BACKGROUND: Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in atherothrombotic diseases. Activation of LOX-1 in humans can be evaluated by use of the LOX index, obtained by multiplying the circulating concentration of LOX-1 ligands containing apolipoprotein B (LAB) times that of the soluble form of LOX-1 (sLOX-1) [LOX index ϭ LAB ϫ sLOX-1]. This study aimed to establish the prognostic value of the LOX index for coronary heart disease (CHD) and stroke in a community-based cohort.

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and atherogenesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other atherogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardiovascular diseases. Further understandings of LOX-1 and its ligands as well as its versatile functions will direct us to ways to find novel diagnostic and therapeutic approaches to cardiovascular disease.

Artificial intelligence (AI) is expected to support clinical judgement in medicine. We constructed a new predictive model for diabetic kidney diseases (DKD) using AI, processing natural language and longitudinal data with big data machine learning, based on the electronic medical records (EMR) of 64,059 diabetes patients. AI extracted raw features from the previous 6 months as the reference period and selected 24 factors to find time series patterns relating to 6-month DKD aggravation, using a convolutional autoencoder. AI constructed the predictive model with 3,073 features, including time series data using logistic regression analysis. AI could predict DKD aggravation with 71% accuracy. Furthermore, the group with DKD aggravation had a significantly higher incidence of hemodialysis than the non-aggravation group, over 10 years (N = 2,900). The new predictive model by AI could detect progression of DKD and may contribute to more effective and accurate intervention to reduce hemodialysis.

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with ␣-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.autoreceptor ͉ heteroreceptor ͉ appetite regulation O besity has recently become a matter of great concern, because it is considered one of the highest risk factors for diabetes mellitus, hyperlipidemia, and arteriosclerosis. To maintain body weight, caloric intake and energy expenditure must be balanced, and excessive caloric intake is a leading cause of obesity (1). There is growing evidence that the brain receives and integrates information related to energy status from peripheral tissues and that appetite is under the control of numerous neurotransmitters and hormones, such as neuropeptide Y, melanocortin, leptin, and ghrelin (2, 3)Histamine is a classical inflammatory mediator in peripheral tissues and also functions as a neurotransmitter in the brain. Histamine plays a pivotal role in various physiological functions, such as feeding behavior and energy homeostasis (4). Intracerebroventricular administration of histamine consistently decreases appetite in several species (4). Mice with genes disrupted for histamine H1 receptor or histidine decarboxylase (HDC), a ratelimiting enzyme for histamine synthesis, are prone to becoming obese on a high-fat diet or at advanced age (5-8). Furthermore, several antipsychotic drugs with high affinities for H1 receptors are known to cause weight gain in rodents and humans (9). These results suggest a significant role for histamine and H1 receptors in feeding behavior and body-weight regulation.Histamine H3 receptors (H3Rs) were pharmacologically identified more than a decade ago and recently cloned (10, 11). They are predominantly ex...

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1 E ects of adrenomedullin and a-calcitonin gene-related peptide (CGRP) on the contractions and cytosolic Ca 2+ concentrations ([Ca 2+ ] i ) of the rat aorta and porcine coronary artery were investigated. Characteristics of the receptors mediating the e ects of adrenomedullin and a-CGRP were also investigated. 2 Adrenomedullin and a-CGRP caused a concentration-dependent relaxation in the rat aorta contracted with noradrenaline. The IC 50 values for adrenomedullin and a-CGRP were 2.4 nM and 4.0 nM, respectively. The relaxant e ects of these peptides were abolished by removal of the endothelium and signi®cantly attenuated by an inhibitor of nitric oxide synthase, N G -monomethyl-L-arginine (L-NMMA, 100 mM), but not by a cyclo-oxygenase inhibitor, indomethacin (10 mM). 3 Adrenomedullin and a-CGRP increased the endothelial [Ca 2+ ] i in the rat aorta with endothelium, whereas they did not change [Ca 2+ ] i in the smooth muscle. 4 An antagonist of the CGRP 1 receptor, CGRP (8 ± 37), antagonized the relaxant e ects of a-CGRP and the b-isoform of CGRP (b-CGRP) but not those of adrenomedullin in the rat aorta. 5 In the porcine coronary artery contracted with U46619, adrenomedullin and a-CGRP caused a concentration-dependent relaxation with an IC 50 of 27.6 and 4.1 nM, respectively. Removal of the endothelium altered neither the IC 50 values nor the maximal relaxations induced by adrenomedullin or a-CGRP. When the artery was contracted with high K + solution (72.7 mM), these peptides caused a small relaxation. 6 Adrenomedullin and a-CGRP increased cyclic AMP content and decreased the smooth muscle [Ca 2+ ] i in the porcine coronary artery. 7 CGRP (8 ± 37) signi®cantly antagonized the relaxant e ects of adrenomedullin and a-CGRP in the porcine coronary artery. However, it had little e ect on the relaxations induced by the b-isoform of CGRP (b-CGRP). 8 These results suggest that in the rat aorta, adrenomedullin and a-CGRP increase the endothelial [Ca 2+ ] i , activate nitric oxide synthase and release nitric oxide, without a direct inhibitory action on smooth muscle. In the porcine coronary artery, in contrast, adrenomedullin and a-CGRP directly act on smooth muscle, increase cyclic AMP content, decrease the smooth muscle [Ca 2+ ] i and inhibit contraction. The rat aortic endothelium seems to express the CGRP receptor which is sensitive to a-CGRP, b-CGRP and CGRP (8 ± 37) and the adrenomedullin speci®c receptor. The porcine coronary smooth muscle, in contrast, seems to express two types of CGRP receptor; one of which is sensitive to a-CGRP, CGRP (8 ± 37) and adrenomedullin and the other is sensitive only to b-CGRP.

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A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H 3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H 3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of 1 between human and rodent P-gps, the observed rodent brain permeability of 1 is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.