Decreased Memory and Learning Ability Mediated by Bmal1/M1 Macrophages/Angptl2/Inflammatory Cytokine Pathway in Mice Exposed to Long-Term Blue Light Irradiation.

Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1ß were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory.

Induction of Skin Cancer by Long-Term Blue Light Irradiation.

Presently, people are not only exposed to sunlight but also to a large amount of blue light from personal computers and smartphones. This blue light has various effects on the living body. However, its effect on the induction of skin cancer is unknown. In this study, we investigated the induction of skin cancer by long-term blue light irradiation. Hairless mice were irradiated with blue light (LED; peak emission 479 nm) every day for one year, and a control was irradiated with white light (LED), green light (LED; peak emission 538 nm), and red light (LED; peak emission 629 nm) for one year, respectively. Skin cancer was induced only in the mice exposed to blue light. Long-term blue light irradiation also increased the migration of neutrophils and macrophages involved in carcinogenesis in the skin. In neutrophils, an increased expression of citH3 and PAD4 was observed, suggesting the possibility of NETosis. Conversely, in macrophages, inflammatory macrophages (type 1 macrophages) increased and anti-inflammatory macrophages (type 2 macrophages) decreased due to continuous blue light irradiation. These findings suggest that long-term continuous irradiation with blue light induces neutrophil NETosis and an increase in type 1 macrophages, resulting in skin cancer.

Periprocedural and 30-day outcomes of robotic-assisted percutaneous coronary intervention used in the intravascular imaging guidance.

In recent years, there have been several reports on robotic-assisted percutaneous coronary intervention (R-PCI), but few studies have been conducted on R-PCI performed under intravascular imaging guidance. To elucidate the periprocedural and postoperative 30-day outcomes of intravascular imaging-guided R-PCI, we performed a retrospective observational study on all patients in 102 consecutive cases who underwent R-PCI under intravascular imaging guidance at a single center in Japan from June 12, 2019 to February 18, 2021. The primary end point was 30-day survival, and the secondary end point was the incidence of complications. Intravascular imaging-guided R-PCI was performed 110 times in total on 125 lesions. The medians of procedural time, fluoroscopy time, contrast volume, patient entrance skin dose, and radiation exposure to the main operator were 49 min, 16 min, 67 mL, 0.62 Gy, and 0 µSv, respectively. Furthermore, 60.0% of target lesion branches were American College of Cardiology Foundation/American Heart Association classification type B2 or type C. However, in all cases, lesion dilatation was successful, and the final Thrombolysis in Myocardial Infarction flow grade was 3. The combination of manual operation was required in 12.7% of all cases, but 30-day survival was confirmed in all cases. There were two problems at the puncture site. One small distal branch artery dissection occurred due to manual operation, but no cardiovascular events (myocardial infarction, stroke) occurred and no target lesion restenosis was observed within 30 days of R-PCI. Hence, R-PCI using intravascular imaging demonstrated highly satisfactory treatment outcomes, and no complication caused by robotic operation was observed.

Prevalence, clinical characteristics, and impact of active cancer in patients with acute myocardial infarction: data from an all-comer registry.

BACKGROUND: Although a history of cancer is a poor prognostic factor in patients with acute myocardial infarction (AMI), the clinical importance of coexisting active cancer remains unclear. METHODS: In this single-center retrospective study, we reviewed an AMI registry and assessed the prevalence and predictors of active cancer, 1-year incidence of cardiac death or major bleeding events (defined as a Bleeding Academy Research Consortium type 3 or 5), and the impact of coexisting active cancer on clinical outcomes. Active cancer was defined as either an already-diagnosed or undiagnosed occult cancer. RESULTS: Between January 2012 and December 2017, 1140 AMI patients (median age, 69 years; male, 76.0%) were enrolled. Active and historical cancers were diagnosed in 63 patients (5.5%) and 50 patients (4.4%), respectively. The most common location was the urinary tract (n=21). In the Kaplan-Meier analysis, the active cancer group had a higher incidence of 1-year cardiac death (17.5% vs. 5.3%, p < 0.001) and major bleeding events (19.0% vs. 5.6%, p < 0.001) than the non-cancer group. In the multivariate Cox proportional hazards regression models, active cancer was an independent predictor of both cardiac death and major bleeding at 1 year. Specifically, gastrointestinal tract and advanced-stage cancers had the poorest outcomes. Compared to the non-cancer group, the 1-year major bleeding rate was higher for all cancer types and stages. In contrast, early-stage cancers had a weaker impact on the 1-year cardiac mortality compared to advanced-stage cancers. Similarly, cardiac death during 1-year also occurred less frequently in occult cancers than in already-known cancers. CONCLUSIONS: In patients with AMI, coexisting active cancer was rare, but it significantly impacted cardiac death and major bleeding events.

A trafficking-deficient KCNQ1 mutation, T587M, causes a severe phenotype of long QT syndrome by interfering with intracellular hERG transport.

BACKGROUND: KCNQ1-T587M is a C-terminal mutation correlated with severe phenotypes of long QT syndrome (LQTS). However, functional analysis of KCNQ1 channels with the T587M mutation showed a mild genotype in the form of haploinsufficiency in a heterologous expression system. This study sought to explore the molecular mechanism underlying the phenotype-genotype dissociation of LQTS patients carrying the KCNQ1-T587M mutation. METHODS: cDNAs for wild-type (WT) and KCNQ1 mutations (R259C and T587M) were transiently transfected into HEK293 cells stably expressing hERG (hERG-HEK), and whole-cell patch-clamp technique was performed to examine the effect of KCNQ1 mutations on IKr-like currents. In addition, fluorescence resonance energy transfer (FRET) was conducted to demonstrate the molecular interaction between KCNQ1 and hERG when co-expressed in HEK293 cells. RESULTS: KCNQ1-T587M mutation produced a significant (p<0.01) decrease in IKr-like tail current densities without affecting the gating kinetics, while KCNQ1-R259C mutation had no significant effect on the IKr-like tail current densities. Consistent with this result, FRET experiments demonstrated that both KCNQ1-WT and -R259C interacted with hERG in the cytosol and on the plasma membrane; however, the interaction between KCNQ1-T587M and hERG was observed only in the cytosol, and hERG proteins were seldom transported to the cell membrane, suggesting that the KCNQ1-T587M mutation impaired the trafficking of hERG to the cell membrane. CONCLUSIONS: The disruption of hERG trafficking caused by the KCNQ1-T587M mutation is likely the reason why some patients exhibit severe LQTS phenotypes.

Adrenergic regulation of the rapid component of delayed rectifier K+ current: implications for arrhythmogenesis in LQT2 patients.

BACKGROUND: KCNH2 gene mutations disrupting rapid component of I(K) (I(Kr)) underlie type 2 congenital long QT syndrome (LQT2). Startled auditory stimuli are specific symptomatic triggers in LQT2, thus suggesting fast arrhythmogenic mechanism. OBJECTIVE: We investigated acute alpha(1A)- and cyclic adenosine monophosphate (cAMP)-related beta-adrenergic modulation of I(Kr) in HL-1 cardiomyocytes, wild type (WT)- and 2 LQT2-associated mutant Kv11.1 channels (Y43D- and K595E-Kv11.1) reconstituted in Chinese hamster ovary (CHO) cells. METHODS: I(Kr) and Kv11.1 currents were recorded using the whole-cell patch-clamp technique and confocal microscopy of HL-1 cardiomyocytes transfected with green fluorescent protein (GFP)-tagged pleckstrin homology domain of phospholipase C-delta(1) visualized fluctuations of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) content. RESULTS: In HL-1 cardiomyocytes expressing human alpha(1A)-adrenoceptor, superfusion with phenylephrine significantly reduced I(Kr) amplitude, shifted current activation to more positive potentials, and accelerated kinetics of deactivation. Confocal images showed a decline of membrane PIP(2) content during phenylephrine exposure. Simultaneous application of adenylyl cyclase activator forskolin and phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) shifted I(Kr) activation to more negative potentials and decreased tail current amplitudes after depolarizations between +10 and +50 mV. In CHO cells, alpha(1A)-adrenoceptor activation downregulated WT-Kv11.1 channels and forskolin/IBMX produced a dual effect. Expressed alone, the Y43D-Kv11.1 or K595E-Kv11.1 channel had no measurable function. However, co-expression of WT-Kv11.1 and each mutant protein evoked currents with loss-of-function alterations but identical to WT-Kv11.1 alpha(1A)- and forskolin/IBMX-induced regulation. CONCLUSION: Acute adrenergic regulation of at least 2 Kv11.1 mutant channels is preserved as in WT-Kv11.1 and native I(Kr). Suppression of alpha(1A)-adrenoceptor-related transduction might have therapeutic implications in some cases of LQT2.

Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation.

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

Identification of a novel NY-ESO-1 promiscuous helper epitope presented by multiple MHC class II molecules found frequently in the Japanese population.

NY-ESO-1 is a cancer-testis antigen that elicits strong cellular and humoral immune responses against NY-ESO-1-expressing tumors. Although CD4(+) T cells play a critical role in inducing antitumor immunity, little is known about MHC class II-restricted helper epitopes of the NY-ESO-1 antigen compared with MHC class I-restricted epitopes. Here, we searched for new NY-ESO-1 helper epitopes presented by MHC class II molecules, especially those found frequently in the Japanese population. We established five NY-ESO-1-specific helper T-cell lines from healthy Japanese donors using NY-ESO-1 recombinant protein and peptide. Using MHC class II-specific antibodies and a panel of Epstein-Barr virus-transformed B-cell lines, it was demonstrated that four out of the five T-cell lines recognized a region within NY-ESO-1(119-143) in the context of HLA-DRB1*0802, DRB1*0901, DRB1*1502 or DRB1*0405/*0410. In addition, using a set of overlapping 15-mer synthetic peptides, we found that NY-ESO-1(122-138) was a promiscuous region that bound to four distinct HLA-DR molecules found in the Japanese population. These findings expand the usefulness of NY-ESO-1 as a tool for tumor vaccine therapy in eliciting NY-ESO-1-specific helper T-cell responses, especially in Japanese cancer patients.

N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome.

BACKGROUND: Long QT syndromes (LQTS) are inherited diseases involving mutations to genes encoding a number of cardiac ion channels and a membrane adaptor protein. The MinK protein is a cardiac K-channel accessory subunit encoded by the KCNE1 gene, mutations of which are associated with the LQT5 form of LQTS. OBJECTIVE: The purpose of this study was to search for the KCNE1 mutations and clarify the function of those mutations. METHODS: We conducted a genetic screen of KCNE1 mutations in 151 Japanese LQTS patients using the denaturing high-performance liquid chromatography-WAVE system and direct sequencing. In two LQTS patients, we identified two KCNE1 missense mutations, located in the MinK N- and C-terminal domains. The functional effects of these mutations were examined by heterologous coexpression with KCNQ1 and KCNH2. RESULTS: One mutation, which was identified in a 67-year-old woman, A8V, was novel. Her electrocardiogram (ECG) revealed marked bradycardia and QT interval prolongation. Another mutation, R98W, was identified in a 19-year-old woman. She experienced syncope followed by palpitation in exercise. At rest, her ECG showed bradycardia with mild QT prolongation, which became more prominent during exercise. In electrophysiological analyses, R98W produced reduced I(Ks) currents with a positive shift in the half activation voltages. In addition, when the A8V mutation was coexpressed with KCNH2, this reduced current magnitude, which is suggestive of a modifier effect by the A8V KCNE1 mutation on I(Kr). CONCLUSION: KCNE1 mutations may be associated with mild LQTS phenotypes, and KCNE1 gene screening is of clinical importance for asymptomatic and mild LQTS patients.

Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity.

1 alpha,25-dihydroxyvitamin D3 [Calcitriol or 1,25(OH)(2)D(3)] is an important active metabolite involved in multiple functions but its calcemic effect in vivo limits its therapeutic applications. On the other hand, 22-oxa-1 alpha,25-dihydroxyvitamin D(3) (22-oxacalcitriol or 22-Oxa-1 alpha,25-D(3)), a low calcemic analog of vitamin D3 (VitD3), has been widely used as a drug for the secondary hyperparathyroidism. Here, we investigated immunomodulating effect of these two VitD3 derivatives on the differentiation of type-1 immunoregulatory cells such as dendritic cells (DC1), cytotoxic T cells (Tc1) and helper T cells (Th1). BALB/c mouse bone marrow-derived DC (BMDC1) induced by culture with Th1 condition (GM-CSF, IL-3, IL-12 and IFN-gamma) expressed higher levels of MHC Class I and Class II molecules and co-stimulatory molecules compared with BMDC0 induced by neutral condition (GM-CSF+IL-3). In addition, BMDC1 showed stronger immunostimulating activity to induce alloantigen (H-2(d))-specific cytotoxic T lymphocytes (CTL) compared with BMDC0. However, if VitD3 derivatives were added into the culture for BMDC1 induction, the expression of functional molecules and type-1 IFNs were greatly inhibited. Moreover, VitD3 derivative-treated BMDC1 lost their immunostimulating activity to induce alloantigen-specific IFN-gamma-producing Tc1. In addition, it was demonstrated that the addition of VitD3 derivatives inhibited the differentiation of IFN-gamma-producing Th1 cells from ovalbumin (OVA)-specific naive Th cells, while it rather augmented the differentiation of IL-4- or IL-10-producing Th2 cells. There was no significant difference in immunomodulating activity between 1,25(OH)(2)D(3) and 22-Oxa-1 alpha,25-D(3). Thus, VitD3 derivatives are demonstrated to inhibit the functional differentiation of DC1, Tc1 and Th1 cells, which play a critical role in type-1 cellular immune responses.