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Abstract Background Mitochondria are semi-autonomous, semi-self-replicating organelles harboring their own DNA (mitochondrial DNA, mtDNA), and their dysregulation is involved in the development of various diseases. While mtDNA does not generally undergo epigenetic modifications, almost all mitochondrial proteins are encoded by nuclear DNA. However, the epigenetic regulation of nuclear-encoded mitochondrial genes (nuclear mt genes) has not been comprehensively analyzed. Results We analyzed the DNA methylation status of 899 nuclear mt genes in the liver, brain, and heart tissues of mouse, and identified 636 nuclear mt genes carrying tissue-dependent and differentially methylated regions (T-DMRs). These nuclar mt genes are involved in various mitochondrial functions and they also include genes related to human diseases. T-DMRs regulate the expression of nuclear mt genes. Nuclear mt genes with tissue-specific hypomethylated T-DMRs were characterized by enrichment of the target genes of specific transcription factors such as FOXA2 in the liver, and CEBPA and STAT1 in the brain. Conclusions A substantial proportion of nuclear mt genes contained T-DMRs, and the DNA methylation status of numerous T-DMRs should underlie tissue-dependent mitochondrial functions.

Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCF FBXL3 ) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development., (© 2024 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

To what extent and how post-transcriptional dysregulation affects aging proteome remains unclear. Here, we provide proteomic data of whole-tissue lysates (WTL) and low-solubility protein-enriched fractions (LSF) of major tissues collected from mice of 6, 15, 24, and 30 months of age. Low-solubility proteins are preferentially affected by age and the analysis of LSF doubles the number of proteins identified to be differentially expressed with age. Simultaneous analysis of proteome and transcriptome using the same tissue homogenates reveals the features of age-related post-transcriptional dysregulation. Post-transcriptional dysregulation becomes evident especially after 24 months of age and age-related post-transcriptional dysregulation leads to accumulation of core matrisome proteins and reduction of mitochondrial membrane proteins in multiple tissues. Based on our in-depth proteomic data and sample-matched transcriptome data of adult, middle-aged, old, and geriatric mice, we construct the Mouse aging proteomic atlas ( https://aging-proteomics.info/ ), which provides a thorough and integrative view of age-related gene expression changes., (© 2024. The Author(s).)

Vital signs are crucial for assessing the condition of a patient and detecting early symptom deterioration. Noncontact sensor technology has been developed to take vital measurements with minimal burden. This study evaluated the accuracy of a mat-type noncontact sensor in measuring respiratory and pulse rates in patients with cardiovascular diseases compared to conventional methods. Forty-eight hospitalized patients were included; a mat-type sensor was used to measure their respiratory and pulse rates during bed rest. Differences between mat-type sensors and conventional methods were assessed using the Bland-Altman analysis. The mean difference in respiratory rate was 1.9 breaths/min (limits of agreement (LOA): -4.5 to 8.3 breaths/min), and proportional bias existed with significance (r = 0.63, p < 0.05). For pulse rate, the mean difference was -2.0 beats/min (LOA: -23.0 to 19.0 beats/min) when compared to blood pressure devices and 0.01 beats/min (LOA: -11.4 to 11.4 beats/min) when compared to 24-h Holter electrocardiography. The proportional bias was significant for both comparisons (r = 0.49, p < 0.05; r = 0.52, p < 0.05). These were considered clinically acceptable because there was no tendency to misjudge abnormal values as normal. The mat-type noncontact sensor demonstrated sufficient accuracy to serve as an alternative to conventional assessments, providing long-term monitoring of vital signs in clinical settings.

Sea buckthorn ( Hippophae rhamnoides L.) is a deciduous shrub of the Elaeagnaceae family and is widely distributed in northern Eurasia. Sea buckthorn berry (SBB) has attracted attention for its use in many health foods, although its physiological function remains unknown. In this study, we investigated the inhibitory effect of SBB extract and its fractions on Type-I allergy using mast cell lines. Among these fractions, SBB fraction with the highest amount of antioxidant polyphenols significantly inhibited the release of chemical mediators such as histamine and leukotriene B 4 (LTB 4 ) from the stimulated mast cells. This fraction also inhibited the influx of calcium ions (Ca 2+ ) and the phosphorylation of tyrosine residues in proteins, including spleen tyrosine kinase, which is associated with signal transduction during the release of chemical mediators. The active SBB fraction contained isorhamnetin as its major flavonol aglycon. Isorhamnetin inhibited histamine and LTB 4 release from the stimulated cells and suppressed intracellular Ca 2+ influx. These results indicate that isorhamnetin is the primary substance responsible for the antiallergic activity in SBB. In conclusion, SBB may alleviate Type-I allergy by inhibiting the release of chemical mediators from mast cells, and polyphenols may contribute to this effect., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (Copyright © 2023 by The Korean Society of Food Science and Nutrition.)

The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although molecular features underlying aging and species maximum lifespan (MLS) have been comprehensively studied by transcriptome analyses, the actual impact of transcriptome on aging and MLS remains elusive. Here, we found that transcriptional signatures that are associated with mammalian MLS exhibited significant similarity to those of aging. Moreover, transcriptional signatures of longer MLS and aging both exhibited significant similarity to that of longer-lived mouse strains, suggesting that gene expression patterns associated with species MLS contribute to extended lifespan even within a species and that aging-related gene expression changes overall represent adaptations that extend lifespan rather than deterioration. Finally, we found evidence of co-evolution of MLS and promoter sequences of MLS-associated genes, highlighting the evolutionary contribution of specific transcription factor binding motifs such as that of E2F1 in shaping MLS-associated gene expression signature. Our results highlight the importance of focusing on adaptive aspects of aging transcriptome and demonstrate that cross-species genomics can be a powerful approach for understanding adaptive aging transcriptome., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Cellular senescence refers to a state of irreversible cell cycle arrest that can be induced by various cellular stresses and is known to play a pivotal role in tumour suppression. While senescence-associated growth arrest can inhibit the proliferation of cancer-prone cells, the altered secretory profile of senescent cells, termed the senescence-associated secretory phenotype, can contribute to the microenvironment that promotes tumour development. Although the senescence-associated secretory phenotype and its effects on tumorigenesis are both highly context dependent, mechanisms underlying such diversity are becoming better understood, thereby allowing the creation of new strategies to effectively target the senescence-associated secretory phenotype and senescent cells for cancer therapy. In this review, we discuss the current knowledge on cellular senescence and the senescence-associated secretory phenotype to develop a structural understanding of their roles in the tumour microenvironment and provide perspectives for future research, including the possibility of senotherapy for the treatment of cancer., (© 2022 Federation of European Biochemical Societies.)

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.

The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour-suppressive and tumour-promoting effects, as observed in senescence surveillance effects (tumour-suppressive) and suppression of anti-tumour immunity in most senescent cancer-associated fibroblasts and senescent T cells (tumour-promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The 6th conference of the international cell senescence association (ICSA) on the theme of "A New Era of Senescence Research: The Challenge of Controlling Aging and Cancer" was held on December 12-15, 2021 in Osaka, Japan as a Hybrid Meeting. The conference brought together basic and translational scientists to discuss recent developments in the field of cellular senescence research. In recent years, the study of cellular senescence has become a very hot field of research. It is clear that the ICSA, founded in 2015, has played an important role in this process. The 6th ICSA conference has provided another opportunity for exchanges and new connections between basic and translational scientists. The scientific program consisted of keynote lectures, invited talks, short talks selected from abstracts, a poster session, and luncheon seminars sponsored by the Japanese Society of Anti-Aging Medicine. In the Meet the Editor session, Dr Christoph Schmitt, Editor-in-Chief of Nature Metabolism, gave a short presentation about the journal and answered questions from the audience. Being a hybrid meeting, there was only so much that could be done, but we hope that the meeting was fruitful., (© 2022 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Naked mole rats (NMRs) are the longest-lived rodents yet their stem cell characteristics remain enigmatic. Here, we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which comprise a myeloid bias toward granulopoiesis together with decreased B-lymphopoiesis. Remarkably, youthful blood and marrow single-cell transcriptomes and cell compositions are largely maintained until at least middle age. Similar to primates, the primitive stem and progenitor cell (HSPC) compartment is marked by CD34 and THY1. Stem cell polarity is seen for Tubulin but not CDC42, and is not lost until 12 years of age. HSPC respiration rates are as low as in purified human stem cells, in concert with a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. By characterizing the NMR hematopoietic landscape, we identified resilience phenotypes such as an increased quiescent HSPC compartment, absence of age-related decline, and neotenic traits likely geared toward longevity., (© 2022 The Authors.)

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, the processes underlying this adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing and mass spectrometry. Our single-cell RNA sequencing analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 knockout mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Osteoarthritis (OA) is the most prevalent disabling disease, affecting quality of life and contributing to morbidity, particularly during aging. Current treatments for OA are limited to palliation: pain management and surgery for end-stage disease. Innovative approaches and animal models are needed to develop curative treatments for OA. Here, we investigated the naked mole-rat (NMR) as a potential model of OA resistance. NMR is a small rodent with the maximum lifespan of over 30 years, resistant to a wide range of age-related diseases. NMR tissues accumulate large quantities of unique, very high molecular weight, hyaluronan (HA). HA is a major component of cartilage and synovial fluid. Importantly, both HA molecular weight and cartilage stiffness decline with age and progression of OA. As increased polymer length is known to result in stiffer material, we hypothesized that NMR high molecular weight HA contributes to stiffer cartilage. Our analysis of biomechanical properties of NMR cartilage revealed that it is significantly stiffer than mouse cartilage. Furthermore, NMR chondrocytes were highly resistant to traumatic damage. In vivo experiments using an injury-induced model of OA revealed that NMRs were highly resistant to OA. While similarly treated mice developed severe cartilage degeneration, NMRs did not show any signs of OA. Our study shows that NMRs are remarkably resistant to OA, and this resistance is likely conferred by high molecular weight HA. This work suggests that NMR is a useful model to study OA resistance and NMR high molecular weight HA may hold therapeutic potential for OA treatment., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Hyaluronan is a major non-protein component of extracellular matrix that affects biomechanical properties of tissues and interacts with cell receptors. Hyaluronan is a linear glycosaminoglycan composed of repeating disaccharides of (β, 1-4)-glucuronic acid (GlcUA) and (β, 1-3)-N-acetyl glucosamine (GlcNAc). The length of hyaluronan can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties. HMW-HA is used in the clinic to treat arthritis, and as a filler in surgery and in the form of rinses to treat local inflammation. However, HMW-HA products used in the clinic come in a range of sizes between 0.5-6 mDa that are used interchangeably. Remarkably, the tissues of a long-lived and cancer-resistant rodent, the naked mole rat, contain abundant HA of very high molecular weight. While human fibroblasts secrete HA up to 2 MDa, naked mole rat fibroblasts produce HA of 6-12 MDa. Does this very high HMW-HA (vHMW-HA) differ functionally from HMW-HA? We found that vHMW-HA has superior cytoprotective properties compared to HMW-HA, and interacts differently with the CD44 receptor leading to distinct transcriptional changes (Takasugi et al. (2020), Nat Commun). These results indicate that vHMW-HA has greater therapeutic benefits than the standard HMW-HA., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (Copyright: © 2020 Gorbunova et al.)

When transcribed DNA is damaged, the transcription and DNA repair machineries must interact to ensure successful DNA repair. The mechanisms of this interaction in the context of chromatin are still being elucidated. Here we show that the SIRT6 protein enhances non-homologous end joining (NHEJ) DNA repair by transiently repressing transcription. Specifically, SIRT6 mono-ADP ribosylates the lysine demethylase JHDM1A/KDM2A leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels. Furthermore, we found that through HP1α binding, H3K36me2 promotes subsequent H3K9 tri-methylation. This results in transient suppression of transcription initiation by RNA polymerase II and recruitment of NHEJ factors to DNA double-stranded breaks (DSBs). These data reveal a mechanism where SIRT6 mediates a crosstalk between transcription and DNA repair machineries to promote DNA repair. SIRT6 functions in multiple pathways related to aging, and its novel function coordinating DNA repair and transcription is yet another way by which SIRT6 promotes genome stability and longevity.

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.

Background: Ambulatory electrocardiogram (ECG)-based microvolt T-wave alternans values measured by the modified moving average method (MMA-TWA) can be disrupted by T-wave changes that mimic true repolarization alternans., Methods: We investigated potential sources of measurement error by studying 19 healthy subjects (12 men; median age, 25) free of known heart disease with 36-month follow-up to establish freedom from significant arrhythmia or syncope. All participants underwent 24-hr continuous 12-lead ECG monitoring. Causes of automated MMA-TWA ≥42 µV episodes were classified based on visual inspection., Results: A total of 2,189 episodes of automated MMA-TWA episodes ≥42 µV were observed in all subjects (peak MMA-TWA: median, 94 μV; interquartile range, 81-112 μV). All episodes included one or more beats with T-wave deformation which lacked "repeating ABAB pattern" and therefore were identified as TWA measurement error. Causes of such error were categorized as: (a) artifact [72.6% (1,589/2,189), observed in 19 (100%) subjects], more frequently in limb than precordial leads; (b) T-wave changes due to changes in heart/body position [25.5% (559/2,189), observed in 14 (73.7%) subjects], frequently observed in leads V1-2; and (c) postextrasystolic T-wave changes [1.9% (41/2,189), observed in 2 (10.5%) subjects]., Conclusions: Relying only on automated MMA-TWA values obtained during ambulatory ECG monitoring can lead to incorrect measurement of TWA. Our findings offer the potential to reduce false-positive TWA results and to achieve more accurate detection of true repolarization alternans., (© 2019 Wiley Periodicals, Inc.)

Background: The aim of study was to investigate effects of beta-blockade on microvolt T-wave alternans (TWA), a precursor of lethal arrhythmia, in patients with long QT syndrome (LQTS)., Methods: Eleven consecutive LQTS patients, types 1 (n = 6), 3 (n = 2), and "non-1, non-2, non-3" (n = 3) were enrolled. All patients underwent 24-hr continuous 12-lead ECG monitoring before and after initiation of beta-blockade therapy. TWA was measured using the modified moving average method., Results: Seven (63.6%) of the 11 patients studied were symptomatic, with history of cardiac arrest or documented Torsade de Pointes (TdP) in 4 and syncope in three patients. After a median follow-up of 34 months, beta-blockade reduced the number of symptomatic patients to 1 with TdP (p < 0.02), in whom TdP frequency decreased from 25 events/60 months (0.42 event/month) to seven events/69 months (0.1 event/month). In association with this reduction in symptoms, peak TWA decreased by 47% in the cohort after a median of eight months of beta-blockade therapy [from 95 (74-130) to 50 (39.5-64.5) µV, p = 0.01]. All patients exhibited TWA ≥42 µV before beta-blockade therapy, which eliminated these episodes in four patients. Daily frequency of TWA ≥42 µV episodes decreased by 87% [from 15 (6-26) to 2 (0-5) episodes/day, p = 0.009]., Conclusions: This study is limited by the small sample size and is mainly hypothesis generating. TWA monitoring deserves further evaluation as a risk marker and a guide to therapy in LQTS patients in future large-scale studies., (© 2019 Wiley Periodicals, Inc.)

This Article contains errors in Fig. 4. In panel d, the lanes of the western blot should have been labeled '1.05','1.06, '1.09', '1.11' '1.13', '1.16', '1.19', '1.22', '1.24', '1.25'. The correct version of Figure 4 appears in the associated Publisher Correction.

Cellular senescence is a cellular program that prevents the proliferation of cells at risk of neoplastic transformation. On the other hand, age-related accumulation of senescent cells promotes aging at least partially due to the senescence-associated secretory phenotype, whereby cells secrete high levels of inflammatory cytokines, chemokines, and matrix metalloproteinases. Emerging evidence, however, indicates that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Senescent cells secrete more EphA2 and DNA via EVs, which can promote cancer cell proliferation and inflammation, respectively. Extracellular vesicles secreted from DNA-damaged cells can also affect telomere regulation. Furthermore, it has now become clear that EVs actually play important roles in many aspects of aging. This review is intended to summarize these recent progresses, with emphasis on relationships between cellular senescence and EVs., (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Leukotrienes (LTs), chemical mediators produced by mast cells, play an important role in allergic symptoms such as food allergies and hay fever. We tried to construct an evaluation method for the anti-LTB 4 activity of chemical substances using a mast cell line, PB-3c. PB-3c pre-cultured with or without arachidonic acid (AA) was stimulated by calcium ionophore (A23187) for 20 min, and LTB 4 production by the cells was determined by HPLC with UV detection. LTB 4 was not detected when PB-3c was pre-cultured without AA. On the other hand, LTB 4 production by PB-3c pre-cultured with AA was detectable by HPLC, and the optimal conditions of PB-3c for LTB 4 detection were to utilize the cells pre-cultured with 50 µM AA for 48 h. MK-886 (5-lipoxygenase inhibitor) completely inhibited LTB 4 production, but AACOCF 3 (phospholipase A 2 inhibitor) slightly increased LTB 4 production, suggesting that LTB 4 was generated from exogenous free AA through 5-lipoxygenase pathway. We applied this technique to the evaluation of the anti-LTB 4 activity of food components. PB-3c pre-cultured with 50 µM AA for 48 h was stimulated with A23187 in the presence of 50 µM soybean isoflavones (daidzin, genistin, daidzein, and genistein), equol, quercetin, or kaempferol. Genistein, equol, quercetin, and kaempferol strongly inhibited LTB 4 production without cytotoxicity. These results suggest that a new assay system using PB-3c is convenient to evaluate LTB 4 inhibition activity by food components. This method could be utilized for elucidation of the mechanisms of LTB 4 release suppression by food components such as flavonoids and the structure-activity relationship.

Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. However, the altered secretome of senescent cells can promote the growth of the surrounding cancer cells. Although extracellular vesicles (EVs) have emerged as new players in intercellular communication, their role in the function of senescent cell secretome has been largely unexplored. Here, we show that exosome-like small EVs (sEVs) are important mediators of the pro-tumorigenic function of senescent cells. sEV-associated EphA2 secreted from senescent cells binds to ephrin-A1, that is, highly expressed in several types of cancer cells and promotes cell proliferation through EphA2/ephrin-A1 reverse signalling. sEV sorting of EphA2 is increased in senescent cells because of its enhanced phosphorylation resulting from oxidative inactivation of PTP1B phosphatase. Our results demonstrate a novel mechanism of reactive oxygen species (ROS)-regulated cargo sorting into sEVs, which is critical for the potentially deleterious growth-promoting effect of the senescent cell secretome.

Emerging evidence is revealing that exosomes contribute to many aspects of physiology and disease through intercellular communication. However, the biological roles of exosome secretion in exosome-secreting cells have remained largely unexplored. Here we show that exosome secretion plays a crucial role in maintaining cellular homeostasis in exosome-secreting cells. The inhibition of exosome secretion results in the accumulation of nuclear DNA in the cytoplasm, thereby causing the activation of cytoplasmic DNA sensing machinery. This event provokes the innate immune response, leading to reactive oxygen species (ROS)-dependent DNA damage response and thus induce senescence-like cell-cycle arrest or apoptosis in normal human cells. These results, in conjunction with observations that exosomes contain various lengths of chromosomal DNA fragments, indicate that exosome secretion maintains cellular homeostasis by removing harmful cytoplasmic DNA from cells. Together, these findings enhance our understanding of exosome biology, and provide valuable new insights into the control of cellular homeostasis.

Background: Prevalence of microvolt T-wave alternans (TWA) and the strength of its association with torsade de pointes (TdP) history have not been fully investigated in patients with long QT syndrome (LQTS)., Methods and Results: Twenty-four-hour continuous 12-lead ECGs were recorded in 10 healthy subjects (5 men; median age, 21.5 years) and 32 patients (13 men; median age, 13 years) with LQTS types 1 (n=18), 2 (n=4), 3 (n=4), and unidentified (n=6). Peak TWA was determined by the Modified Moving Average method. None of the healthy subjects had TWA ≥42 µV. All 8 (100%) LQTS patients with a history of TdP exhibited TWA ≥42 µV, whereas only 14 (58.3%) of the 24 LQTS patients without TdP history reached ≥42 µV (p=0.04). Thus, the 42-µV cut point provided 100% sensitivity and 41.7% specificity for an association with TdP history. In the 22 (68.8%) LQTS patients with TWA ≥42 µV, only 2 (median; interquartile range, 1-3) leads exhibited TWA ≥42 µV. Highest TWA levels were recorded in precordial leads (V1-V6) in 30 (93.8%) patients, most frequently in lead V2 (43.8%). A single ECG lead detected only ≤63.6% of TWA ≥42 µV episodes, whereas the combined leads V2 to V5 detected 100% of TWA ≥42 µV., Conclusions: Microvolt TWA is far more prevalent in LQTS patients than previously reported and is strongly associated with TdP history. TWA should be monitored from precordial leads in LQTS patients. The use of a limited set of ECG leads in conventional monitoring has led to underestimation of TWA and its association with TdP., (© 2016 American Heart Association, Inc.)

Objectives: To compare the diagnostic performance of two norovirus rapid immunochromatographic kits (QuickNavi(®)-Norovirus [QN] and QuickNavi®-Norovirus 2 [QN2]; Denka Seiken, Niigata, Japan) for neonatal and infant faecal specimens., Methods: Monthly faecal samples were collected from infants from birth to 12 months of age, and tested for norovirus using QN and QN2. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used as the gold standard for norovirus detection. The diagnostic performance of the kits was calculated., Results: A total of 343 specimens from 81 infants were analysed. In all samples, the specificity of QN and QN2 was 80% (275/343) and 99% (339/343), respectively. In infants aged <1 month, the specificity of QN was 33% (23/70), increasing to 93% at 4 months of age. Specificity of QN2 was ≥94% in infants between 0 and 12 months of age., Conclusions: QN2 offers improved performance and is more useful than QN for the diagnosis of norovirus infection in the neonatal and infant period., (© The Author(s) 2015.)

The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of α-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in α-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of α-klotho expression. Indeed, p16(INK4a) represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of α-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating α-klotho expression during ageing.