Did we abandon probucol too soon?

Yamashita, Shizuya; Masuda, Daisuke; Matsuzawa, Yūji

doi:10.1097/mol.0000000000000199

Cited by 47 publications

(29 citation statements)

References 101 publications

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“…Gain of dysfunction will require the elimination of harmful components or blockage of their formation and their cellular responders. In this situation, although at first sight paradoxically, therapies that enhance the catabolism of HDL and thereby lower HDL cholesterol, such as probucol 243 or testosterone, 244 will be rather beneficial. Such therapies may benefit from combination with HDL mimetics or stimulators of HDL production.…”

Section: Therapy and Drug Developmentmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Therapy and Drug Developmentmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…Probucol is a lipid-lowering drug which increases the fraction rate of LDL catabolism and has been used to treat hyperlipidemia [24]. e antioxidant and anti-inflammatory properties of probucol have been investigated using in vitro cell cultures and in vivo animal models [13,14].…”

Section: Discussionmentioning

confidence: 99%

Probucol Prevents Diabetes-Induced Retinal Neuronal Degeneration through Upregulating Nrf2

Liu

Luo

Zhou

et al. 2020

BioMed Research International

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Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. This study investigated the therapeutic effect of probucol in a mouse model of diabetic retinopathy. C57BL/6 mice were rendered diabetic through Streptozotocin (STZ) intraperitoneal injection. Mice were treated with probucol (150 mg/kg, gavage administration) or vehicle (DMSO) for 12 weeks. Optical coherence tomography (OCT), fundus photography (FP), and fundus fluorescein angiography (FFA) were conducted to evaluate retinal structure and damage. Eyes were collected for histology, reactive oxygen species (ROS) assay, apoptotic cells count, and western blot. After STZ injection, all mice developed hyperglycemia. Compared with the retina of the control group, the retina of diabetic mice showed enhanced arterial reflex and beaded vein dilatation. Besides, reduced inner and middle retinal thickness and significantly fewer nuclei were found in diabetic retina. Moreover, the diabetic retina also presented increased ROS generation and more TUNEL-positive cells. Probucol treatment prevented diabetes-induced lesions. In addition, the treatment also upregulated Nrf2 expression in diabetic retina. It was suggested that probucol attenuated diabetes-induced retinal neuronal degeneration via upregulating the Nrf2 signaling pathway possibly. Probucol may be repurposed for DR management.

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“…There is controversy regarding the use of probucol in cardiovascular diseases and some western countries have stopped its use because of the reduction in serum HDL-cholesterol (HDL-C). However the HDL-C reduction may not be a 'side effect' but may reflect a mechanism of action of probucol as it causes a decrease in HDL-C by enhancing plasma cholesteryl ester transfer protein activity and hepatic scavenger receptor class B type I. Probucol also accelerates the antioxidant function of HDL via increasing paraoxonase 1 activity (42). In particular, a significant coronary artery disease risk reduction has been demonstrated in the long-term treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan with probucol (43).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, a significant coronary artery disease risk reduction has been demonstrated in the long-term treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan with probucol (43). And there is also evidence for the pleiotropic and beneficial therapeutic effects of probucol on the cardiovascular system and in chronic kidney disease (42,44). As a result of these studies it is clear that probucol may have beneficial therapeutic effects in certain suitable CKD patients.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX‑1/ROS/MAPK signaling

et al. 2017

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Oxidized low-density lipoprotein (Ox-LDL), as a strong oxidant, results in renal injury through multiple mechanisms. The aim of the present study was to determine the injury effects of Ox‑LDL and the potential protective effects of the antioxidant reagent probucol on epithelial‑mesenchymal transition (EMT) in human renal proximal tubular epithelial cells (HK‑2) and to further explore the role and interrelation of lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1), reactive oxygen species (ROS) and mitogen‑activated protein kinase (MAPK) pathway. In the present study, concentrations of 0‑100 µg/ml Ox‑LDL were used to induce HK‑2 cell EMT. Then, probucol (20 µmol/l) and the LOX‑1 inhibitor, polyinosinic acid (250 µg/ml), were also used to pretreat HK‑2 cells. Intracellular ROS activity was evaluated using the specific probe 2',7'‑dichlorodihydrofluorescein diacetate (DCFH‑DA). Concentration of nitric oxide (NO) was determined using a biochemical colorimetric method. Expression of E‑cadherin, α‑smooth muscle actin (SMA), LOX‑1, NADPH oxidase 4 (NOX4), cytochrome b‑245 α chain (p22phox), extracellular signal‑regulated kinase (ERK), and p38 MAPK protein levels were examined by western blotting. The results revealed that Ox‑LDL induced the expression of LOX‑1 and α‑SMA and reduced the expression of E‑cadherin in a dose‑dependent manner, and these effects were inhibited by polyinosinic acid or probucol pretreatment. Stimulation with 50 µg/ml Ox‑LDL induced the expression of NOX4 and p22phox and increased intracellular ROS activity, but NO production in the cell supernatants was not affected. The Ox‑LDL‑mediated increases in Nox4 and p22phox expression and in ROS activity were inhibited by probucol pretreatment. Further investigations into the underlying molecular pathways demonstrated that ERK and p38 MAPK were activated by Ox‑LDL stimulation and then inhibited by probucol pretreatment. The findings of the present study therefore suggest that Ox‑LDL induced EMT in HK‑2 cells, the mechanism of which may be associated with LOX‑1‑related oxidative stress via the ERK and p38 MAPK pathways. Notably, pretreatment with probucol inhibited the Ox‑LDL‑induced oxidative stress by reducing the expression of LOX‑1, and blocked the progression of EMT.

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Did we abandon probucol too soon?

Abstract: Probucol has pleiotropic and beneficial therapeutic effects on cardiovascular system. Although statins are effective for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease risk, probucol should be considered as an option in case statins are not effective.

Cited by 47 publications

References 101 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Probucol Prevents Diabetes-Induced Retinal Neuronal Degeneration through Upregulating Nrf2

Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX‑1/ROS/MAPK signaling

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