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"Yamamoto, Takeshi"
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Teasing Master Takagi-san
Middle schooler Nishikata has had it with his classmate Takagi--the chronic teaser who sits nearby. Day in and day out, she comes after him with every sort of trick or prank. Even when he tries to get her back, she's always one step ahead. But rest assured, it's only the beginning. He's not about to give up that easily in this battle of cunning and youth! -- back cover of volume 1.
Book
Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity
Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in “autophagic stagnation” characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, “Obesity-Related Proximal Tubulopathy.” This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.
Journal Article
Mechanical circulatory support in cardiogenic shock
Cardiogenic shock is a complex and diverse pathological condition characterized by reduced myocardial contractility. The goal of treatment of cardiogenic shock is to improve abnormal hemodynamics and maintain adequate tissue perfusion in organs. If hypotension and insufficient tissue perfusion persist despite initial therapy, temporary mechanical circulatory support (t-MCS) should be initiated. This decade sees the beginning of a new era of cardiogenic shock management using t-MCS through the accumulated experience with use of intra-aortic balloon pump (IABP) and venoarterial extracorporeal membrane oxygenation (VA-ECMO), as well as new revolutionary devices or systems such as transvalvular axial flow pump (Impella) and a combination of VA-ECMO and Impella (ECPELLA) based on the knowledge of circulatory physiology. In this transitional period, we outline the approach to the management of cardiogenic shock by t-MCS. The management strategy involves carefully selecting one or a combination of the t-MCS devices, taking into account the characteristics of each device and the specific pathological condition. This selection is guided by monitoring of hemodynamics, classification of shock stage, risk stratification, and coordinated management by the multidisciplinary shock team.
Journal Article
Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells
Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.
Journal Article
Management of patients with high-risk pulmonary embolism: a narrative review
High-risk pulmonary embolism (PE) is a life-threatening disorder associated with high mortality and morbidity. Most deaths in patients with shock occur within the first few hours after presentation, and rapid diagnosis and treatment is therefore essential to save patients’ lives. The main manifestations of major PE are acute right ventricular (RV) failure and hypoxia. RV pressure overload is predominantly related to the interaction between the mechanical pulmonary vascular obstruction and the underlying cardiopulmonary status. Computed tomography angiography allows not only adequate visualization of the pulmonary thromboemboli down to at least the segmental level but also RV enlargement as an indicator of RV dysfunction. Bedside echocardiography is an acceptable alternative under such circumstances. Although it does not usually provide a definitive diagnosis or exclude pulmonary embolism, echocardiography can confirm or exclude severe RV pressure overload and dysfunction. Extracorporeal membrane oxygenation support can be an effective procedure in patients with PE-induced circulatory collapse. Thrombolysis is generally accepted in unstable patients with high-risk PE; however, thrombolytic agents cannot be fully administered to patients with a high risk of bleeding. Conversely, catheter-directed treatment is an optimal treatment strategy for patients with high-risk PE who have contraindications for thrombolysis and is a minimally invasive alternative to surgical embolectomy. It can be performed with a minimum dose of thrombolytic agents or without, and it can be combined with various procedures including catheter fragmentation or embolectomy in accordance with the extent of the thrombus on a pulmonary angiogram. Hybrid catheter-directed treatment can reduce a rapid heart rate and high pulmonary artery pressure and can improve the gas exchange indices and outcomes. Surgical embolectomy is also performed in patients with contraindications for or an inadequate response to thrombolysis. Large hospitals having an intensive care unit should preemptively establish diagnostic and therapeutic protocols and rehearse multidisciplinary management for patients with high-risk PE. Coordination with a skilled team comprising intensivists, cardiologists, cardiac surgeons, radiologists, and other specialists is crucial to maximize success.
Journal Article
Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca
2+
homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in
App
NL-G-F
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from
App
NL-G-F
mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
Journal Article
Current characteristics and management of ST elevation and non-ST elevation myocardial infarction in the Tokyo metropolitan area: from the Tokyo CCU network registered cohort
Limited data exists on ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) managed by a well-organized cardiac care network in a metropolitan area. We analyzed the Tokyo CCU network database in 2009–2010. Of 4329 acute myocardial infarction (AMI) patients including STEMI (
n
= 3202) and NSTEMI (
n
= 1127), percutaneous coronary intervention (PCI) was performed in 88.8 % of STEMI and 70.4 % of NSTEMI patients. Mean onset-to-door and door-to-balloon times in STEMI patients were shorter than those in NSTEMI patients (167 vs 233 and 60 vs 145 min, respectively,
p
< 0.001). Coronary artery bypass graft surgery was performed in 4.2 % of STEMI and 11.4 % of NSTEMI patients. In-hospital mortality was significantly higher in STEMI patients than NSTEMI patients (7.7 vs 5.1 %,
p
< 0.007). Independent correlates of in-hospital mortality were advanced age, low blood pressure, and high Killip classification, statin-treated dyslipidemia and PCI within 24 h were favorable predictors for STEMI. High Killip classification, high heart rate, and hemodialysis were significant predictors of in-hospital mortality, whereas statin-treated dyslipidemia was the only favorable predictor for NSTEMI. In conclusion, patients with MI received PCI frequently (83.5 %) and promptly (door-to-balloon time; 66 min), and had favorable in-hospital prognosis (in-hospital mortality; 7.0 %). In addition to traditional predictors of in-hospital death, statin-treated dyslipidemia was a favorable predictor of in-hospital mortality for STEMI and NSTEMI patients, whereas hemodialysis was the strongest predictor for NSTEMI patients.
Journal Article
Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
Twenty years after the thalidomide disaster in the late 1950s, Blaschke
et al
. reported that only the (
S
)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert
in vivo
, which begs the question: why is teratogen activity not observed in animal experiments that use (
R
)-thalidomide given the ready
in vivo
racemization (“thalidomide paradox”)? Herein, we disclose a hypothesis to explain this “thalidomide paradox” through the
in-vivo
self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes
in vivo
, followed by precipitation of racemic thalidomide in (
R
/
S
)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (
R
/
S
)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (
S
)-enantiomer is teratogenic, while the (
R
)-enantiomer is not.
Journal Article
Effects of pemafibrate on left ventricular diastolic function in patients with type 2 diabetes mellitus: a pilot study
Aims/introduction
Diabetic cardiomyopathy (DCM) is characterized predominantly by diastolic dysfunction. The multiple mechanisms underlying DCM include altered energy substrate utilization. Recent studies indicate that PPARα plays an important role in the pathogenesis of lipotoxic cardiomyopathy. Pemafibrate is known to be a selective PPARα modulator (SPPARMα). We thus investigated the effects of pemafibrate on cardiac diastolic function in patients with type 2 diabetes.
Materials and methods
Seventeen patients with type 2 diabetes (T2D) and hypertriglyceridemia were screened and treated with pemafibrate at a dose of 0.2 mg/day for 8–16 weeks. Fourteen patients were eligible for analysis. Echocardiography was used for assessment of diastolic function. Early diastolic filling velocity (E), late atrial filling velocity (A) and the E/A ratio were included in this study. Peak early diastolic annular velocities (e′) were also assessed using color tissue Doppler images. The primary endpoints were changes in the ratio of E to A (E/A), e’, and the ratio of E to e’ (E/e’) from baseline.
Results
Pemafibrate significantly increased average e’ (7.24 ± 0.58 vs 7.94 ± 0.67,
p
= 0.019) and a significant reduction in E/e’ (9.01 ± 0.94 vs 8.20 ± 0.91,
p
= 0.041). The increase in e’ was significantly related to increases in fasting blood glucose (
r
= 0.607,
p
= 0.021) and non-esterified fatty acid (
r
= 0.592,
p
= 0.026).
Conclusion
Pemafibrate improved diastolic function in patients with T2D and hypertriglyceridemia, suggesting that PPARα activation by pemafibrate prevents the development of DCM at an early stage.
Journal Article
Sex differences in the burden of multiple long-term conditions among Japanese individuals with heart failure
BackgroundMultiple long-term conditions (MLTCs) are common among individuals with heart failure (HF); however, the influence of sex on clinical characteristics and prognosis remains unclear. This study investigated sex-related differences in clinical characteristics and prognosis in individuals with HF and a high MLTC burden.MethodsWe conducted a multicentre retrospective study of 3004 hospitalised patients with HF who survived to discharge. Comorbid chronic conditions were defined using the Charlson Comorbidity Index (CCI), and MLTC burden was quantified using the age-adjusted CCI. Patients were stratified into high (CCI≥6; n=1514) and low (CCI<6; n=1490) MLTC burden groups based on the median age-adjusted CCI, and comparisons were made by sex. The primary outcome was a composite of all-cause death or HF readmission within 1 year.ResultsThe prevalence of ≥2 comorbid conditions increased with age, peaking before age 85 and declining slightly thereafter. This trend differed by sex, with a steeper age-related increase observed in men. In the high MLTC burden group, females were older, had higher left ventricular ejection fraction and were prescribed fewer medications than men. Dementia and rheumatologic disease were more common in women. Although no significant sex differences in event-free survival were observed overall in either MLTC group, among individuals aged≥75 years with high MLTC burden, men had a significantly higher risk of adverse events than women (HR: 1.334; 95% CI 1.031 to 1.727). A spline-based three-way interaction analysis (age×sex×MLTC burden) demonstrated that male risk exceeded female risk after age 70, only in the high MLTC burden group.ConclusionIn individuals with HF and a high MLTC burden, age-dependent sex differences in prognosis were evident. These findings highlight the importance of incorporating age-specific and sex-specific approaches into personalised HF care.Trial registration numberUMIN000054854.
Journal Article