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Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene ( Clk/Clk ) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure. Alteration of circadian rhythms is often observed in patients with chronic kidney disease (CKD). Here, the authors show that CKD-induced dysfunction of the circadian clock increases the expression of G protein-coupled receptor 68 in circulating monocytes and that their cardiac infiltration exacerbates inflammation and fibrosis of heart.

In ferroptosis, the roles of mitochondria have been controversial. To explore the role of mitochondrial events in ferroptosis, we employed mitochondrial DNA-depleted ρ 0 cells that are resistant to cell death due to enhanced expression of antioxidant enzymes. Expression of mitochondrial-type GPx4 (mGPx4) but no other forms of GPx4 was increased in SK-Hep1 ρ 0 cells. Likely due to high mGPx4 expression, SK-Hep1 ρ 0 cells were resistant to ferroptosis by erastin inhibiting xCT channel. In contrast, SK-Hep1 ρ 0 cells were susceptible to cell death by a high concentration of RSL3 imposing ferroptosis by GPx4 inhibition. Accumulation of cellular ROS and oxidized lipids was observed in erastin- or RSL3-treated SK-Hep1 ρ + cells but not in erastin-treated SK-Hep1 ρ 0 cells. Mitochondrial ROS and mitochondrial peroxidized lipids accumulated in SK-Hep1 ρ + cells not only by RSL3 but also by erastin acting on xCT on the plasma membrane. Mitochondrial ROS quenching inhibited SK-Hep1 ρ + cell death by erastin or a high dose of RSL3, suggesting a critical role of mitochondrial ROS in ferroptosis. Ferroptosis by erastin or RSL3 was inhibited by a more than 20-fold lower concentration of MitoQ, a mitochondrial ROS quencher, compared to DecylQ, a non-targeting counterpart. Ferroptosis of SK-Hep1 ρ + cells by erastin or RSL3 was markedly inhibited by a VDAC inhibitor, accompanied by significantly reduced accumulation of mitochondria ROS, total peroxidized lipids, and mitochondrial peroxidized lipids, strongly supporting the role of mitochondrial events in ferroptotic death and that of VDAC in mitochondrial steps of ferroptosis induced by erastin or RSL3. SK-Hep1 ρ + cell ferroptosis by sorafenib was also suppressed by mitochondrial ROS quenchers, accompanied by abrogation of sorafenib-induced mitochondrial ROS and mitochondrial peroxidized lipid accumulation. These results suggest that SK-Hep1 ρ 0 cells are resistant to ferroptosis due to upregulation of mGPx4 expression and mitochondrial events could be the ultimate step in determining final cell fate.

Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared to WT mice. The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.

Identification of driver genes contributes to the understanding of cancer etiology and is imperative for the development of individualized therapies. Gene amplification is a major event in oncogenesis. Driver genes with tumor-specific amplification-dependent overexpression can be therapeutic targets. In this study, we aimed to identify amplification-dependent driver genes in 1,454 solid tumors, across more than 15 cancer types, by integrative analysis of gene expression and copy number. Amplification-dependent overexpression of 64 known driver oncogenes were found in 587 tumors (40%); genes frequently observed were MYC (25%) and MET (18%) in colorectal cancer; SKP2 (21%) in lung squamous cell carcinoma; HIST1H3B (19%) and MYCN (13%) in liver cancer; KIT (57%) in gastrointestinal stromal tumors; and FOXL2 (12%) in squamous cell carcinoma across tissues. Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%). Further analyses of 820 cancer-related genes revealed 16 as potential driver genes, with amplification-dependent overexpression restricted to the remaining 22% of samples (327 tumors) initially undetermined genetic drivers. Among them, AXL , which encodes a receptor tyrosine kinase, was recurrently overexpressed and amplified in sarcomas. Our studies of amplification-dependent overexpression identified potential drug targets in individual tumors.

In the mitochondria-mediated vicious cycle of Alzheimer’s disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aβ in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aβ aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1 (P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aβ. These results provide new insights into potential novel therapeutic targets.

An anodized aluminum oxide (AAO) thick film with numerous nanochannels was synthesized by a cathodic exfoliation technique from a metallic aluminum rod. The nanochannel diameter D and length L were about 60 nm and 60 µm, respectively. The aspect ratio L / D reached ~ 1000. A rectangular pulsed potential deposition technique was applied to electrochemically grow the multilayered nanocylinders with alternating Cu and Co thin layers in the AAO nanochannels. The Co/Cu bilayer thickness was decreased to around 7 nm at the minimum by controlling the pulsed potential and duty cycle during the electrodeposition process. An electrochemical in situ single contact process was demonstrated by monitoring the observed current until a Co/Cu multilayered nanocylinder reached the nanoporous Au film on the AAO thick film. The resistance of the Co/Cu multilayered nanocylinder was determined to range from 1 to 2 kΩ, which corresponded well with a theoretical estimation. Current-perpendicular-to-plane giant magnetoresistance (CPP-GMR) of a Co/Cu multilayered nanocylinder with ~ 6000 bilayers (Cu = 2.4 nm, Co = 7.1 nm) reached up to 31.5% at room temperature. Valet–Fert model agreed well with the present study concerning the effect of Cu-layer thickness on CPP-GMR.

Training opportunities, work satisfaction, and the factors that influence them according to gender and subspecialties are understudied among Japanese cardiologists. We investigated the career development of Japanese cardiologists with an e-mail questionnaire. Feelings of inequality in training opportunities, work dissatisfaction, and reasons were assessed by examining the cardiologists' gender and invasiveness of subspecialties. Responses were received from 2,566 cardiologists. Female cardiologists were underrepresented in invasive subspecialties compared to males (14.2% vs. 85.8%, p<0.0001). In both invasive and non-invasive subspecialties, female cardiologists felt more inequality in training opportunities than males (invasive: 50.0% vs. 36.2%, non-invasive: 41.6% vs. 30.9%, p<0.001, respectively) and were less satisfied with their work (invasive: 26.0% vs. 18.3%, non-invasive: 24.7% vs. 14.7%, p = 0.001, respectively). Although female cardiologists in invasive subspecialties did not feel significantly more inequal and dissatisfied than those in non-invasive subspecialties (p = 0.063 and p = 0.758, respectively), male cardiologists in invasive subspecialties felt more inequal and dissatisfied than those in non-invasive subspecialties (p = 0.015 and p = 0.040, respectively). Female cardiologists were more influenced by gender bias and family issues for inequality in training opportunities (p = 0.0001, respectively), whereas male cardiologists were likely to be affected by specifications of belonging hospitals. Both genders felt dissatisfied when their expectations were unmet and they were overworked. Female cardiologists felt more inequality regarding training opportunities and dissatisfaction with career development than male cardiologists in both the invasive and non-invasive subspecialties. Diversity support is warranted for achieving satisfying career course regardless of gender and subspecialty.

Intensive care unit-acquired weakness (ICU-AW) is recognized as newly-acquired bilateral muscle weakness, which is a complication of critical illness in the ICU; however, there are no reports on the pathogenesis and early predictors of ICU-AW specifically associated with cardiogenic shock (CS). Therefore, this study aimed to investigate the clinical characteristics of ICU-AW in patients with CS requiring mechanical circulatory support (MCS). This study was a single-center, prospective, and observational study. Patients aged 16 years and older who underwent MCS for CS were included. ICU-AW was diagnosed based on Medical Research Council (MRC) score after awakening. The ICU-AW group included patients with the MRC score < 48 points, and the non-ICU-AW group included those with ≥ 48 points. Twenty-eight cases were enrolled on admission and MRC score was evaluated in 23 cases after awakening. Eleven patients were included in the non-ICU-AW group and 12 patients (52%) were in the ICU-AW group. The ICU-AW group showed a higher prevalence of extracorporeal membrane oxygenation and ventilator use. Creatine kinase, troponin T, interleukin (IL)-15 levels on admission were significantly higher, whereas hemoglobin and albumin levels were significantly lower in the ICU-AW group. A strong negative correlation was observed between the initial MRC scores and IL-15 levels. ICU-AW occurred 52% of patients with CS using MCS, indicating the significance of recognizing and managing this complication for those patients. In addition, IL-15 can be a potential biomarker for the early prediction of ICU-AW.

BackgroundMalnutrition influences prognosis in patients with heart failure, but current nutritional evaluation methods are excessively complex for routine clinical use. The role of the serum albumin concentration, a widely used surrogate marker, in acute heart failure remains unclear. We assessed whether changes in serum albumin during heart failure hospitalisation can serve as a prognostic marker.MethodsAmong 14 847 patients in a nationwide heart failure registry in 2013, 5836 eligible patients (mean age: 77.7 years, 51.2% men) were categorised into two groups: the albumin-increase group (n=2048) and the no-albumin-increase group (n=3788). The incidences of primary (all-cause mortality) and secondary (a composite of cardiovascular death and rehospitalisation for worsening heart failure) outcomes were compared between the groups. The prognostic impact of serum albumin changes was also evaluated.ResultsThe median follow-up period was 1545 days (95% CI 1535 to 1557 days). Event-free survival rates for clinical outcomes were higher in the albumin-increase group than in the no-albumin-increase group (primary outcome: 54.5% vs 45.4%, 95% CI 51.4% to 57.6% vs 42.9% to 47.8%, p<0.005; secondary outcome: 40.5% vs 36.9%, 95% CI 36.4% to 44% vs 34.1% to 39.6%, p<0.005). A generalised additive model revealed a linear relationship between serum albumin changes and prognosis; declines had a stronger negative effect than the positive impact of increases, but the change rate better reflected the relationship with prognosis. Survival classification and regression tree analysis indicated that a 25% decrease in the serum albumin concentration identified the most vulnerable population; even a 3% decrease was associated with worse outcomes.ConclusionsSerum albumin changes during hospitalisation can predict prognosis in patients with heart failure, indicating potential as a target for interventions.