: 10.2147/DDDT.S86724 -
Japanese Circulation Journal Jun 1999Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the... (Comparative Study)
Comparative Study
Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate-treated group, but a significant (p<0.05) reduction in HDL-C was observed in both the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no significant difference was observed between groups 3 and 5. Significant correlation (p<0.01) was found between serum low density lipoprotein cholesterol (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no correlation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafibrate-fed groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of covariance showed that the CETP activity responded more sensitively to drug treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed by Northern blotting at 8 weeks, but no changes were observed among the 5 groups. Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP activity without affecting liver CETP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate.
Topics: Animals; Anticholesteremic Agents; Base Sequence; Bezafibrate; Blotting, Northern; Carrier Proteins; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Chromatography, High Pressure Liquid; Glycoproteins; Hypolipidemic Agents; Lipids; Lipoproteins; Liver; Male; Molecular Sequence Data; Probucol; RNA, Messenger; Rabbits; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 10406588
DOI: 10.1253/jcj.63.471 -
The American Journal of the Medical... Jul 2009Hypomagnesemia continues to be a significant clinical disorder that is present in patients with diabetes mellitus, alcoholism, and treatment with magnesuric drugs... (Review)
Review
Hypomagnesemia continues to be a significant clinical disorder that is present in patients with diabetes mellitus, alcoholism, and treatment with magnesuric drugs (diuretics, cancer chemotherapy agents, etc.). To determine the role of magnesium in cardiovascular pathophysiology, we have used dietary restriction of this cation in animal models. This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses. SP acts primarily through neurokinin-1 receptors of inflammatory and endothelial cells, and may induce production of reactive oxygen and nitrogen species (superoxide anion, NO*, peroxynitrite, hydroxyl radical), leading to enhanced consumption of tissue antioxidants; stimulate release of inflammatory mediators; promote tissue adhesion molecule expression; and enhance inflammatory cell tissue infiltration and cardiovascular lesion formation. These SP-mediated events may predispose the heart to injury if faced with subsequent oxidative stressors (ischemia/reperfusion, certain drugs) or facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction. Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.
Topics: Animals; Cardiomyopathies; Diet; Endotoxemia; Humans; Magnesium Deficiency; Myocardial Reperfusion Injury; Neurogenic Inflammation; Neuropeptides; Oxidative Stress; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurokinin-1
PubMed: 19593099
DOI: 10.1097/MAJ.0b013e3181aaee4d -
TheScientificWorldJournal 2014Uric acid has ever been considered as one of contrast induced acute kidney injury's risk factors. Atorvastatin and probucol can both improve contrast induced acute...
Uric acid has ever been considered as one of contrast induced acute kidney injury's risk factors. Atorvastatin and probucol can both improve contrast induced acute kidney injury separately. This prospective study is to assess their effect on reducing serum uric acid level and contrast induced acute kidney injury during perioperative period of interventional procedure. On the basis of different doses of atorvastatin and probucol, 208 cases admitted for coronary angiography or percutaneous coronary intervention were randomly classified into standard combined group (S-C group), intensive combined group (I-C group), and intensive atorvastatin group (I-A group). Patients' blood urea nitrogen, serum creatinine, and serum uric acid were measured and estimated glomerular filtration rate was evaluated 24 hours before and after the procedure. After procedure, blood urea nitrogen in all the three groups decreased; Scr of S-C group and I-A group increased significantly, while estimated glomerular filtration decreased in the S-C group (P < 0.05); serum uric acid in S-C group and I-C group decreased significantly (P < 0.05). Combination treatment of atorvastatin and probucol before intervention could reduce perioperative serum uric acid level; meanwhile, the intensive combined treatment can improve the contrast induced acute kidney injury. The result was the same for hypertensive patients.
Topics: Acute Kidney Injury; Aged; Antioxidants; Atorvastatin; Biomarkers; Contrast Media; Drug Therapy, Combination; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney Function Tests; Male; Middle Aged; Perioperative Period; Probucol; Prospective Studies; Pyrroles; Risk Factors; Uric Acid
PubMed: 24672331
DOI: 10.1155/2014/565367 -
Biological & Pharmaceutical Bulletin 2024Probucol is a hyperlipidemic drug with antioxidant properties. It has been reported to prevent mitochondrial dysfunction, reduce oxidative stress, and suppress...
Probucol is a hyperlipidemic drug with antioxidant properties. It has been reported to prevent mitochondrial dysfunction, reduce oxidative stress, and suppress neurotoxicity in neurodegenerative disease models, including Parkinson's disease models. However, the molecular mechanisms underlying the neuroprotective effects of probucol have been not examined yet. Thus, in this study, we investigated whether probucol can alleviate the effects of a mitochondrial complex I inhibitor, rotenone, on a human neuroblastoma cell line (SH-SY5Y). We evaluated the cell viability and cytotoxicity and apoptosis rates of SH-SY5Y cells treated with rotenone and probucol or edaravone, a known free-radical scavenger. Subsequently, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels in the cells were evaluated to determine the effects of probucol on mitochondrial function. We found that rotenone caused cytotoxicity, cell apoptosis, and mitochondrial dysfunction, enhanced ROS generation, and impaired MMP. However, probucol could inhibit this rotenone-induced decrease in cell viability, MMP loss, intracellular ROS generation, and apoptosis. These results suggest that probucol exerts neuroprotective effects via MMP stabilization and the inhibition of ROS generation. Additionally, this effect of probucol was equal to or greater than and more persistent than that of edaravone. Thus, we believe probucol may be a promising drug for the treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases.
Topics: Probucol; Rotenone; Humans; Reactive Oxygen Species; Neuroprotective Agents; Cell Line, Tumor; Cell Survival; Apoptosis; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Antioxidants
PubMed: 38880623
DOI: 10.1248/bpb.b24-00099 -
JACC. Cardiovascular Interventions Jun 2016This study sought to perform a systematic review and network meta-analysis to compare the relative safety and efficacy of contemporary DES and BVS. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This study sought to perform a systematic review and network meta-analysis to compare the relative safety and efficacy of contemporary DES and BVS.
BACKGROUND
To improve outcomes of patients undergoing percutaneous coronary revascularization, there have been advances in the design of drug-eluting stents (DES), including the development of drug-eluting bioresorbable vascular scaffolds (BVS).
METHODS
Prospective, randomized, controlled trials comparing bare-metal stents (BMS), paclitaxel-eluting stents (PES), sirolimus-eluting stents (SES), Endeavor zotarolimus-eluting stents (E-ZES), cobalt-chromium (CoCr) everolimus-eluting stents (EES), platinum-chromium (PtCr)-EES, biodegradable polymer (BP)-EES, Resolute zotarolimus-eluting stents (R-ZES), BP biolimus-eluting stents (BP-BES), hybrid sirolimus-eluting stents (H [Orsiro]-SES), polymer-free sirolimus- and probucol-eluting stents, or BVS were searched in online databases. The primary endpoint was definite or probable stent thrombosis at 1 year.
RESULTS
A total of 147 trials including 126,526 patients were analyzed in this study. All contemporary DES were superior to BMS and PES in terms of definite or probable stent thrombosis at 1 year. CoCr-EES, PtCr-EES, and H-SES were associated with significantly lower risk than BVS. CoCr-EES and H-SES were superior to SES and BP-BES. The risk of myocardial infarction was significantly lower with H-SES than with BVS. There were no significant differences regarding all-cause or cardiac mortality. Contemporary devices including BVS showed comparably low risks of repeat revascularization.
CONCLUSIONS
Contemporary DES, including biocompatible DP-DES, BP-DES, and polymer-free DES, showed a low risk of definite or probable stent thrombosis at 1 year. BVS had an increased risk of device thrombosis compared with CoCr-EES, PtCr-EES, and H-SES. Data from extended follow-up are warranted to confirm the long-term safety of contemporary coronary devices.
Topics: Absorbable Implants; Bayes Theorem; Coronary Disease; Coronary Thrombosis; Drug-Eluting Stents; Humans; Markov Chains; Monte Carlo Method; Network Meta-Analysis; Odds Ratio; Percutaneous Coronary Intervention; Prosthesis Design; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 27262860
DOI: 10.1016/j.jcin.2016.03.038 -
Autophagy Apr 2024We have employed artificial intelligence to streamline the small molecule drug screening pipeline and identified the cholesterol-reducing compound probucol in the...
We have employed artificial intelligence to streamline the small molecule drug screening pipeline and identified the cholesterol-reducing compound probucol in the process. Probucol augmented mitophagy and prevented loss of dopaminergic neurons in flies and zebrafish challenged with mitochondrial toxins. Further dissection of the mechanism of action led to the identification of ABCA1, the target of probucol, as a mitophagy modulator. Probucol treatment regulates lipid droplet dynamics during mitophagy and ABCA1 is required for these effects. Here we will summarize the combination of in silico and cell-based screening that led us to identify and characterize probucol as a compound that enhances mitophagy and include thoughts about future directions for the topics explored in our study. ABCA1: ATP binding cassette transporter protein 1; ATP: Adenosine tri-phosphate; CCCP: carbonyl cyanide m-chlorophenylhydrazone; DsRed: Discosoma red; FDA: Food and drug administration; GFP: Green fluorescent protein; LAMP: lysosome-associated membrane glycoproteins; LD: Lipid droplet; PD: Parkinson's disease; PINK: PTEN-induced kinase.
Topics: Artificial Intelligence; Animals; Drug Discovery; Humans; Mitophagy; Semantics
PubMed: 37179524
DOI: 10.1080/15548627.2023.2210995 -
Pharmaceutics Aug 2021Probucol (PB) is a highly lipophilic drug with potential protective effects on pancreatic β-cells from inflammation and oxidation. PB has poor bioavailability and...
Probucol (PB) is a highly lipophilic drug with potential protective effects on pancreatic β-cells from inflammation and oxidation. PB has poor bioavailability and solubility, and despite many attempts, significant improvement in antidiabetic effects or absorption has yet to be discovered. Recently, the role of bile acids has been established in significant drug formulation stabilisation effects and as cell-penetrating agents. Promising results in pharmaceutical formulation studies on drug stability and release patterns when lithocholic acid (LCA) is conjugated with PB and sodium alginate (SA) have been demonstrated. Thus, this study aimed to develop and characterise PB microcapsules incorporating LCA and examine the biological effects of the microcapsules in vitro and in vivo. PB/LCA microcapsules were prepared using an encapsulation method, ionic gelation vibrational jet flow technology. LCA incorporation in PB microcapsules showed positive effects on β-cells with improved insulin release, antioxidant activity, and PB intracellular uptake. Diabetic mice gavaged LCA-PB microcapsules showed a significant reduction in diabetes signs and symptoms, better survival rate, reduced blood glucose levels, and pro-inflammatory cytokines, with an increase PB level in blood and tissues suggesting a potential therapy for treating diabetes mellitus.
PubMed: 34452184
DOI: 10.3390/pharmaceutics13081223 -
Journal of the American College of... Apr 2003Research into the oxidation of lipoproteins has yielded many new insights into the pathogenesis of atherosclerosis. However, despite lipoprotein oxidation's biologically... (Review)
Review
Research into the oxidation of lipoproteins has yielded many new insights into the pathogenesis of atherosclerosis. However, despite lipoprotein oxidation's biologically plausible role in atherogenesis, several studies have reported inconsistent effects of antioxidants on clinical coronary end points, in sharp contrast with the studies of lipid modification with the 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, or statins. There appears to be little support for the use of antioxidants in coronary prevention. However, the picture remains incomplete. What are the limitations of available antioxidant studies and the agents used? Until the picture can be clarified, lipid modification with strategies proved to reduce the risk for coronary events, such as statins or dietary changes in the style of the Mediterranean diet, should be better implemented in clinical practice.
Topics: Animals; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Probucol; Rabbits; Vitamin E; beta Carotene
PubMed: 12679223
DOI: 10.1016/s0735-1097(03)00082-2