Danthron attenuates experimental atherosclerosis by targeting foam cell formation

Abstract

New Findings What is the central question of this study?Does danthron alleviate experimental atherosclerosis by inhibiting the formation of foam cells? What are the main findings and their importance?Danthron improved serum lipid profiles and significantly reduced the atherosclerotic plaque areas and lipid accumulation in the aortic root of ApoE−/− mice. Danthron inhibited foam cell formation in oxidized low‐density lipoprotein‐induced RAW264.7 macrophages. Furthermore, danthron exerted its function in atherosclerosis at least partly through activating the AMP‐activated protein kinase–sirtuin 1 signalling pathway. These findings suggest that danthron has the potential to alleviate atherosclerosis. Abstract Danthron, an ingredient isolated from Rheum palmatum L., has been revealed to reduce lipid accumulation in vitro. This study aimed to discover the effects of danthron on the development of atherosclerosis and to delineate the underlying mechanisms. For in vivo studies, male ApoE−/− mice were fed a high‐fat diet and orally treated with danthron (30 or 60 mg/kg/day) for 12 weeks. For in vitro studies, RAW264.7 cells were induced by oxidized low‐density lipoprotein (ox‐LDL, 50 μg/ml) for 48 h and subsequently administered danthron at appropriate concentrations for 24 h. AMP‐activated protein kinase (AMPK) inhibitor compound C was added to ox‐LDL‐stimulated RAW264.7 cells 2 h before danthron administration to confirm the role of the AMPK signalling pathway in the regulation by danthron of foam cell formation. We found that danthron improved serum lipid profiles, and significantly reduced atherosclerotic plaque areas and lipid accumulation in the aortic root of atherosclerotic mice. Moreover, danthron upregulated the mRNA and protein expression of ATP‐binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor α (LXRα), which play a crucial role in lipid metabolism, and activated the AMPK–sirtuin 1 (SIRT1) pathway. In an in vitro study, danthron inhibited foam cell formation in ox‐LDL‐induced RAW264.7 macrophages with an increase in the expression of ABCA1, ABCG1 and LXRα as well as activation of the AMPK–SIRT1 pathway. Furthermore, compound C abolished the effects of danthron on lipid accumulation and the protein expression of ABCA1/G1 and LXRα in vitro. Our results highlight that danthron possesses potential benefits in alleviating experimental atherosclerosis by targeting foam cell formation by activating the AMPK–SIRT1 signalling pathway.

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“… 373 The inducing effects on ABCA1 expression of vitamin D 3 and TO901317 were additive. 331 Danthron, EGCG, geniposide, and rutaecarpine demonstrated also reduced atherosclerotic lesions in Apoe knock-out C57BL/6 mice, 369 , 370 , 375 , 367 and isothiocyanate ameliorated the aortic injury of the high-fat diet in the same mice. 373 …”

“…Gas-liquid chromatography has also been used in some reports. 353 , 355 An extraction-free staining of cholesterol inside of cells was also demonstrated (filipin III 251 , 331 , 333 , 341 , 358 or Oil Red O staining 330 , 332 , 364 , 366 , 369 , 375 , 388 , 389 , 392 , 393 , 399 , 402 , 410 , 417 , 421 , 425 , 448 …”

“… 331 , 348 , 350 , 368 , 369 , 370 , 371 , 372 , 373 , 374 The garlic ingredient allicin, 350 the alkaloid berberine, 256 the coumarin bergapten A, 368 certain Pestalotiopsis neglecta -derived chromene derivatives, 348 the Rheum palmatum -derived anthraquinone danthron, 369 the lacton 1,6- O,O -diacetylbritannilactone, 371 epigallocatechin gallate (EGCG), 370 the glycoside geniposide, 375 the vegetable ingredient phenethyl isothiocyanate, 373 the carotenoid lycopene, 372 the Pestalotiopsis neglecta -derived hydroquinone pestalotioquinoside C, 349 the alkaloid rutaecarpine, 367 selenium, 374 the macrolactone soraphene A, 272 and vitamin D 3 331 led to increased ABCA1 / Abca1 mRNA 256 , 272 , 331 , 348 , 369 , 256 , 367 , 370 , 372 , 373 and ABCA1 protein 256 , 272 , 331 , 349 , 350 , 368 , 369 , 256 , 367 , 371 , 373 , 374 content in vitro 331 , 349 , 350 , ...…”

“…In terms of ABCA1, most studies have been conducted with human THP1, 231 , 245 , 249 , 256 , 268 , 272 , 275 , 292 , 308 , 310 , 312 - 316 , 321 , 328 , 335 , 338 , 339 , 341 , 342 , 360 , 363 , 364 , 366 , 377 , 384 , 388 - 397 murine J774.A1, 252 , 254 , 255 , 259 , 265 , 271 , 278 , 289 - 292 , 384 , 392 , 393 or murine RAW264.7 macrophages. 230 , 249 , 312 , 313 , 321 , 336 , 339 , 342 , 352 , 360 , 365 , 367 , 369 , 375 , 376 , 381 , 385 , 399 , 402 , 404 , 406 , 408 , 410 , 416 - ...…”

“…As a final note, it must be mentioned that other colorimetric analyses were also used to quantify the ABCA transporter-mediated function, specifically for transport of cholesterol or choline-containing lipids, using commercially available assay kits. 202 , 205 , 246 , 251 , 268 , 272 , 275 , 329 - 332 , 334 , 336 , 354 , 365 , 366 , 369 , 372 , 374 - 376 , 386 - 389 , 392 , 405 , 406 , 416 , 418 , 421 , 422 , 424 , 425 , 441 , 511 However these methodologies require time-consuming extraction processes of the lipids, and hence, are less suitable to track the function of ABCA transporters in real-time and to determine kinetic aspects of their cholesterol and lipid transport.…”