1 The presence of inhibitors of drug e ux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was con®rmed based on the uptake of [ 3 H]-vinblastine (VBL) by Caco-2 cells. 2 The uptake of [ 3 H]-VBL by Caco-2 cells was signi®cantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [ 3 H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3 These results show that the major inhibitor of e ux transport of VBL is di erent from that of CYP3A4. 4 Further separation of the 60% methanol eluate a orded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [ 3 H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [ 3 H]-VBL by Caco-2 cells. 5 The order of inhibitory potency of these compounds was FC7264DHBG4bergamottin4ber-gapten4bergaptol. While, the IC 50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and 420 mM, respectively. Bergaptol speci®cally inhibited VBL e ux. 6 DHBG was thus identi®ed as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7 Therefore, the inhibition of e ux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

To survive in the iron-devoid environment of their host, pathogenic bacteria have devised multifarious cunning tactics such as evolving intricate heme transport systems to pirate extracellular heme. Yet, the potential of heme transport systems as antimicrobial targets has not been explored. Herein we developed a strategy to deliver antimicrobials by exploiting the extracellular heme acquisition system protein A (HasA) of Pseudomonas aeruginosa. We demonstrated that, analogous to heme uptake, HasA can specifically traffic an antimicrobial, gallium phthalocyanine (GaPc), into the intracellular space of P. aeruginosa via the interaction of HasA with its outer membrane receptor HasR. HasA enables water-insoluble GaPc to be mistakenly acquired by P. aeruginosa, permitting its sterilization (>99.99%) by irradiation with near-infrared (NIR) light, irrespective of antibiotic resistance. Our findings substantiate that bacterial heme uptake via protein−protein recognition is an attractive target for antimicrobials, enabling specific and effective sterilization.

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Although the pathogenesis of pulmonary fibrosis remains unclear, it is known to involve epithelial injury and epithelial-mesenchymal transformation (EMT) as a consequence of cigarette smoke (CS) exposure. Moreover, smoking deposits iron in the mitochondria of alveolar epithelial cells. Iron overload in mitochondria causes the Fenton reaction, leading to reactive oxygen species (ROS) production, and ROS leakage from the mitochondria induces cell injury and inflammation in the lungs. Nevertheless, the mechanisms underlying iron metabolism and pulmonary fibrosis are yet to be elucidated. In this study, we aimed to determine whether iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. We demonstrated that administration of the iron chelator deferoxamine (DFO) reduced CS-induced pulmonary epithelial cell death, mitochondrial ROS production, and mitochondrial DNA release. Notably, CS-induced cell death was reduced by the administration of an inhibitor targeting ferroptosis, a unique iron-dependent form of non-apoptotic cell death. Transforming growth factor-β-induced EMT of pulmonary epithelial cells was also reduced by DFO. The preservation of mitochondrial function reduced Transforming growth factor-β-induced EMT. Furthermore, transbronchial iron chelation ameliorated bleomycin-induced pulmonary fibrosis and leukocyte migration in a murine model. Our findings indicate that iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. Thus, they may be leveraged as new therapeutic targets for pulmonary fibrosis.