Midkine antisense oligodeoxyribonucleotide inhibits renal damage induced by ischemic reperfusion

Midkine antisense oligodeoxyribonucleotide inhibits renal damage induced by ischemic reperfusion.BackgroundMidkine, a heparin-binding growth factor, is involved in the migration of inflammatory cells. The inflammatory cell migration to the tubulointerstitium of the kidney after ischemia/reperfusion (I/R) injury is attenuated in midkine gene–deficient mice, resulting in better preservation of the tubulointerstitium compared with wild-type mice. In the present investigation, we planned to evaluate the usefulness of antisense midkine for the therapy of ischemic renal failure.MethodsMidkine antisense phosphorothioate oligodeoxyribonucleotide (ODN) at a dose of 1 mg/kg in saline was intravenously administered to mice 1 day before or after I/R. The kidneys were removed for examination 1, 2, 3, and 7 days after I/R.ResultsIt was rapidly incorporated into proximal tubular epithelial cells, and inhibited midkine synthesis, leading to reduced migration of inflammatory cells to the injured epithelial layer. Consequently, the midkine antisense ODN-treated animals exhibited less severe renal damage than untreated or midkine sense ODN-treated animals 2 days after I/R as assessed by morphologic criteria and blood urea nitrogen (BUN) and serum creatinine levels. Midkine expression, BUN, and serum creatinine levels were not significantly different between injection of midkine antisense ODN before and after ischemic injury.ConclusionThese results indicate that intravenous injection of midkine antisense ODN is a candidate for a novel therapeutic strategy against acute tubulointerstitial injury induced by I/R injury

Fast and effective mitochondrial delivery of omega-Rhodamine-B-polysulfobetaine-PEG copolymers

Mitochondrial targeting and entry, two crucial steps in fighting severe diseases resulting from mitochondria dysfunction, pose important challenges in current nanomedicine. Cell-penetrating peptides or targeting groups, such as Rhodamine-B (Rho), are known to localize in mitochondria, but little is known on how to enhance their effectiveness through structural properties of polymeric carriers. To address this issue, we prepared 8 copolymers of 3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate and poly(ethyleneglycol) methacrylate, p(DMAPS-ran-PEGMA) (molecular weight, 18.0 <M-n <74.0 kg/mol) with two different endgroups. We labeled them with Rho groups attached along the chain or on one of the two endgroups (alpha or omega). From studies by flow cytometry and confocal fluorescence microscopy of the copolymers internalization in HeLa cells in the absence and presence of pharmacological inhibitors, we established that the polymers cross the cell membrane foremost by translocation and also by endocytosis, primarily clathrin-dependent endocytosis. The most effective mitochondrial entry was achieved by copolymers of M-n <30.0 kg/mol, lightly grafted with PEG chains (<5 mol %) labeled with Rho in the omega-position. Our findings may be generalized to the uptake and mitochondrial targeting of prodrugs and imaging agents with a similar polymeric scaffold.Peer reviewe

A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population

Recently, we reported that genetic polymorphisms within the human IL18 gene were associated with disease susceptibility to adult-onset Still's disease (AOSD), which is characterized by extraordinarily high serum levels of IL-18. Because high serum IL-18 induction has also been observed in the systemic type of juvenile idiopathic arthritis (JIA), we investigated whether similar genetic skewing is present in this disease. Three haplotypes, S01, S02, and S03, composed of 13 genetic polymorphisms covering two distinct promoter regions, were determined for 33 JIA patients, including 17 with systemic JIA, 10 with polyarthritis, and 6 with oligoarthritis. Haplotypes were also analyzed for 28 AOSD patients, 164 rheumatoid arthritis (RA) patients, 102 patients with collagen diseases, and 173 healthy control subjects. The frequency of individuals carrying a diplotype configuration (a combination of two haplotypes) of S01/S01 was significantly higher in the JIA patients, including all subgroups, than in the healthy controls (P = 0.0045, Fischer exact probability test; odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.55–8.14). In patients with systemic JIA, its frequency did not differ statistically from that of normal controls. Nevertheless, it is possible that haplotype S01 is associated with the phenotype of high IL-18 production in systemic JIA because the patients carrying S01/S01 showed significantly higher serum IL-18 levels compared with patients with other diplotype configurations (P = 0.017, Mann-Whitney U test). We confirmed that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects (P = 0.011, OR = 3.45, 95% CI = 1.42–8.36). Furthermore, the RA patients were also more predisposed to have S01/S01 (P = 0.018, OR = 2.00, 95% CI = 1.14–3.50) than the healthy control subjects, whereas the patients with collagen diseases did not. In summary, the diplotype configuration of S01/S01 was associated with susceptibility to JIA as well as AOSD and RA, and linked to significantly higher IL-18 production in systemic JIA. Possession of the diplotype configuration of S01/S01 would be one of the genetic risk factors for susceptibility to arthritis in the Japanese population

GEOTAIL observation of the SGR1806-20 Giant Flare: The first 600 ms

On December 27, 2004, plasma particle detectors on the GEOTAIL spacecraft detected an extremely strong signal of hard X-ray photons from the giant flare of SGR1806-20, a magnetar candidate. While practically all gamma-ray detectors on any satellites were saturated during the first ~500 ms interval after the onset, one of the particle detectors on GEOTAIL was not saturated and provided unique measurements of the hard X-ray intensity and the profile for the first 600 ms interval with 5.48 ms time resolution. After ~50 ms from the initial rapid onset, the peak photon flux (integrated above ~50 keV) reached the order of 10^7 photons sec^{-1} cm^{-2}. Assuming a blackbody spectrum with kT=175 keV, we estimate the peak energy flux to be 21 erg sec^{-1} cm^{-2} and the fluence (for 0-600 ms) to be 2.4 erg cm^{-2}. The implied energy release comparable to the magnetic energy stored in a magnetar (~10^{47} erg) suggests an extremely efficient energy release mechanism.Comment: 6 pages, 2 color figures, submitted to Natur

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection