Distinct roles of TIR and non-TIR regions in the subcellular localization and signaling properties of MyD88

AbstractMyD88 is a cytoplasmic adaptor protein that is critical for Toll-like receptor (TLR) signaling. The subcellular localization of MyD88 is characterized as large condensed forms in the cytoplasm. The mechanism and significance of this localization with respect to the signaling function, however, are currently unknown. Here, we demonstrate that MyD88 localization depends on the entire non-TIR region and that the correct cellular targeting of MyD88 is indispensable for its signaling function. The Toll-interleukin I receptor-resistance (TIR) domain does not determine the subcellular localization, but it mediates interaction with specific TLRs. These findings reveal distinct roles for the TIR and non-TIR regions in the subcellular localization and signaling properties of MyD88

Investigation of drugs affecting hypertension in bevacizumab-treated patients and examination of the impact on the therapeutic effect

Background: In patients treated with bevacizumab, hypertension may be a biomarker of therapeutic efficacy. However, it is not clear whether drugs that control blood pressure influence bevacizumab's efficacy. In this study, we investigated drugs that may affect hypertension in bevacizumab-treated patients and examined the impact on the therapeutic effect. Patients and methods: We analyzed 3,724,555 reports from the third quarter of 2010 to the second quarter of 2015. All data were obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) analysis. In this retrospective cohort study, we investigated a total of 58 patients diagnosed with colorectal cancer and treated for the first time with bevacizumab containing XELOX or mFOLFOX6 at The University of Tokushima Hospital between January 2010 and December 2015. The effect of the treatment was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.0. Thereafter, the effect was confirmed using Gene Expression Omnibus (GEO) and cultured cells. Results: There are few reports in FAERS of hypertension in patients treated with omeprazole on bevacizumab. Based on the chart review, patients who used proton pump inhibitors (PPI) had a lower response to treatment than those who did not (response rate: 25% vs 50%). Furthermore, experiments on GEO and cell lines suggested that induction of vascular endothelial growth factor (VEGF) gene expression by PPIs is the cause of the reduced therapeutic effect. Conclusion: PPIs prevent hypertension in bevacizumab-treated patients but may reduce bevacizumab's anti-tumoral effects by inducing VEGF expression

Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency

Diphenhydramine against cisplatin nephrotoxicity

Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes nephrotoxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced nephrotoxicity is currently available. This study identified that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced nephrotoxicity based on the results of the analysis of medical big data. We evaluated the actual efficacy of diphenhydramine via in vitro and in vivo experiments in a mouse model. Diphenhydramine inhibited cisplatin-induced cell death in renal proximal tubular cells. Mice administered cisplatin developed kidney injury with renal dysfunction (plasma creatinine: 0.43 ± 0.04 mg/dl vs 0.15 ± 0.01 mg/dl, p<0.01) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and mitogen-activated protein kinases activation; however, most of these symptoms were suppressed by treatment with diphenhydramine. Further, the renal concentration of cisplatin was attenuated in diphenhydramine-treated mice (platinum content: 70.0 ± 3.3 µg/g dry kidney weight vs 53.4 ± 3.6 µg/g dry kidney weight, p<0.05). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. Moreover, a retrospective clinical study of 1467 cancer patients treated with cisplatin showed that patients who had used diphenhydramine exhibited less acute kidney injury than patients who had not used diphenhydramine (6.1 % vs 22.4 %, p<0.05). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced nephrotoxicity

A Call for a Rational Polypharmacy Policy: International Insights From Psychiatrists

OBJECTIVE: Recently, rational polypharmacy approaches have been proposed, regardless of the lower risk and cost of monotherapy. Considering monotherapy as first-line treatment and polypharmacy as rational treatment, a balanced attitude toward polypharmacy is recommended. However, the high prevalence of polypharmacy led the Japanese government to establish a polypharmacy reduction policy. Based on this, the association between the policy and psychiatrists' attitude toward polypharmacy has been under debate. METHODS: We developed an original questionnaire about Psychiatrists' attitudes toward polypharmacy (PAP). We compared the PAP scores with the treatment decision-making in clinical case vignettes. Multiple regression analyses were performed to quantify associations of explanatory variables including policy factors and PAP scores. The anonymous questionnaires were administered to psychiatrists worldwide. RESULTS: The study included 347 psychiatrists from 34 countries. Decision-making toward polypharmacy was associated with high PAP scores. Multiple regression analysis revealed that low PAP scores were associated with the policy factor (β=-0.20, p=0.004). The culture in Korea was associated with high PAP scores (β=0.34, p<0.001), whereas the culture in India and Nepal were associated with low scores (β=-0.15, p=0.01, and β=-0.17, p=0.006, respectively). CONCLUSION: Policy on polypharmacy may influence psychiatrists' decision-making. Thus, policies considering rational polypharmacy should be established

ヒドロコルチゾン投与は日本人心肺停止患者の生存率改善に関連する

There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60–10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge

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

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Carbonyl Compounds in the Gas Phase of Cigarette Mainstream Smoke and Their Pharmacological Properties

Cigarette mainstream smoke is composed of gas and tar phases and contains >4000 chemical constituents, including nicotine and tar. The substances in the gas phase but not in the tar phase can pass through the airway epithelial barrier, enter the systemic circulation via the pulmonary circulation, and increase systemic oxidative damage, leading to the development of cigarette smoking-related diseases such as atherosclerosis. Recently, we identified some stable carbonyl compounds, including acrolein (ACR) and methyl vinyl ketone (MVK), as major cytotoxic factors in nicotine- and tar-free cigarette smoke extract (CSE) of the gas phase. CSE, ACR, and MVK induce protein kinase C (PKC)-dependent activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and subsequent generation of reactive oxygen species (ROS) via NOX, causing plasma membrane damage and cell apoptosis. CSE, ACR, and MVK also trigger carbonylation of PKC, which is an irreversible oxidative modification. Cell damage and PKC carbonylation in response to treatment with CSE, ACR, or MVK are abolished by thiol-containing antioxidants such as N-acetyl-L-cysteine and reduced glutathione. Thus pharmacological modulation of PKC and NOX activities and the trapping of ROS are potential strategies for the prevention of diseases related to cigarette smoking

Comparison of cytotoxicity of cigarette smoke extract derived from heat-not-burn and combustion cigarettes in human vascular endothelial cells

The present study compared the properties of mainstream smoke generated from heat-not-burn (HNB) cigarettes and a combustion cigarette (hi-lite (TM) brand). Three types of cigarette heating devices were used to generate cigarette smoke at different heating temperatures [Ploom S (TM) (200 degrees C), glo (TM) (240 degrees C), and IQOS (TM) (300-350 degrees C)]. Mainstream smoke was generated using the following puffing regimen: volume, 55 mL; duration, 3 s; and interval, 30 s. The rank order of particulate phase (nicotine and tar) amounts trapped on a Cambridge filter was Ploom S < glo < IQOS < hi-lite. Heated cigarette-derived smoke extract (hCSE) from the devices except for Ploom S, and burned CSE (bCSE) decreased mitochondria) metabolic activity (glo < IQOS < hi-lite) in human vascular endothelial cells. Furthermore, the cytotoxicity was reduced by removing the particulate phase from the mainstream smoke. Endothelial nitric oxide synthase activity was reduced by nicotine- and tar-free CSE of IQOS and hi-lite (IQOS < hi-lite), but not Ploom S and glo. These inhibitory effects were diminished by removing the carbonyl compounds from the mainstream smoke. These results indicated that the cytotoxicity of hCSE was lower than that of bCSE in vascular endothelial cells. (C) 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society