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USE OF GOLD NANOCLUSTERS IN TREATING HYPERCHOLESTEROLEMIA OR HYPERCHOLESTEROLEMIA-ASSOCIATED DISEASES

Taiwan
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Introduction
Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects
of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles with intrinsic antioxidant activity. In Western-type diet-fed ApoE-deficient mice, FANC given either intraperitoneally by osmotic
minipump or orally in drinking water reduced aortic atheroma burden, serum total cholesterol and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels, and hepatic lipid deposit, with changed expression of lipid homeostasis-related genes, including HMGCR, SREBP, PCSK9, and LDLr, in a pattern similar to those of mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC were repeatedly shown in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor beta (IRbeta via the capped ligand DHLA, leading to AKT activation. However, unlike insulin, which also bound IRbeta to activate AKT to
induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free
NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1, consistent with suppression by FANC of ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In parallel, in macrophages,
FANC up-regulated ABCA1, and in macrophages treated with ox-LDL, reversed the suppressed cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed multiple actions and mechanisms of FANC worked coherently
against atherosclerosis.
Features / strengths
FANC are different from classical organic synthesized lipid lowering drugs and are not accumulated and metabolized in liver, suggesting without hepatic toxicity. We conducted one year of animal study showed that FANC do not cause infertility,
embryo abnormality and no accumulation in vital organs. Importantly, the cost of FANC in therapy is reasonable. FANC markedly reduced atherosclerosis and cholesterol in 8-week animal tests, showing the marketing potential.Commercialization of FANC will be a novel drug for cardiovascular disease, benefit to patients worldwide and contribute to the development of bio- and nanotechnology
of our country.
Specification in detail
已完成動物實驗
已完成動物實驗

Information
Introduction
Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects
of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles with intrinsic antioxidant activity. In Western-type diet-fed ApoE-deficient mice, FANC given either intraperitoneally by osmotic
minipump or orally in drinking water reduced aortic atheroma burden, serum total cholesterol and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels, and hepatic lipid deposit, with changed expression of lipid homeostasis-related genes, including HMGCR, SREBP, PCSK9, and LDLr, in a pattern similar to those of mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC were repeatedly shown in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor beta (IRbeta via the capped ligand DHLA, leading to AKT activation. However, unlike insulin, which also bound IRbeta to activate AKT to
induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free
NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1, consistent with suppression by FANC of ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In parallel, in macrophages,
FANC up-regulated ABCA1, and in macrophages treated with ox-LDL, reversed the suppressed cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed multiple actions and mechanisms of FANC worked coherently
against atherosclerosis.
Features / strengths
FANC are different from classical organic synthesized lipid lowering drugs and are not accumulated and metabolized in liver, suggesting without hepatic toxicity. We conducted one year of animal study showed that FANC do not cause infertility,
embryo abnormality and no accumulation in vital organs. Importantly, the cost of FANC in therapy is reasonable. FANC markedly reduced atherosclerosis and cholesterol in 8-week animal tests, showing the marketing potential.Commercialization of FANC will be a novel drug for cardiovascular disease, benefit to patients worldwide and contribute to the development of bio- and nanotechnology
of our country.
Specification in detail
已完成動物實驗
已完成動物實驗

USE OF GOLD NANOCLUSTERS IN TREATING HYPERCHOLESTEROLEMIA OR HYPERCHOLESTEROLEMIA-ASSOCIATED DISEASES

Taiwan
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