Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

ATP binding cassette transporters and cancer: revisiting their controversial role

The expression of ATP-binding cassette transporter (ABC transporters) has been reported in various tissues such as the lung, liver, kidney, brain and intestine. These proteins account for the efflux of different compounds and metabolites across the membrane, thus decreasing the concentration of the toxic compounds. ABC transporter genes play a vital role in the development of multidrug resistance, which is the main obstacle that hinders the success of chemotherapy. Preclinical and clinical trials have investigated the probability of overcoming drug-associated resistance and substantial toxicities. The focus has been put on several strategies to overcome multidrug resistance. These strategies include the development of modulators that can modulate ABC transporters. This knowledge can be translated for clinical oncology treatment in the future.

Copper affect the multixenobiotic resistance mechanism (MXR) in embryo and larvae of Rhamdia quelen

P-glycoproteins (P-gp) and Multidrug resistance protein (MRP) represent a family of ABC (ATP-binding cassette) transporters responsible for multixenobiotic resistance mechanism (MXR) in aquatic organisms. In the current study the modulation of P-gp and MRP proteins was evaluated in embryo and larvae of Rhamdia quelen fish species exposed to copper. Adult females were exposed by gavage during 60 days to copper (5 mg Cu kg-1) and eggs, embryos, and larvae from exposed and unexposed females were exposed to 30 mg Cu L-1. The activity of ABC transporters was accessed via calcein accumulation assay using the specific inhibitors: Verapamil (P-gp) and MK571 (MRP). P-gp activity was detected in all analyzed stages whereas MRP activity was observed after 36 and 96 hpf. Oocytes from females previously exposed and larvae stages (36 and 96 hpf) accumulated less calcein than no exposed oocytes, showing higher ABC transporters activity. In individuals exposed to copper, a higher inhibitory effect was observed 1 hpf. The modulation of ABC transporter proteins is time dependent throughout the development, and the initial stages are more sensible to copper. These findings highlight the MXR mechanism as a biomarker of pollutant exposure in early stages of development of R. quelen.

The Mechanisms of Yu Ping Feng San in Tracking the Cisplatin-Resistance by Regulating ATP-Binding Cassette Transporter and Glutathione S-Transferase in Lung Cancer Cells

Cisplatin is one of the first line anti-cancer drugs prescribed for treatment of solid tumors; however, the chemotherapeutic drug resistance is still a major obstacle of cisplatin in treating cancers. Yu Ping Feng San (YPFS), a well-known ancient Chinese herbal combination formula consisting of Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, is prescribed as a herbal decoction to treat immune disorders in clinic. To understand the fast-onset action of YPFS as an anti-cancer drug to fight against the drug resistance of cisplatin, we provided detailed analyses of intracellular cisplatin accumulation, cell viability, and expressions and activities of ATP-binding cassette transporters and glutathione S-transferases (GSTs) in YPFS-treated lung cancer cell lines. In cultured A549 or its cisplatin-resistance A549/DDP cells, application of YPFS increased accumulation of intracellular cisplatin, resulting in lower cell viability. In parallel, the activities and expressions of ATP-binding cassette transporters and GSTs were down-regulated in the presence of YPFS. The expression of p65 subunit of NF-κB complex was reduced by treating the cultures with YPFS, leading to a high ratio of Bax/Bcl-2, i.e. increasing the rate of cell death. Prim-O-glucosylcimifugin, one of the abundant ingredients in YPFS, modulated the activity of GSTs, and then elevated cisplatin accumulation, resulting in increased cell apoptosis. The present result supports the notion of YPFS in reversing drug resistance of cisplatin in lung cancer cells by elevating of intracellular cisplatin, and the underlying mechanism may be down regulating the activities and expressions of ATP-binding cassette transporters and GSTs.

Beauvericin potentiates the activity of pesticides by neutralizing the ATP-binding cassette transporters in arthropods

Multi-drug resistance is posing major challenges in suppressing the population of pests. Many herbivores develop resistance, causing a prolonged survival after exposure to a previously effective pesticide. Consequently, resistant pests reduce the yield of agricultural production, causing significant economic losses and reducing food security. Therefore, overpowering resistance acquisition of crop pests is a must. The ATP binding cassette transporters (ABC transporters) are considered as the main participants to the pesticide efflux and their neutralization will greatly contribute to potentiate failed treatments. Real-Time PCR analysis of 19 ABC transporter genes belonging to the ABCB, ABCC, ABCG, and ABCH revealed that a broad range of efflux pumps is activated in response to the exposure to pesticides. In this study, we used beauvericin (BEA), a known ABC transporters modulator, to resensitize different strains of Tetranychus urticae after artificial selection for resistance to cyflumetofen, bifenazate, and abamectin. Our results showed that the combinatorial treatment of pesticide (manufacturer’s recommended doses) + BEA (sublethal doses: 0.15 mg/L) significantly suppressed the resistant populations of T. urticae when compared to single-drug treatments. Moreover, after selective pressure for 40 generations, the LC50 values were significantly reduced from 36.5, 44.7, and 94.5 (pesticide) to 8.3, 12.5, and 23.4 (pesticide + BEA) for cyflumetofen, bifenazate, and abamectin, respectively. While the downstream targets for BEA are still elusive, we demonstrated hereby that it synergizes with sub-lethal doses of different pesticides and increases their effect by inhibiting ABC transporters. This is the first report to document such combinatorial activity of BEA against higher invertebrates paving the way for its usage in treating refractory cases of resistance to pesticides. Moreover, we demonstrated, for the first time, using in silico techniques, the higher affinity of BEA to ABC transformers subfamilies when compared to xenobiotics; thus, elucidating the pathway of the mycotoxin.