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British Journal of Clinical Pharmacology May 1981
Topics: Adult; Aged; Bile; Cholesterol; Diet; Female; Humans; Hypercholesterolemia; Lipid Metabolism; Male; Middle Aged; Phenols; Probucol
PubMed: 7272170
DOI: 10.1111/j.1365-2125.1981.tb01166.x -
Journal of Atherosclerosis and... Feb 2006To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary... (Randomized Controlled Trial)
Randomized Controlled Trial
To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 +/- 7.5 to 8.1 +/- 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 +/- 8.8 to 6.8 +/- 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 +/- 4.9 to 9.2 +/- 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 +/- 8.2 to 6.67 +/- 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anticholesteremic Agents; Antioxidants; Atorvastatin; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Male; Middle Aged; Oxidative Stress; Probucol; Pyrroles; Treatment Outcome
PubMed: 16505594
DOI: 10.5551/jat.13.68 -
International Ophthalmology Dec 2023This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action.
PURPOSE
This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action.
METHODS
Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot.
RESULTS
We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells.
CONCLUSIONS
Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.
Topics: Humans; Ependymoglial Cells; Glucose; NF-E2-Related Factor 2; Probucol; Signal Transduction
PubMed: 37688651
DOI: 10.1007/s10792-023-02859-z -
Journal of Pharmacological Sciences Feb 2019Probucol has antioxidant effects and inhibits inflammation. Farnesoid X receptor (FXR) is a nuclear receptor that regulates autophagy, which is regarded as the key cause...
Probucol has antioxidant effects and inhibits inflammation. Farnesoid X receptor (FXR) is a nuclear receptor that regulates autophagy, which is regarded as the key cause of the activation of hepatic stellate cell (HSC). In this study, the effects of probucol on HSC activation and autophagy in vitro and vivo and the role of FXR in this progress were investigated. Results showed that probucol ameliorated hepatic fibrosis and autophagy, and increased the expression of FXR in liver in a mouse model of fibrosis induced by CCl. And probucol could alleviate lipopolysaccharide-induced autophagy and HSC activation in vitro. In addition, probucol increased FXR expression, and the Z-guggulsterone, an antagonist of FXR, could block the effects of probucol on HSC activation and autophagy. Additionally, agonists of FXR could suppress LPS-induced autophagy and activation. These results suggest that probucol could ameliorate hepatic fibrosis, and inhibit HSC autophagy and activation, and these effects are associated with FXR.
Topics: Animals; Antioxidants; Autophagy; Cell Line; Cells, Cultured; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Probucol; Rats; Receptors, Cytoplasmic and Nuclear
PubMed: 30638990
DOI: 10.1016/j.jphs.2018.12.005 -
Oxidative Medicine and Cellular... 2021Osteoarthritis (OA) is a chronic joint disease characterized by cholesterol accumulation in chondrocytes, cartilage degeneration, as well as extracellular matrix (ECM)...
The Combination Treatment of Curcumin and Probucol Protects Chondrocytes from TNF- Induced Inflammation by Enhancing Autophagy and Reducing Apoptosis via the PI3K-Akt-mTOR Pathway.
Osteoarthritis (OA) is a chronic joint disease characterized by cholesterol accumulation in chondrocytes, cartilage degeneration, as well as extracellular matrix (ECM) destruction, and joint dysfunction. Curcumin, a chemical that can reduce cholesterol levels in OA patients, also can inhibit the progression of OA. However, a high concentration of curcumin may also trigger apoptosis in normal chondrocytes. Besides curcumin, probucol that is found can also effectively decrease the cholesterol level in OA patients. Considering that high cholesterol is a risk factor of OA, it is speculated that the combination treatment of curcumin and probucol may be effective in the prevention of OA. To investigate the possible effects of such two chemicals on OA pathophysiology, chondrocyte apoptosis and autophagy behavior under inflammatory cytokine stress were studied, and specifically, the PI3K-Akt-mTOR signaling pathway was studied. . Cell proliferation, colony formation, and EdU assay were performed to identify the cytotoxicity of curcumin and probucol on chondrocytes. Transwell assay was conducted to evaluate chondrocyte migration under TNF- inflammation stress. Immunofluorescence, JC-1, flow cytometry, RT-PCR, and western blot were used to investigate the signal variations related to autophagy and apoptosis in chondrocytes and cartilage. A histological study was carried out on OA cartilage. Glycosaminoglycan (GAG) release was determined to evaluate the ECM degradation under stress. . Compared with a single intervention with curcumin or probucol, a combined treatment of these two chemicals is more effective in terms of protecting chondrocytes from stress injury induced by inflammatory cytokines. The promoted protection may be attributed to the inhibition of apoptosis and the blockage of the autophagy-related PI3K/Akt/mTOR pathway. Such results were also verified in vitro by immunofluorescence staining of OA chondrocytes and in vivo by immunohistochemistry staining of cartilage. Besides, in vivo studies also showed that when applied in combination, curcumin and probucol could block the PI3K-AKT-mTOR signaling pathway; promote COL-II expression; suppress P62, MMP-3, and MMP-13 expression; and inhibit TNF--stimulated cartilage degradation. Moreover, the combined medication could help reduce the release of ECM GAGs in OA cartilage and alleviate the severity of OA. . A combined treatment of curcumin and probucol could be used to protect chondrocytes from inflammatory cytokine stress via inhibition of the autophagy-related PI3K/Akt/mTOR pathway both in vitro and in vivo, which might be of potential pharmaceutical value for OA prevention and therapy.
Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Autophagy; Chondrocytes; Curcumin; Humans; Inflammation; Osteoarthritis; Phosphatidylinositol 3-Kinases; Probucol; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha
PubMed: 34257809
DOI: 10.1155/2021/5558066 -
Molecular Medicine (Cambridge, Mass.) Jun 2022Probucol (PBC) is a potent cholesterol-lowering drug and has been studied extensively for its powerful antioxidative stress. The purpose of this study is to investigate...
Probucol (PBC) is a potent cholesterol-lowering drug and has been studied extensively for its powerful antioxidative stress. The purpose of this study is to investigate the role of PBC in ovariectomized rat model and to explore the mechanism of osteogenic differentiation of MC3TE-E1 Cells. RT-qPCR and Immunofluorescence were used to measure the expression level of SOD2, SIRT1, intracellular oxidative stress levels and osteogenic markers proteins. Moreover, CCK-8 assay was conducted to detect cell viability. Alizarin red staining and alkaline phosphatase staining were applied to examine osteogenic function and calcium deposits. The ovariectomized rat model was set up successfully and HE staining were employed to examine femoral trabeculae tissue. Our results showed that PBC suppressed MC3TE-E1 resist oxidative stress to promote osteogenic differentiation. Additionally, it was confirmed that PBC promoted osteogenic differentiation of MC3TE-E1 through inhibiting oxidative stress. Further study indicated that PBC exerted its beneficial function by suppressing oxidative stress-mediated alter bone metabolism to alleviate osteoporosis in vivo. Our research suggested that the PBC-modulated oxidative stress inhibition is responsible for activation of the process of osteogenic differentiation, providing a novel insight into the treatment of osteoporosis.
Topics: Animals; Osteoblasts; Osteogenesis; Osteoporosis; Oxidative Stress; Probucol; Rats
PubMed: 35764958
DOI: 10.1186/s10020-022-00503-7 -
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 -
Current Pharmaceutical Design 2020The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a...
BACKGROUND
The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a crucial determinant of cardiac repolarization. The reduction of hERG current is commonly believed to cause Long QT Syndrome (LQTs). Probucol, a cholesterol-lowering drug, induces LQTs by inhibiting the expression of the hERG channel. Unfortunately, there is currently no effective therapeutic method to rescue probucol-induced LQTs.
METHODS
Patch-clamp recording techniques were used to detect the action potential duration (APD) and current of hERG. Western blot was performed to measure the expression levels of proteins.
RESULTS
In this study, we demonstrated that 1 μM matrine and oxymatrine could rescue the hERG current and hERG surface expression inhibited by probucol. In addition, matrine and oxymatrine significantly shortened the prolonged action potential duration induced by probucol in neonatal cardiac myocytes. We proposed a novel mechanism underlying the probucol induced decrease in the expression of transcription factor Specificity protein 1 (Sp1), which is an established transactivator of the hERG gene. We also demonstrated that matrine and oxymatrine were able to upregulate Sp1 expression which may be one of the possible mechanisms by which matrine and oxymatrine rescued probucol-induced hERG channel deficiency.
CONCLUSION
Our current results demonstrate that matrine and oxymatrine could rescue probucol-induced hERG deficiency in vitro, which may lead to potentially effective therapeutic drugs for treating acquired LQT2 by probucol in the future.
Topics: Alkaloids; Animals; Cell Line; Ether-A-Go-Go Potassium Channels; Humans; Myocytes, Cardiac; Patch-Clamp Techniques; Probucol; Quinolizines; Rats, Sprague-Dawley; Matrines
PubMed: 31657676
DOI: 10.2174/1381612825666191026170033 -
Journal of Atherosclerosis and... Feb 2021In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time.
METHODS
Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints.
RESULTS
Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; -0.12±0.36 mm vs. probucol; -0.11 ±0.32 mm vs. combo; -0.16±0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p=0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions.
CONCLUSION
Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.
Topics: Anticholesteremic Agents; Carotid Intima-Media Thickness; Cholesterol, HDL; Cholesterol, LDL; Cilostazol; Coronary Artery Disease; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Probucol; Time; Treatment Outcome
PubMed: 32336696
DOI: 10.5551/jat.55616 -
Turkish Journal of Pharmaceutical... Feb 2021Probucol is a bisphenol antioxidant with antiinflammatory, antilipidemic and antidiabetic effect. Development and progression of cancer is closely related to chronic...
OBJECTIVES
Probucol is a bisphenol antioxidant with antiinflammatory, antilipidemic and antidiabetic effect. Development and progression of cancer is closely related to chronic inflammation and oxidative stress. Agents that target these processes have been shown to modulate cancer cell proliferation. In this regard, the effect of probucol on proliferation of different cancer cell lines was investigated.
MATERIALS AND METHODS
Different concentrations of probucol solutions were prepared and applied to the following cancer cell lines: K562S (imatinib sensitive) and K562R (imatinib resistant) chronic myeloid leukemia (CML) cells; U937 histiocytic lymphoma cells; HL60 acute myeloid leukemia cells; U266, H929, and RPMI8226 multiple myeloma cells; and L929 fibroblast cells. Cell viability was conducted by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
RESULTS
Significant toxicity was not exhibited due to probucol treatment (0.1-10 µM) in K562S and K562R CML cells, U937 histiocytic lymphoma cells, HL60 acute myeloid leukemia cells, U266 multiple myeloma cells, and L929 fibroblast cells. However, probucol treatment significantly inhibited the viability of H929 and RPMI8226 multiple myeloma cells at the concentration of 0.5-10 µM and 5-10 µM, respectively.
CONCLUSION
Probucol treatment slightly inhibited the viability of other cancer cell lines, but significantly inhibited the viability of H929 and RPMI8226 multiple myeloma cells. However, its effect was not potent, since a 50% reduction in cell viability could not be achieved at the concentrations of probucol treatment administered.
PubMed: 33634671
DOI: 10.4274/tjps.galenos.2019.04657