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The long-term effect of changes in maternal dietary composition during pregnancy on the offspring's metabolic homeostasis is uncertain. We aimed to investigate the long-term effects of maternal balanced low-fat interventions on metabolic homeostasis of the offspring using a mouse model of gestational obesity induced by a high-fat diet (HFD). Male newborns in the balanced low-fat intervention group had significantly lower serum insulin and higher serum adiponectin levels than those in the HFD group. Changes in maternal dietary composition improved glucose tolerance in pups at 3 and 12 weeks of age. We also performed transcriptomic analysis of the liver in neonatal and 3-week-old pups. Genes in the peroxisome proliferator-activated receptor signaling pathway were significantly down-regulated in neonates in the balanced low-fat intervention group compared with the HFD group. A maternal balanced low-fat diet fully compensated for the detrimental effects of a maternal HFD on glucose metabolism, insulin tolerance, circulating insulin, dyslipidemia, and body weight gain in male offspring by changing the gene expression profile. These data suggest that maternal balanced low-fat intervention is critical for improving the metabolic health of future generations., (Copyright © 2022. Published by Elsevier Inc.)

The incidence of colon cancer increased worldwide in 2019 and its treatment is urgent from a quality of life perspective. A relationship has been reported between elevated numbers of tumor-associated macrophages (TAMs) in the tumor microenvironment and a poor prognosis in cancer patients, and M2 TAMs have been shown to promote tumor growth by immunosuppression through the stimulation of programmed death-1 (PD-1, an immune check point receptor), interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1. We herein examined the effects of three synthetic dihydroxystilbenes (2,3-, 3,4-, and 4,4'-dihydroxystilbenes) on colon carcinogenesis, colon tumor growth, and colon cytokines (IL-1β, IL-6, and tumor necrosis factor (TNF)-α), a chemokine (MCP-1), vascular endothelial growth factor (VEGF), and PD-1 levels in azoxymethane (AOM) plus dextran sulfate sodium (DSS)-treated C57BL/6J mice. The three dihydroxystilbenes inhibited colon carcinogenesis and tumor growth as well as increases in colon IL-1β, IL-6, MCP-1, and PD-1 levels in AOM/DDS-treated mice (in vivo). The three dihydroxystilbenes also suppressed COX-2 expression in colon tumors (in vivo). The results obtained also revealed that the three dihydroxystilbenes inhibited PD-1 elevations in M2-THP-1 macrophages (in vitro). Therefore, the inhibition of AOM/DSS-induced colon carcinogenesis and colon tumor growth by 2,3-, 3,4-, and 4,4'-dihydroxystilbenes appears to be due to the suppression of M2 TAM differentiation and activation and PD-1 expression (immunosuppression) via reductions in COX-2 expression levels in the colon tumor microenvironment., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Estrogen deficiency caused by bilateral ovariectomy (OVX) has been reported to lead to morphological changes in otoconia. Thus, we examined the morphological changes in the otoconial layer after OVX. We also investigated whether micro-computed tomography (µCT) is useful for the detection of morphological changes in the otoconial layer., Methods: The otic capsules of C57BL/6 J mice were removed and evaluated using histological techniques and µCT at 2, 4, and 8 weeks after OVX or sham surgery. The volume of the utricle otoconial layer was measured and compared between the OVX and sham groups. The µCT scan and histological study results were also compared., Results: The volume of the utricle otoconial layer was significantly increased 4 weeks after OVX compared to the sham group in both histological and µCT studies (p < 0.05). The volume of the otoconial layer measured using µCT was significantly correlated with the histological study results (p < 0.05)., Conclusion: The volume of the utricle otoconial layer increased after OVX. These morphological changes could be detected by µCT., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier B.V.)

Chèdiak-Higashi syndrome is a rare autosomal recessive disease that causes hypopigmentation, recurrent infections, mild coagulation defects and neurological problems. Beige mice carry a mutation in the lysosome trafficking regulator (LYST) gene and display some of the key characteristics of human Chèdiak-Higashi syndrome, in particular, a high susceptibility to infection due to aberrant natural killer (NK) cell and polymorphonuclear leucocyte function. Morphological analysis of beige mice reveals the presence of enlarged lysosomes in a variety of cell types, including leucocytes, hepatocytes, fibroblasts and renal tubule cells. To examine the process of granule maturation and degranulation in beige mice mast cells, morphological studies have been conducted using a combination of electrophysiological techniques; however, few functional studies have been conducted with mast cells, such as mediator release. The aim of the present study was to determine the morphological and functional characteristics of skin and peritoneal mast cells and bone marrow-derived mast cells of homozygous (bg/bg) and heterozygous (bg/+) beige mice and wild-type (+/+) mice. The histamine concentration was lower in the peritoneal and bone marrow-derived mast cells of bg/bg mice compared with those of bg/+ and +/+ mice, but the histamine release response was potentiated. In vivo studies of passive cutaneous anaphylaxis showed no differences between bg/bg mice and either bg/+ or +/+ mice. Although bg/bg mast cells with enlarged granules display specific exocytotic processes in vitro, the consequences of mast cell activation in beige mice were similar to those of wild-type mice in vivo., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the efficacy and safety of YM-58483, a small molecular antagonist of Ca 2+ release-activated Ca 2+ (CRAC) channels, for the treatment of rheumatoid arthritis (RA), in vivo and ex vivo. YM-58483 was continuously injected subcutaneously in a collagen-induced arthritis (CIA) mouS.E.M.odel using an implanted osmotic pump. The severity of CIA was evaluated using the following parameters: body weight, hind paw volume, clinical score, histological analysis, cytokine levels, Ca 2+ influx, and specific IgG production. The efficacy of long-term application of YM-58483 was also verified ex vivo in RA patient-derived peripheral blood monocytes. Assessment of the clinical severity of CIA, cytokine profile in serum and joint protein extracts, and specific IgG production showed that continuous application of YM-58483 suppressed synovial inflammation by inhibiting immune cell activity. Chemical screening and hepatography indicated that long-term subcutaneous delivery of YM-58483 was safer than oral administration for systemic application. Moreover, constant preincubation with YM-58483 at an IC 50 of 0.1-1 nM altered proinflammatory cytokine production ex vivo in peripheral T cells derived from RA patients. Our findings suggest that continuous long-term application of appropriate CRAC inhibitors such as YM-58483 is a potential therapeutic strategy for global immunosuppression in RA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which block the mevalonate pathway. The activity of statins not only decreases cholesterol levels but also ameliorates inflammation and modulates the immune system. In this study, we investigated the effects of simvastatin on histamine release using rat basophilic leukaemia (RBL-2H3) cells, and examined its interaction with proteins involved in the exocytosis process. Treatment with simvastatin for 24h inhibited histamine release in RBL-2H3 cells in a concentration-dependent manner after stimulation with dinitrophenylated bovine serum albumin (DNP-BSA, as an antigen), ionomycin (a calcium ion [Ca 2+ ] ionophore), and thapsigargin (an inhibitor of Ca 2+ -ATPase in the endoplasmic reticulum). Simvastatin-induced inhibition was counteracted by co-administration of mevalonolactone or geranylgeraniol, but not farnesol. Indeed, several exocytotic proteins were post-translationally modified by isoprenylation, which is required for proper localization in the lipid membrane. RBL-2H3 cells express proteins involved in the fusion of granules and the plasma membrane, such as Ras-like protein in the brain 27a (Rab27a), synaptosome-associated protein 23 (SNAP23), and vesicle-associated membrane protein 7 (VAMP7), as well as Ca 2+ binding proteins, such as double C2 alpha (Doc2a), synaptotagmin2, and mammalian uncoordinated13-4 (munc13-4). The interaction of Rab27a and Doc2a proteins was detected using proximity ligation assays. Antigen stimulation caused these proteins to interact, and this interaction could be disrupted by co-administration of simvastatin. In conclusion, simvastatin inhibited the mevalonate pathway, which suppressed the geranylgeranylation of Rab27a by depleting geranylgeranyl pyrophosphate and interfering with the Rab27a-Doc2a interaction. This activity resulted in the inhibition of exocytosis in RBL-2H3 cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epilepsy is associated with several psychiatric disorders, including cognitive impairment, autism and attention deficit/hyperactivity disorder (ADHD). However, the psychopathology of epilepsy is frequently unrecognized and untreated in patients. In the present study, we investigated the effects of ABT-418, a neuronal nicotinic acetylcholine receptor agonist, on pentylenetetrazol (PTZ)-kindled mice with behavioral and motor abnormalities. PTZ-kindled mice displayed impaired motor coordination (in the rotarod test), anxiety (in the elevated plus maze test) and social approach impairment (in the three-chamber social test) compared with control mice. ABT-418 treatment (0.05 mg/kg, intraperitoneally) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 nicotinic acetylcholine receptor subunit in the medial habenula was similar in control and PTZ-kindled mice. However, expression was significantly decreased in the piriform cortex in PTZ-kindled mice. In addition, we examined the expression of the synaptic adhesion molecule neuroligin 3 (NLG3). NLG3 expression in the piriform cortex was significantly higher in PTZ-kindled mice compared with control mice. Collectively, our findings suggest that ADHD-like or autistic-like behavioral abnormalities associated with epilepsy are closely related to the downregulation of the α4 nicotinic receptor and the upregulation of NLG3 in the piriform cortex. In summary, this study indicates that ABT-418 might have therapeutic potential for attentional impairment in epileptic patients with psychiatric disorders such as autism and ADHD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

HB-EGF Shedding inhibitors have been expected to become effective medicines for skin diseases caused by the proliferation of keratinocytes. In order to discover novel HB-EGF shedding inhibitors and clarify their structure-activity relationships, 5,6,7,8-tetrahydronaphthylidine-based hydroxamic acid and 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids have been synthesized. Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A. The structural modification of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids enabled us to establish the following structure-activity relationships; the existence of the hydroxamic acid, the sulfonamide, and the phenyl moieties are crucial for a potent HB-EGF shedding inhibitory activity, and the stereochemistry of the alpha carbon of hydroxamic acid is also important. In addition, from the comparison of their HB-EGF shedding inhibitory activities with their MMPs inhibitory activities, we found that the S1' pocket of the responsible enzyme for HB-EGF shedding is deep unlike that of MMP-1.

As a part of study of selectin blockers, we have already reported that a non-sugar selectin antagonist (3) was successfully discovered using a computational screening (Hiramatsu, Y.; Tsukida, T.; Nakai, Y.; Inoue, Y.; Kondo, H. J. Med. Chem. 2000, 43, 1476). To investigate the SARs of compound 3 against E-, P-, and L-selectins, we synthesized the derivatives of compound 3 and evaluated their inhibitory activities toward selectin bindings. The structural diversity of compound 3 contained the following: (1) a modification of the spacer unit (4--7), (2) a modification of the tail unit (8--11), (3) a modification of the head unit (12--18). As a result, it was found that a non-sugar based selectin blocker (3) could be a potential lead compound for E-, P-, and L-selectin blockers and some of the derivatives showed broad and/or selective inhibitory activities toward the E-, P-, and L-selectins. In addition, it was found that the experimental evidence well supported that the computational screening using 3D-pharmacophore model could be useful methodology to find out a new lead for the several type of selectin blockers, which included a broad and/or a selective inhibitor.

We have developed an effective synthesis of sLe(x) pentasaccharide glycolipid analogue 2. As a part of application of sLe(x) pentasaccharide glycolipid 2 synthesized here, we have investigated the construction of a high-through-put screening system for discovery of selectin blockers. As a result, it was found that compound 2 was a useful ligand for in vitro ELISA assay and could be an important material for high-throughput screening of selectin blockers.

A practical synthesis of the sialyl Lewis X (sLex) pentasaccharide, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta OEt (1), as a potential blocker for E-selectin has been described. The glycosylation of a trisaccharide acceptor, Fuc alpha (1-3)GlcNAc beta (1-3)Gal beta OEt, with a disaccharide donor, NeuAc alpha (2-3)Gal beta SMe, did not yield the desired sLex pentasaccharide 1 at all. However, the glycosylation of a disaccharide acceptor, GlcNAc beta (1-3)Gal beta OEt, with a disaccharide donor, NeuAc alpha (2-3)Gal beta SMe, quantitatively yielded the tetrasaccharide NeuAc alpha (2-3)Gal beta (1-4)GlcNAc beta (1-3)Gal beta OEt. This tetrasaccharide is readily converted to the title compound in a high yield by fucosylation, followed by deprotection. The inhibitory activities of compound 1 toward the binding of the natural ligand (sLex) with the E-, P-, and L-selectins were stronger than those of the sLex tetrasaccharide.