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The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood–brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is only recently that the important transporter components, expressed in the tightly knit capillary endothelial cells, have been deciphered. These transporters are ATP-binding cassette (ABC) transporters and, so far, the major clinically important ones that functionally contribute to the blood–brain barrier are ABCG2 and ABCB1. A further limitation to cancer therapy of brain tumors or brain metastases is the blood–tumor barrier, where tumors erect a barrier of transporters that further impede drug entry. The expression and regulation of these two transporters at these barriers, as well as tumor derived alteration in expression and/or mutation, are likely obstacles to effective therapy.

Infected or damaged tissues release multiple “alert” molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.

The scientific evidence based on experiences with past disasters points to the possibility of the occurrence of future mental health issues among those who were affected by the recent Turkey–Syria earthquake. However, post-disaster care information on factors that could give rise to mental health issues among those affected have yet to be provided. In March 2011, Tohoku University compiled and published a booklet with post-disaster healthcare information based on the experiences with the Great East Japan Earthquake. This study aimed to promote the introduction and use of this booklet for post-disaster care in Turkey and Syria by presenting the results of a satisfaction survey conducted with relevant Japanese organizations about the booklet. A total of 505 Japanese organizations participated in the satisfaction survey of, and evaluated, the booklet. The results indicated the need to consider the ease of understanding for the general public when providing information on post-disaster care through booklets. We hope that this study leads to the appropriate provision of easy-to-understand, post-disaster healthcare information to the victims of the Turkey–Syria earthquake and future disasters.

Earthquakes that cause extensive damage occur frequently in Japan, the most recent being the Noto Peninsula earthquake on January 1, 2024. To facilitate such a recovery, we introduce a community-based participatory research program implemented through cooperation between universities and local communities after the 2011 Great East Japan Earthquake. In this project, the university and the town of Shichigahama, one of the affected areas, collaborated to hold annual workshops in the target area, which evolved into a climate monitoring survey. Even in Japan, where disaster prevention planning is widespread, various problems arise in the process of emergency response, recovery and reconstruction, and building back better when disasters occur. As is difficult for residents and local governments to solve these problems alone, it is helpful when experts participate in the response process. In this study, we interviewed town hall and university officials as representatives of local residents regarding this project and discussed their mutual concerns. The community-based participatory research framework developed in the Shichigahama project could be used in the recovery from the Noto Peninsula Earthquake as well as in future reconstruction and disaster management projects.

ABCG2 is a medically important ATP-binding cassette transporter with crucial roles in the absorption and distribution of chemically-diverse toxins and drugs, reducing the cellular accumulation of chemotherapeutic drugs to facilitate multidrug resistance in cancer. ABCG2’s capacity to transport both hydrophilic and hydrophobic compounds is not well understood. Here we assess the molecular basis for substrate discrimination by the binding pocket. Substitution of a phylogenetically-conserved polar residue, N436, to alanine in the binding pocket of human ABCG2 permits only hydrophobic substrate transport, revealing the unique role of N436 as a discriminator. Molecular dynamics simulations show that this alanine substitution alters the electrostatic potential of the binding pocket favoring hydration of the transport pore. This change affects the contact with substrates and inhibitors, abrogating hydrophilic compound transport while retaining the transport of hydrophobic compounds. The N436 residue is also required for optimal transport inhibition of ABCG2, as many inhibitors are functionally impaired by this ABCG2 mutation. Overall, these findings have biomedical implications, broadly extending our understanding of substrate and inhibitor interactions. ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.

Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

ObjectiveStatus epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE.MethodsWe initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000–3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug.ResultsA total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI −4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061).ConclusionThe efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT.Trial registration numberjRCTs031190160.

ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function. ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition that can present with hearing loss. Here, the authors use zebrafish and mice to perform experiments suggesting that ABCB6 plays a role in inner ear development.