Purpose: The brain is a pharmacologic sanctuary site, due to the presence of the blood-brain barrier (BBB).Whereas the effect of P-glycoprotein (P-gp) at the BBB is well established, the role of breast cancer resistance protein (BCRP) that is also expressed at the BBB is not. Experimental Design: We have studied the effect of BCRP by administering topotecan to wildtype (WT), single Mdr1a/b (-/-) and Bcrp1 (-/-) , and compound Mdr1a/b(-/-) Bcrp1 (-/-) knockout mice. Drug levels in plasma and tissues were determined by high-performance liquid chromatography. Results: The area under the plasma and tissue concentration-time curve (AUC) of topotecan in brains of Mdr1a/b (-/-) and Bcrp1 (-/-) mice was only 1.5-fold higher compared with WT mice, but in(-/-) mice, where both transporters are absent, the AUC increased by 12-fold. The AUC in plasma was f0.75-, 2.4-, and 3.7-fold higher in Mdr1a/b (-/-) , Bcrp1 (-/-) , and(-/-) mice, respectively, resulting in 2.0-fold (P < 0.01), 0.65-fold (P, not significant), and 3.2-fold (P < 0.01), respectively, higher brain-to-plasma AUC ratios. Results using Mrp4(-/-) mice showed that this transporter had no effect on the brain penetration of topotecan. The P-gp/BCRP inhibitor elacridar fully inhibited P-gp^mediated transport of topotecan, whereas inhibition of Bcrp1-mediated transport by elacridar was minimal. Conclusions: Our results using Mdr1a/b(-/-) mice clearly show the effect of Bcrp1 at the BBB and also show how two drug transporters act in concert to limit the brain penetration of topotecan.We expect that this finding will also apply to other drugs that are substrates of both P-gp and BCRP. Consequently, to improve the brain penetration of such compounds for targeting intracranial malignancies in patients, it will be essential to use potent inhibitors of both drug transporters.

A new defect mechanism for the ORR was proposed based on the theoretical calculations and our experimental results.

Tuberculosis remains one of the world’s deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1–6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6–8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.

We utilized a facile method for creating unique defects in the activated carbon (AC), which makes it highly active for the oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER). The ORR activity of the defective AC (D-AC) is comparable to the commercial Pt/C in alkaline medium, and the D-AC also exhibits excellent HER activity in acidic solution.

Both P-gp and Bcrp1 reduce the brain penetration of erlotinib. Although P-gp appears to be the most effective factor limiting the brain penetration of erlotinib, the highest brain accumulation was observed when Bcrp1 was also absent. Strategies to inhibit P-gp/BCRP in patients to improve delivery of (novel molecular-targeted) substrate agents, such as erlotinib, to the brain may be required for treatment of intracranial malignancies.