title: Berberine-sonodynamic therapy induces autophagy and lipid unloading in macrophage.
abstract: Impaired autophagy in macrophages accompanies the progression of atherosclerosis and contributes to lipid loading in plaques and ineffective lipid degradation. Therefore, evoking autophagy and its associated cholesterol efflux may provide a therapeutic treatment for atherosclerosis. In the present study, berberine-mediated sonodynamic therapy (BBR-SDT) was used to induce autophagy and cholesterol efflux in THP-1 macrophages and derived foam cells. Following BBR-SDT, autophagy was increased in the macrophages, autophagy resistance in the foam cells was prevented, and cholesterol efflux was induced. The first two effects were blocked by the reactive oxygen species scavenger, N-acetyl cysteine. BBR-SDT also reduced the phosphorylation of Akt and mTOR, two key molecules in the PI3K/AKT/mTOR signaling pathway, which is responsible for inducing autophagy. Correspondingly, treatment with the autophagy inhibitor, 3-methyladenine, or the PI3K inhibitor, LY294002, abolished the autophagy-induced effects of BBR-SDT. Furthermore, induction of cholesterol efflux by BBR-SDT was reversed by an inhibition of autophagy by 3-methyladenine or by a small interfering RNA targeting Atg5. Taken together, these results demonstrate that BBR-SDT effectively promotes cholesterol efflux by increasing reactive oxygen species generation, and this subsequently induces autophagy via the PI3K/AKT/mTOR signaling pathway in both 'normal' macrophages and lipid-loaded macrophages (foam cells). Thus, BBR-SDT may be a promising atheroprotective therapy to inhibit the progression of atherosclerosis and should be further studied.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Jiayuan Y
authors.initials: JY
authors.lastname: Kou
authors.affiliation: Department of Oncology, The First Affiliated Clinic College of Harbin Medical University, Harbin, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Zhaoyu Y
authors.initials: ZY
authors.lastname: Zhong
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Yueqing Q
authors.initials: YQ
authors.lastname: Jiang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Xuesong S
authors.initials: XS
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Xiaobo B
authors.initials: XB
authors.lastname: Han
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Zhongni N
authors.initials: ZN
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.|Division of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, PR China.
authors.forename: Liming M
authors.initials: LM
authors.lastname: Yang
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001599:Berberine / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D002867:Chromones / Q000008:administration & dosage; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014463:Ultrasonography
chemical_list: D001599:Berberine; D002784:Cholesterol; D002867:Chromones; D008055:Lipids; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human