Compensatory role of neuregulin-1 in diabetic cardiomyopathy.

Diabetes mellitus is a prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy patients present with left ventricular (LV) diastolic dysfunction at an early stage, then systolic dysfunction as the disease progresses. The mechanism underlying the development of diabetic cardiomyopathy has not yet been fully understood.

Pathogenic Mechanism of Dry Eye-Induced Chronic Ocular Pain and a Mechanism-Based Therapeutic Approach.

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy.

A Novel Non-Invasive Method for Estimating Elevated Pulmonary Vascular Resistance Based on Echocardiographic Assessment of Pulmonary Artery Wave Reflection.

Background: Several non-invasive methods for pulmonary vascular resistance (PVR) measurement are proposed, but none are sufficiently accurate for use in clinical practice. This study proposes a new echocardiographic method of pulmonary artery wave reflection and investigates its efficacy in managing patients with pulmonary hypertension.

Methods and results: In total, 83 patients with left heart disease, pulmonary arterial hypertension, and chronic thromboembolic pulmonary hypertension (CTEPH), who underwent Doppler echocardiography and right heart catheterization, were included in the study.

Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer.

Background: The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC.

Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer.

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11) cells are not fully understood. To characterize IL-11 cells in vivo, we generate Il11 reporter mice.

[Roles of p38 MAPK signaling in the skeletal muscle formation, regeneration, and pathology].

Sarcopenia and frailty in aging, or cancer cachexia shows an abnormal decrease in skeletal muscle mass and muscle strength. However, the underlying mechanisms are not clear, and the promising drug seeds have not been discovered. The formation of skeletal muscle occurs not only during embryonic development but also in adulthood, and the muscle can be regenerated even if it is damaged by exercise overload or physical injury.

Osmostress enhances activating phosphorylation of Hog1 MAP kinase by mono-phosphorylated Pbs2 MAP2K.

The MAP kinase (MAPK) Hog1 is the central regulator of osmoadaptation in yeast. When cells are exposed to high osmolarity, the functionally redundant Sho1 and Sln1 osmosensors, respectively, activate the Ste11-Pbs2-Hog1 MAPK cascade and the Ssk2/Ssk22-Pbs2-Hog1 MAPK cascade. In a canonical MAPK cascade, a MAPK kinase kinase (MAP3K) activates a MAPK kinase (MAP2K) by phosphorylating two conserved Ser/Thr residues in the activation loop.

Addendum: A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.

The cDNA sequence of human SMART described in this Article was misreported, as described in the accompanying Addendum. This error does not affect the results or any conclusion of the Article.

A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.

Necroptosis is a regulated form of necrosis that depends on receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like (MLKL). While danger-associated molecular pattern (DAMP)s are involved in various pathological conditions and released from dead cells, the underlying mechanisms are not fully understood. Here we develop a fluorescence resonance energy transfer (FRET) biosensor, termed SMART (a sensor for MLKL activation by RIPK3 based on FRET).

Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex.

The medial prefrontal cortex (mPFC) has been considered to participate in many higher cognitive functions, such as memory formation and spatial navigation. These cognitive functions are modulated by cholinergic afferents via muscarinic acetylcholine receptors. Previous pharmacological studies have strongly suggested that the M1 receptor (M1R) is the most important subtype among muscarinic receptors to perform these cognitive functions.

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses.

PKA phosphorylates multiple molecules involved in calcium (Ca2+) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca2+ storage and the magnitude of Ca2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility.

A subset of thalamocortical projections to the retrosplenial cortex possesses two vesicular glutamate transporter isoforms, VGluT1 and VGluT2, in axon terminals and somata.

Vesicular glutamate transporter isoforms, VGluT1-VGluT3, accumulate glutamate into synaptic vesicles and are considered to be important molecules in glutamatergic transmission. Among them, VGluT2 mRNA is expressed predominantly throughout the dorsal thalamus, whereas VGluT1 mRNA is expressed in a few thalamic nuclei. In the thalamic nuclei that project to the retrosplenial cortex (RSC), VGluT1 mRNA is expressed strongly in the anterodorsal thalamic nucleus (AD), is expressed moderately in the anteroventral and laterodorsal thalamic nuclei, and is not expressed in the anteromedial thalamic nucleus.

Inter-organ communication in the regulation of lipid metabolism: focusing on the network between the liver, intestine, and heart.

Recent studies have shown that lipid metabolism is regulated through the orchestration of multiple organs. Gut microbiota influences the metabolism of the liver through the production of fatty acids and phosphatidylcholine as well as the modulation of bile acid profile. Microbiota also affects the cardiovascular system through the production of metabolites from nutrients.

Cardiohemodynamic and electrophysiological effects of anti-influenza drug oseltamivir in vivo and in vitro.

Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.

Disruption of Stard10 gene alters the PPARα-mediated bile acid homeostasis.

STARD10, a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) protein family, is highly expressed in the liver and has been shown to transfer phosphatidylcholine. Therefore it has been assumed that STARD10 may function in the secretion of phospholipids into the bile. To help elucidate the physiological role of STARD10, we produced Stard10 knockout mice (Stard10(-/-)) and studied their phenotype.

Spinal mechanism underlying the antiallodynic effect of gabapentin studied in the mouse spinal nerve ligation model.

We studied the antiallodynic effect of gabapentin (GBP) in the mouse model of neuropathic pain, aiming at clarifying the underlying mechanism. The L5 spinal nerve ligation induced tactile allodynia, an increase of CD11b expression, and an increase in the protein expression level of the voltage-dependent Ca(2+) channel α(2)/δ-1 subunit in the spinal dorsal horn on the injured side. The chronic intrathecal administration of GBP (100 µg/body per day) as well as ω-conotoxin MVIIA, an N-type Ca(2+)-channel blocker, completely suppressed allodynia, but did not attenuate the CD11b expression.

Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects (pages.

Aims: There is no consensus as to what extent the results of thorough QT interval/corrected QT interval (QT/QTc) studies need to be bridged.

Methods: The results of two studies using levofloxacin in Japanese and Caucasian subjects were compared in a post hoc analysis to investigate the similarity of dose–effect responses.

Results: Concentration–response analysis based on the change of QT interval corrected using Fridericia's formula (QTcF) from time-matched placebo was planned and performed in the combined data sets.

Effects of S(+)-efonidipine on the rabbit sinus node action potential and calcium channel subunits Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1.

The effect of S(+)-efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R(-)-efonidipine. S(+)-efonidipine (1 μM), inhibited the expressed Ca(V)1.

In vivo canine model comparison of cardiovascular effects of antidepressants milnacipran and imipramine.

Milnacipran is a specific serotonin and norepinephrine reuptake inhibitor, which has been widely used against major depressive episodes. In this study, cardiovascular effects of milnacipran were assessed in comparison with those of a typical tricyclic antidepressant imipramine using the halothane-anesthetized dogs. Milnacipran (n = 6) or imipramine (n = 6) was intravenously administrated in three escalating doses of 0.

Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex.

In the rodent neocortex, the dopamine D5 receptor (D5R) appears to be the predominant subtype of D1-like receptors that are generally considered to play important roles in cognitive functions subserved by the prefrontal cortex (PFC). In this study, to identify the precise localization of D5R in rat PFC, we used a receptor-specific antibody and observed the immunolabeled structures by light and confocal laser scanning microscopies. D5R immunolabeling was found in nearly all neurons, both excitatory and inhibitory neurons.

Role of glycine residues highly conserved in the S2-S3 linkers of domains I and II of voltage-gated calcium channel alpha(1) subunits.

The pore-forming component of voltage-gated calcium channels, alpha(1) subunit, contains four structurally conserved domains (I-IV), each of which contains six transmembrane segments (S1-S6). We have shown previously that a Gly residue in the S2-S3 linker of domain III is completely conserved from yeasts to humans and important for channel activity. The Gly residues in the S2-S3 linkers of domains I and II, which correspond positionally to the Gly in the S2-S3 linker of domain III, are also highly conserved.

T-type Ca2+ channels promote oxygenation-induced closure of the rat ductus arteriosus not only by vasoconstriction but also by neointima formation.

The ductus arteriosus (DA), an essential vascular shunt for fetal circulation, begins to close immediately after birth. Although Ca(2+) influx through several membrane Ca(2+) channels is known to regulate vasoconstriction of the DA, the role of the T-type voltage-dependent Ca(2+) channel (VDCC) in DA closure remains unclear. Here we found that the expression of alpha1G, a T-type isoform that is known to exhibit a tissue-restricted expression pattern in the rat neonatal DA, was significantly up-regulated in oxygenated rat DA tissues and smooth muscle cells (SMCs).

Dihydropyridine- and voltage-sensitive Ca2+ entry in human parathyroid cells.

Patch-clamp and fluorescence measurements of cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) were performed to directly detect extracellular Ca(2+) entry into cultured parathyroid cells from patients with secondary hyperparathyroidism. Cells loaded with fluo-3 AM or fluo-4 AM showed a transient increase in fluorescence (Ca(2+) transient) following 10 s exposure to 150 mm K(+) solution in the presence of millimolar concentrations of external Ca(2+). The Ca(2+) transient was completely inactivated after 30-40 s exposure to the high-K(+) solution, was reduced by dihydropyridine antagonists and was enhanced by FPL-64176, an L-type Ca(2+) channel agonist.