Publications by authors named "Nozomi Takahashi"

85 Publications

Challenge for management without tracheostomy tube after laryngo-tracheal separation in children with neurological disorders.

Laryngoscope Investig Otolaryngol 2021 Apr 6;6(2):332-339. Epub 2021 Feb 6.

Department of General Pediatrics and Interdisciplinary medicine National Center for Child Health and Development Tokyo Japan.

Objectives: The present study analyzed surgical outcomes of laryngotracheal separation (LTS) in children with neurological disorders. The purpose of this study was to investigate respiratory impairment and severe complications after LTS in children, and identify the possibility of permanent tracheostomy without a tracheostomy tube as the safest respiratory management method.

Methods: Twenty-eight patients (male:female = 16:12) with neurological disorders (6 months to 32 years) who underwent LTS between January 2012 and April 2018 were reviewed. Tracheal diameter, Cobb angle, and sternocervical spine distance (SCD) were measured to assess the potential risk and possibility of removing tracheostomy tube management.

Results: Tracheostomy tube could be removed shortly after LTS in 57% (16/28). However, nine of these patients developed respiratory problems that required tracheostomy tube placement 2 years after LTS. New requirements for a tracheostomy tube as a stent were strongly correlated with SCD ( < .05, odds ratio > 1) as well as tracheal deformity.

Conclusions: Respiratory management in neurologically impaired children after LTS without a tracheostomy tube is challenging because thoracic deformity during physical growth affects tracheal disfiguration. Thoracic deformities and progression of scoliosis should be considered in respiratory management approaches in children with neurological disorders, and long-term follow-up by computed tomography is necessary.

Level Of Evidence: IV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lio2.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035946PMC
April 2021

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.

Elife 2021 Mar 23;10. Epub 2021 Mar 23.

Department of Genetics, University of Cambridge, Cambridge, United Kingdom.

Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant () recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (), lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the variant. methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.65233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084528PMC
March 2021

Significance of lactate clearance in septic shock patients with high bilirubin levels.

Sci Rep 2021 Mar 18;11(1):6313. Epub 2021 Mar 18.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.

Lactate clearance is affected by hepatic function. However, it is unclear whether the association between hepatic dysfunction and lactate clearance can act as a prognostic marker of clinical outcomes in patients with septic shock. We aimed to evaluate the association between lactate clearance and mortality in two cohorts of septic shock patient who had hepatic dysfunction based on their total serum bilirubin levels (TBIL). Lactate clearance at 24 h after the onset of septic shock was analyzed using two cohorts, sub-categorized into two groups based on TBIL: < 2 mg/dL and ≥ 2 mg/dL. In the derivation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while there was no significant difference in lactate clearance between non-survivors and survivors with TBIL < 2 mg/dL. Multivariate logistic regression analysis revealed that increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio [OR]: 0.88, 95% confidence interval (CI): 0.80-0.97, P = 0.0075), Creatinine level ≥ 2 mg/dL group (adjusted OR: 0.88, 95% CI: 0.81-0.95, P = 0.00069) and APACHE II score ≥ 35 group (adjusted OR: 0.93, 95% CI: 0.87-0.98, P = 0.013). In the validation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while no significant difference in lactate clearance was observed between non-survivors and survivors with TBIL < 2 mg/dL. Increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted OR: 0.89, 95% CI: 0.83-0.96, P = 0.0038) and the association was just about significant in APACHE II score ≥ 35 group (adjusted OR: 0.86, 95% CI: 0.74-1.00, P = 0.051). In conclusion, increased lactate clearance in septic shock patients with hepatic dysfunction (TBIL ≥ 2 mg/dL) or high severity (APACHE II score ≥ 35) was associated with decreased 28-day mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85700-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973422PMC
March 2021

Endoplasmic reticulum stress: a key regulator of the follicular microenvironment in the ovary.

Mol Hum Reprod 2021 01;27(1)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo, Tokyo 113-8655, Japan.

Intra-ovarian local factors regulate the follicular microenvironment in coordination with gonadotrophins, thus playing a crucial role in ovarian physiology as well as pathological states such as polycystic ovary syndrome (PCOS). One recently recognized local factor is endoplasmic reticulum (ER) stress, which involves the accumulation of unfolded or misfolded proteins in the ER related to various physiological and pathological conditions that increase the demand for protein folding or attenuate the protein-folding capacity of the organelle. ER stress results in activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which affect a wide variety of cellular functions. Recent studies have revealed diverse roles of ER stress in physiological and pathological conditions in the ovary. In this review, we summarize the most current knowledge of the regulatory roles of ER stress in the ovary, in the context of reproduction. The physiological roles of ER stress and the UPR in the ovary remain largely undetermined. On the contrary, activation of ER stress is known to impair follicular and oocyte health in various pathological conditions; moreover, ER stress also contributes to the pathogenesis of several ovarian diseases, including PCOS. Finally, we discuss the potential of ER stress as a novel therapeutic target. Inhibition of ER stress or UPR activation, by treatment with existing chemical chaperones, lifestyle intervention, or the development of small molecules that target the UPR, represents a promising therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molehr/gaaa088DOI Listing
January 2021

Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome.

Mol Hum Reprod 2021 02;27(3)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan.

Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously showed that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molehr/gaab003DOI Listing
February 2021

Involvement of APOBEC3B in mutation induction by irradiation.

J Radiat Res 2020 Nov;61(6):819-827

Department of Radiopharmacy, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

To better understand the cancer risk posed by radiation and the development of radiation therapy resistant cancer cells, we investigated the involvement of the cancer risk factor, APOBEC3B, in the generation of radiation-induced mutations. Expression of APOBEC3B in response to irradiation was determined in three human cancer cell lines by real-time quantitative PCR. Using the hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation assay, mutations in the HPRT gene caused by irradiation were compared between APOBEC3B-deficient human hepatocellular carcinoma (HepG2) cells [APOBEC3B knocked out (KO) using CRISPR-Cas9 genome editing] and the parent cell line. Then, HPRT-mutated cells were individually cultured to perform PCR and DNA sequencing of HPRT exons. X-Irradiation induced APOBEC3B expression in HepG2, human cervical cancer epithelial carcinoma (HeLa) and human oral squamous cell carcinoma (SAS) cells. Forced expression of APOBEC3B increased spontaneous mutations. By contrast, APOBEC3B KO not only decreased the spontaneous mutation rate, but also strongly suppressed the increase in mutation frequency after irradiation in the parent cell line. Although forced expression of APOBEC3B in the nucleus caused DNA damage, higher levels of APOBEC3B tended to reduce APOBEC3B-induced γ-H2AX foci formation (a measure of DNA damage repair). Further, the number of γ-H2AX foci in cells stably expressing APOBEC3B was not much higher than that in controls before and after irradiation, suggesting that a DNA repair pathway may be activated. This study demonstrates that irradiation induces sustained expression of APOBEC3B in HepG2, HeLa and SAS cells, and that APOBEC3B enhances radiation-induced partial deletions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jrr/rraa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674755PMC
November 2020

Clinical course of a critically ill patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

J Artif Organs 2020 Dec 16;23(4):397-400. Epub 2020 Jun 16.

Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba, 260-8677, Japan.

Although several studies have reported on the clinical and epidemiological characteristics of the patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinical course of the most severe cases requiring treatment in ICU have been insufficiently reported. A 73-year-old man traveling on a cruise ship with history of hypertension and dyslipidemia developed high fever, dyspnea and cough after 7 days of steroid treatment for sudden sensorineural hearing loss, and tested positive for SARS-CoV-2 in sputa polymerase chain reaction (PCR) examination. His respiratory function deteriorated despite treatments with lopinavir/ritonavir, oseltamivir, azithromycin and meropenem at a regional hospital. He was intubated and transferred to the ICU in the tertiary university hospital on day 10 (ICU day 1). Interferon beta-1b subcutaneous injection was initiated immediately to enhance anti-viral therapy, and favipiravir on ICU day 10 upon availability. Progression of organ dysfunctions necessitated inhalation of nitrogen oxide for respiratory dysfunction, noradrenaline for cardiovascular dysfunction and continuous renal replacement therapy for renal dysfunction. His blood samples PCR also tested positive for SARS-CoV-2, indicating viremia, concomitantly with elevated IL-6 levels. VV-ECMO was initiated after sudden exacerbation of respiratory dysfunction on ICU day 7 to maintain oxygenation. The sustained excessive inflammatory cytokines in the present case might have led to the exacerbation of the disease, requiring vigorous organ support therapies to allow for survival and recovery from the rapid progression of multiple organ dysfunctions and severe respiratory failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10047-020-01183-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298923PMC
December 2020

Inhibition of autophagy in theca cells induces CYP17A1 and PAI-1 expression via ROS/p38 and JNK signalling during the development of polycystic ovary syndrome.

Mol Cell Endocrinol 2020 05 19;508:110792. Epub 2020 Mar 19.

Department of Obstetrics and Gynaecology, University of Toyama, Toyama, 930-0194, Japan. Electronic address:

Polycystic ovary syndrome (PCOS) is a clinical syndrome characterized by hyperandrogenism, oligo/anovulation, and polycystic ovary. Autophagy is an intracellular system that degrades cytosolic proteins and organelles. The relationship between autophagy and PCOS has not been clarified. We found that p62 and ubiquitin were significantly increased in theca cells of women with PCOS using immunohistochemistry. Autophagy inhibition by palmitic acid and chloroquine in bovine theca cells increased p62 and ubiquitin and induced the expression of cytochrome P450 17A1 (CYP17A1) and plasminogen activator inhibitor-1 (PAI-1) mRNA. Furthermore, palmitic acid and chloroquine exposure significantly increased reactive oxygen species (ROS) and activated p38 and c-Jun N-terminal kinase (JNK). Inhibition of p38 and JNK significantly reduced CYP17A1 and PAI-1 mRNA expression. We showed that inhibition of autophagy in theca cells may have contributed to the pathogenesis of PCOS, based on CYP17A1 and PAI-1 mRNA expression via the ROS/p38 and JNK signalling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2020.110792DOI Listing
May 2020

Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration.

Ther Drug Monit 2020 08;42(4):588-594

Division of Pharmacy, University Hospital.

Background: The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF).

Methods: Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software.

Results: Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L.

Conclusions: A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FTD.0000000000000741DOI Listing
August 2020

Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS.

Endocrinology 2020 02;161(2)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, and we previously found that androgens activate endoplasmic reticulum (ER) stress in granulosa cells from patients with PCOS. In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to the pathology. Therefore, we hypothesized that androgens upregulate the receptor for AGEs (RAGE) expression in granulosa cells by activating ER stress, thereby increasing the accumulation of AGEs in these cells and contributing to the pathology. In the present study, we show that testosterone increases RAGE expression and AGE accumulation in cultured human granulosa-lutein cells (GLCs), and this is reduced by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response factor activated by ER stress, inhibits testosterone-induced RAGE expression and AGE accumulation. The expression of RAGE and the accumulation of AGEs are upregulated in granulosa cells from PCOS patients and dehydroepiandrosterone-induced PCOS mice. Administration of the RAGE inhibitor FPS-ZM1 or TUDCA to PCOS mice reduces RAGE expression and AGE accumulation in granulosa cells, improves their estrous cycle, and reduces the number of atretic antral follicles. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress, and that targeting the AGE-RAGE system, either by using a RAGE inhibitor or a clinically available ER stress inhibitor, may represent a novel approach to PCOS therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/endocr/bqaa015DOI Listing
February 2020

Preclinical validation of the new vitrification device possessing a feature of absorbing excess vitrification solution for the cryopreservation of human embryos.

J Obstet Gynaecol Res 2020 Feb 10;46(2):302-309. Epub 2020 Jan 10.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: The cryopreservation of embryos is essential for assisted reproductive technology field. The aim of the present study is to examine the efficacy and ease of use of a new vitrification device, Kitasato Vitrification System (KVS), in cryopreservation of human embryos.

Methods: Human embryos at the cleavage or blastocyst stage were vitrified and warmed by KVS or Cryotop (control device). The survival of cleavage- and blastocyst-stage embryos and the developmental competence of cleavage-stage embryos were evaluated. Four individuals inexperienced in vitrification and warming embryos tested both KVS and Cryotop. The vitrification time and the detachment time of the embryos were evaluated.

Results: At the cleavage stage, there were no significant differences in the survival rate and the development rate to the blastocyst stage between KVS and Cryotop (100 vs 96.8% and 63.3 vs 61.3%, respectively). At the blastocyst stage, there was no significant difference in the re-expansion rate between KVS and Cryotop (100 vs 88.9%). The vitrification time was shorter for KVS than Cryotop. There was no significant difference in the detachment time between KVS and Cryotop.

Conclusion: Kitasato Vitrification System is easy to operate, even for inexperienced users, and the viability of human embryos vitrified by KVS is comparable to that of Cryotop, a widely used vitrification device.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jog.14176DOI Listing
February 2020

Activation of endoplasmic reticulum stress mediates oxidative stress-induced apoptosis of granulosa cells in ovaries affected by endometrioma.

Mol Hum Reprod 2020 01;26(1):40-52

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.

Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress-induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molehr/gaz066DOI Listing
January 2020

Quantitative analysis of ovarian cysts and tumors by using T2 star mapping.

J Obstet Gynaecol Res 2020 Jan 19;46(1):140-146. Epub 2019 Nov 19.

Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.

Aim: The aim of this study was to investigate the efficacy of T2 star (T2*) mapping in diagnosing ovarian cysts/ tumors.

Methods: Pelvic magnetic resonance examinations including T2*WI were performed before surgery in 35 patients. The region of interest, consisted of a 10 mm diameter circle, was set as much as possible inside ovarian tumors/cysts to measure T2*values, and mean T2* values were compared in ovarian cyst/tumor types, retrospectively. Diagnoses of 40 ovarian cysts/tumors were determined by pathological reports, in which 17 were endometriomas, 13 were mature cystic teratomas, 6 were mucinous cystadenomas and 4 were serous cystadenomas.

Results: The average T2* values of endometrioma was 56.8 ± 8.7 ms (mean ± SEM), which was significantly lower than that of mucinous cystadenoma (334.2 ± 58.5 ms, mean ± SEM) or serous cystadenoma (237.0 ± 45.4 ms, mean ± SEM). There was no difference in T2* values between endometrioma and mature cystic teratoma (64.1 ± 22.6 ms, mean ± SEM). Receiver operating characteristics curve analysis revealed that optimal cut-off value for differential diagnosis of endometrioma and mucinous or serous cystadenoma was 149.2 ms as T2* value, which has an area under the curve of 0.95 (sensitivity = 92.4%, specificity = 78.6%).

Conclusion: T2* values were useful to diagnose various types of ovarian cyst/tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jog.14157DOI Listing
January 2020

A CO removal system using extracorporeal lung and renal assist device with an acid and alkaline infusion.

J Artif Organs 2020 Mar 4;23(1):54-61. Epub 2019 Oct 4.

Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba, 260-8677, Japan.

The patients with respiratory failure need high tidal volume by mechanical ventilation, which lead to the ventilator-induced lung injury. We developed an extracorporeal lung and renal assist device (ELRAD), comprising acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. To evaluate this system, we conducted in vivo studies using experimental swine which were connected to the new system. In vivo experiments consist of four protocols; baseline = hemodiafiltration only (no O gas flow to membrane lung); membrane lung = "Baseline" plus O gas flow to membrane lung; "Acid infusion" = "Membrane lung" plus continuous acid infusion; ELRAD = "Acid infusion" plus continuous alkaline infusion. We changed the ventilatory rate of the mechanical ventilation to maintain PCO at 50-55 mmHg during the four protocols. The results showed that there was statistically no significant difference in the levels of pH, HCO, and base excess when each study protocol was initiated. The amount of CO eliminated by the membrane lung significantly increased by 1.6 times in the acid infusion protocol and the ELRAD protocol compared to the conventional membrane lung protocol. Minute ventilation in the ELRAD protocol significantly decreased by 0.5 times compared with the hemodiafiltration only protocol (P < 0.0001), the membrane lung (P = 0.0006) and acid infusion protocol (P = 0.0017), respectively. In conclusion, a developed CO removal system efficiently removed CO at low blood flow and reduced minute ventilation, while maintaining acid-base balance within the normal range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10047-019-01136-0DOI Listing
March 2020

Accumulation of advanced glycation end products in follicles is associated with poor oocyte developmental competence.

Mol Hum Reprod 2019 11;25(11):684-694

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan.

Advanced glycation end products (AGEs) affect the follicular microenvironment. The close relationship between AGEs, proinflammatory cytokine production and activation of the unfolded protein response (UPR), which involves activating transcription factor 4 (ATF4), is crucial for regulation of various cellular functions. We examined whether accumulation of AGEs in follicles was associated with proinflammatory cytokine production and activation of the UPR in granulosa cells and decreased oocyte developmental competence. Concentrations of AGEs, soluble receptor for AGE (sRAGE), interleukin (IL)-6 and IL-8 in follicular fluid (FF) were examined by ELISAs in 50 follicles. mRNA expression of ATF4, IL-6 and IL-8 in cumulus cells (CCs) were examined by quantitative RT-PCR in 77 samples. Cultured human granulosa-lutein cells (GLCs) were treated with AGE-bovine serum albumin (BSA) alone or following transfection of ATF4-targeting small interfering RNA. The AGE concentration and the AGE/sRAGE ratio in FF were significantly higher in follicles containing oocytes that developed into poor-morphology embryos (group I) than those with good-morphology embryos (group II). When compared with sibling follicles from the same patients, the AGE/sRAGE and concentrations of IL-6 and IL-8 in FF, as well as ATF4, IL-6 and IL-8 mRNA expression in CCs, were significantly higher in group I follicles than group II. AGE treatment increased mRNA expression of ATF4, IL-6 and IL-8 in cultured GLCs. Knockdown of ATF4 abrogated the stimulatory effects of AGE on mRNA expression and protein secretion of IL-6 and IL-8. Our findings support the idea that accumulation of AGEs in follicles reduces oocyte competence by triggering inflammation via activation of ATF4 in the follicular microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molehr/gaz050DOI Listing
November 2019

ZFP57 regulation of transposable elements and gene expression within and beyond imprinted domains.

Epigenetics Chromatin 2019 08 9;12(1):49. Epub 2019 Aug 9.

Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK.

Background: KRAB zinc finger proteins (KZFPs) represent one of the largest families of DNA-binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental origin at genomic imprints. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at imprints, unique and repetitive regions of the genome.

Results: Over 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though the loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibit alterations in expression. Comparison of ZFP57 mutants with DNA methyltransferase-deleted ES cells (TKO) identifies a remarkably similar pattern of H3K9me3 loss across the genome. These data define regions where H3K9me3 is secondary to DNA methylation and we propose that ZFP57 is the principal if not sole methylation-sensitive KZFP in mouse ES cells. Finally, we examine dynamics of DNA and H3K9 methylation during pre-implantation development and show that sites bound by ZFP57 in ES cells maintain DNA methylation and H3K9me3 at imprints and at non-imprinted regions on the maternally inherited chromosome throughout preimplantation development.

Conclusion: Our analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline-derived imprinting control regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13072-019-0295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688207PMC
August 2019

The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF.

J Exp Med 2019 09 11;216(9):2010-2023. Epub 2019 Jul 11.

Laboratory for Endoplasmic Reticulum Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20 cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20 cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20182164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719426PMC
September 2019

Delayed aortic regurgitation due to traumatic pseudoaneurysm of the sinus of Valsalva.

Acute Med Surg 2019 Apr 28;6(2):185-187. Epub 2019 Jan 28.

Department of Emergency and Critical Care Medicine Chiba University Graduate School of Medicine Chiba Japan.

Case: Pseudoaneurysm of the sinus of Valsalva (PSV) caused by trauma is rare. Surgical intervention is the standard treatment approach for traumatic PSV, as it has a high risk of rupture and is potentially fatal.We hereby report a 59-year-old man with traumatic PSV due to a traffic accident. Imaging studies revealed traumatic PSV. However, he refused surgery due to the lack of symptoms and was discharged on day 9. Two years later, he visited our hospital with cardiac failure due to severe aortic valve regurgitation (AR) induced by PSV.

Outcome: A Bentall operation was carried out and the patient was discharged without any complications.

Conclusions: This case illustrates progression to aortic valve regurgitation as a complication of traumatic PSV and stresses the point that surgical intervention should be considered even in asymptomatic cases of traumatic PSV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ams2.386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442520PMC
April 2019

Survival of Single Positive Thymocytes Depends upon Developmental Control of RIPK1 Kinase Signaling by the IKK Complex Independent of NF-κB.

Immunity 2019 02 5;50(2):348-361.e4. Epub 2019 Feb 5.

Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK. Electronic address:

NF-κB (nuclear factor κB) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-κB, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-κB transcription, had no impact upon thymocyte development. While IKK-deficient thymocytes were acutely sensitive to tumor necrosis factor (TNF)-induced cell death, Rel-deficient cells remained resistant, calling into question the importance of NF-κB as the IKK target required for thymocyte survival. Instead, we found that IKK controlled thymocyte survival by repressing cell-death-inducing activity of the serine/threonine kinase RIPK1. We observed that RIPK1 expression was induced during development of SP thymocytes and that IKK was required to prevent RIPK1-kinase-dependent death of SPs in vivo. Finally, we showed that IKK was required to protect Rel-deficient thymocytes from RIPK1-dependent cell death, underscoring the NF-κB-independent function of IKK during thymic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2019.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382466PMC
February 2019

The origins of genomic imprinting in mammals.

Reprod Fertil Dev 2019 Jul;31(7):1203-1218

Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.

Genomic imprinting is a process that causes genes to be expressed according to their parental origin. Imprinting appears to have evolved gradually in two of the three mammalian subclasses, with no imprinted genes yet identified in prototheria and only six found to be imprinted in marsupials to date. By interrogating the genomes of eutherian suborders, we determine that imprinting evolved at the majority of eutherian specific genes before the eutherian radiation. Theories considering the evolution of imprinting often relate to resource allocation and recently consider maternal-offspring interactions more generally, which, in marsupials, places a greater emphasis on lactation. In eutherians, the imprint memory is retained at least in part by zinc finger protein 57 (ZFP57), a Kruppel associated box (KRAB) zinc finger protein that binds specifically to methylated imprinting control regions. Some imprints are less dependent on ZFP57invivo and it may be no coincidence that these are the imprints that are found in marsupials. Because marsupials lack ZFP57, this suggests another more ancestral protein evolved to regulate imprints in non-eutherian subclasses, and contributes to imprinting control in eutherians. Hence, understanding the mechanisms acting at imprinting control regions across mammals has the potential to provide valuable insights into our understanding of the origins and evolution of genomic imprinting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1071/RD18176DOI Listing
July 2019

ZNF445 is a primary regulator of genomic imprinting.

Genes Dev 2019 01;33(1-2):49-54

School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne 1015, Switzerland.

Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation, causing parental origin-specific monoallelic gene expression. Zinc finger protein 57 (ZFP57) is critical for maintenance of this epigenetic memory during post-fertilization reprogramming, yet incomplete penetrance of mutations in humans and mice suggests additional effectors. We reveal that ZNF445/ZFP445, which we trace to the origins of imprinting, binds imprinting control regions (ICRs) in mice and humans. In mice, ZFP445 and ZFP57 act together, maintaining all but one ICR in vivo, whereas earlier embryonic expression of ZNF445 and its intolerance to loss-of-function mutations indicate greater importance in the maintenance of human imprints.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.320069.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317318PMC
January 2019

Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis.

Nat Commun 2018 11 19;9(1):4846. Epub 2018 Nov 19.

Department of Internal Medicine, Ghent University, Ghent, B-9052, Belgium.

Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07386-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242954PMC
November 2018

Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS.

Endocrinology 2019 01;160(1):119-132

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and growth arrest of antral follicles. Previously, we found that endoplasmic reticulum (ER) stress is activated in granulosa cells of antral follicles in PCOS, evidenced by activation of unfolded protein response (UPR) genes. Based on this observation, we hypothesized that ER stress is activated by androgens in granulosa cells of antral follicles, and that activated ER stress promotes apoptosis via induction of the UPR transcription factor C/EBP homologous protein (CHOP) and subsequent activation of death receptor (DR) 5. In this study, we found that testosterone induced expression of various UPR genes, including CHOP, as well as DR5, in cultured human granulosa-lutein cells (GLCs). Pretreatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) inhibited testosterone-induced apoptosis and expression of DR5 and CHOP. Knockdown of CHOP inhibited testosterone-induced DR5 expression and apoptosis, and knockdown of DR5 inhibited testosterone-induced apoptosis. Pretreatment with flutamide, as well as knockdown of androgen receptor, decreased testosterone-induced DR5 and CHOP expression, as well as apoptosis. Expression of DR5 and CHOP was upregulated in GLCs obtained from patients with PCOS, as well as in granulosa cells of antral follicles in ovarian sections obtained from patients with PCOS and dehydroepiandrosterone-induced PCOS mice. Treatment of PCOS mice with TUDCA decreased apoptosis and DR5 expression in granulosa cells of antral follicles, with a concomitant reduction in CHOP expression. Taken together, our findings indicate that ER stress activated by hyperandrogenism in PCOS promotes apoptosis of granulosa cells of antral follicles via induction of DR5.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2018-00675DOI Listing
January 2019

The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages.

Immunity 2018 08 31;49(2):312-325.e5. Epub 2018 Jul 31.

Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104815PMC
August 2018

Factors associated with successful pregnancy in women of late reproductive age with uterine fibroids who undergo embryo cryopreservation before surgery.

J Obstet Gynaecol Res 2018 Oct 13;44(10):1956-1962. Epub 2018 Jul 13.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: The objective of this study is to determine the factors associated with successful pregnancy in women of late reproductive age with uterine fibroids who undergo embryo cryopreservation before surgery (ECBS).

Methods: Patients who underwent in vitro fertilization treatment with controlled ovarian stimulation from November 2010 to January 2017 in our university hospital were included. Twenty-two patients older than 35 years of age at the first visit with cavity-distorting uterine fibroids underwent ECBS, a three-step therapeutic approach consisting of oocyte pick-up, myomectomy and embryo transfer (ET), which are performed in this order. We retrospectively calculated the pregnancy rate and determined the factors associated with successful pregnancy.

Results: The mean age at ET of the patients who underwent ECBS was 40.9 years, with a pregnancy rate per ET of 36.8% (21/57). Of 22 patients, 10 (45.5%) successfully continued pregnancy beyond 12 weeks of gestation (ongoing pregnancy). An ongoing pregnancy was observed only among the patients with more than three frozen embryos. The ongoing pregnancy rates of patients with ≤five fibroids and ≤5 cm in the maximal diameter were significantly higher compared to the respective remaining group (90.0% vs 14.3% and 87.5% vs 33.3%).

Conclusion: ECBS is an effective strategy for infertile women of late reproductive age with cavity-distorting uterine fibroids, especially when it is applied to the patients who can freeze at least three embryos before myomectomy, with five or less fibroids smaller than 5 cm in the maximal diameter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jog.13754DOI Listing
October 2018

Efficient CO removal using extracorporeal lung and renal assist device.

J Artif Organs 2018 Dec 6;21(4):427-434. Epub 2018 Jul 6.

Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba, 260-8677, Japan.

We developed a novel system comprising acid infusion, membrane lung, and a continuous renal replacement therapy console for efficient CO removal at a low blood flow. To evaluate the new system, we used an ex vivo experimental model using swine blood. A liter of aliquoted blood adjusted to pH 7.25 and pCO 65 mm Hg was mixed with acid (0, 10, or 20 mL of lactic or hydrochloric acid [1 mol/L]) and was immediately delivered to the system in a single pass. We collected blood samples at each point of the circuit and calculated the amount of CO eliminated by the membrane lung. The new system removed 13.2 ± 0.8, 32.0 ± 2.1, and 51.6 ± 3.7 mL/min of CO (with 0, 10, and 20 mEq/L of lactic acid) and 21.2 ± 1.2, 27.3 ± 0.3, and 42.0 ± 1.3 mL/min (with 0, 10, and 20 mEq/L of hydrochloric acid), respectively. The levels of lactate and Cl ions for acid-base equilibrium were restored after continuous hemodiafiltration. Thus, the amount of CO eliminated by the membrane lung was 3.9 times higher with lactic acid and 2.0 times higher with hydrochloric acid compared with non-acid controls. In conclusion, this easy-to-setup CO removal system was safe, effective, and removed CO at a low blood flow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10047-018-1058-xDOI Listing
December 2018

Interleukin-6 as a diagnostic marker for infection in critically ill patients: A systematic review and meta-analysis.

Am J Emerg Med 2019 02 22;37(2):260-265. Epub 2018 May 22.

Chiba University Graduate School of Medicine, Department of Emergency and Critical Care Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8677, Japan.

Background: The ability of blood levels of interleukin (IL)-6 to differentiate between infection and non-infection in critically ill patients with suspected infection is unclear. We assessed the diagnostic accuracy of serum IL-6 levels for the diagnosis of infection in critically ill patients.

Methods: We systematically searched the PubMed, MEDLINE, Cochrane Resister of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, and Igaku Chuo Zasshi databases for studies published from 1986 to August 2016 that evaluated the accuracy of IL-6 levels for the diagnosis of infection. We constructed 2 × 2 tables and calculated summary estimates of sensitivity and specificity using a bivariate random-effects model.

Results: The literature search identified 775 articles, six of which with a total of 527 patients were included according to the predefined criteria. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.73 (95% confidence interval [CI], 0.61-0.82), 0.76 (95% CI, 0.61-0.87), and 2.31 (95% CI, 1.20-3.48), respectively. The area under the curve (AUC) of the summary receiver operator characteristic (SROC) curve was 0.81 (95% CI, 0.78-0.85). In the secondary analysis of two studies with a total of 263 adult critically ill patients with organ dysfunction, the pooled sensitivity, specificity, and diagnostic odds ratio were 0.81 (95% CI, 0.75-0.86), 0.77 (95% CI, 0.67-0.84), and 2.87 (95% CI 2.15-3.60), respectively.

Conclusions: Blood levels of IL-6 have a moderate diagnostic value and a potential clinical utility to differentiate infection in critically ill patients with suspected infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajem.2018.05.040DOI Listing
February 2019

Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice.

J Clin Invest 2018 08 25;128(8):3265-3279. Epub 2018 Jun 25.

VIB Center for Inflammation Research, Ghent, Belgium.

TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI96636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063488PMC
August 2018

Tozasertib Analogues as Inhibitors of Necroptotic Cell Death.

J Med Chem 2018 03 20;61(5):1895-1920. Epub 2018 Feb 20.

Laboratory of Medicinal Chemistry , University of Antwerp , Universiteitsplein 1 , Wilrijk-Antwerp 2610 , Belgium.

Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.7b01449DOI Listing
March 2018