A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

How Can Apartment-Complex Landscaping Space Improve Residents' Psychological Well-Being?: The Case of the Capital Region in South Korea.

Urban green spaces have a positive impact on citizens' mental health and have contributed to improving their quality of life during the COVID-19 pandemic. In South Korea, where more than 50% of all households live in apartments, apartment-complex landscaping space plays the role of urban green space. This study aimed to investigate the relationships among a perceived restorative environment, restorative experience, life satisfaction, and psychological well-being by conducting a survey between residents living in apartments with landscape space. More specifically, an online survey was conducted from 8 to 15 June 2021 among residents in apartment complexes (500 households or more) located in the capital region in South Korea. We applied partial least squares structural equation modelling (PLS-SEM) using 220 samples to test the causal relationship presented in the conceptual model of this study. The results revealed that residents' perceptions of the restorative environment of landscape space, including fascination, being away, and coherence had positive effects on restorative attention. Among the restorative environmental factors, the higher the "being away", the greater the effect on restorative attention. Second, the effects of fascination and coherence on life satisfaction were mediated by restorative attention. Third, restorative attention and life satisfaction significantly influenced psychological well-being. Additionally, life satisfaction acts as a mediator in the relationship between restorative attention and psychological well-being. In summary, this study has theoretical implications, in that it explores the effects of apartment complex landscaping space as urban green spaces on residents' mental health.

Planning a Green Infrastructure Network to Integrate Potential Evacuation Routes and the Urban Green Space in a Coastal City: The Case Study of Haeundae District, Busan, South Korea.

Coastal cities face increasing natural disaster risks. Developing a green infrastructure network can reduce coastal vulnerability by connecting green spaces. Only a few researchers have examined practical guidelines for a green infrastructure network in coastal cities. Therefore, the purpose of this study is to build a green infrastructure network by integrating potential evacuation routes and green spaces in a coastal city. The Haeundae District in South Korea was chosen as the study site. We constructed a green infrastructure network using space syntax and GIS network analysis. The results of this study showed that first, we created an integrated green infrastructure network by building evacuation route networks and urban ecological networks. Second, we evaluated the evacuation function and flood risk. Finally, we proposed green infrastructure network planning for coastal disasters, including hub and corridor design. This study can contribute to establishing strategies to reduce vulnerability in coastal cities.

Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT(2A), 5-HT(2C) receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 33 and 34 were identified as lead compounds. Consequently, this pyrrole series of compounds appears to be promising enough to warrant further investigation.

Isolation and characterization of a Glutamate decarboxylase (GAD) gene and their differential expression in response to abiotic stresses from Panax ginseng C. A. Meyer.

Glutamate decarboxylase (GAD) catalyzes the conversion of L-glutamate to γ-aminobutyric acid (GABA). A full-length cDNA encoding GAD (designated as PgGAD) was isolated and characterized from the root of Panax ginseng C. A. Meyer. The length cDNA of PgGAD was 1881 bp and contained a 1491 bp open reading frame (ORF) encoding a glutamate decarboxylase protein of 496 amino acids, possessing a Ser-X-X-Lys active site, which belongs to the GAD group. The deduced amino acid sequence of the PgGAD was classified in the plant GAD family and has 76-85% high similarity with other plants as like petunia, Arabidopsis, tomato. Secondary structure of PgGAD was predicted by using SOPMA software program. Southern blot analysis of genomic DNA suggests that, there is more than one copy of the PgGAD gene. The organ specific gene expression pattern also studied in P. ginseng seedlings, in which the stem showed elevated expression than root, leaf, bud and rhizomes. Along with this, we also confirmed the gene expression of PgGAD under various abiotic stresses like temperature stress, osmotic stress, anoxia, oxidative stress, and mechanical damage. Temporal analysis of gene expression except exposure of oxidative stress revealed an enhanced expression after each stresses. The enzyme activity of PgGAD was stimulated to 2-fold under cold stress.

Screening of Kit inhibitors: suppression of Kit signaling and melanogenesis by emodin.

In search of novel antipigmentation agents, a set of 3,840 compounds with natural-like synthetic or natural origin were screened against Kit (stem cell factor receptor). Emodin from the seed of Cassia tora and baicalin from Scutellariae radix showed potent inhibitory effects (IC(50) = 4.9 and 9.0 microM, respectively) on the phosphorylation of Kit. Emodin also blocked other receptor tyrosine kinase activities, such as epithelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR-2), fibroblast growth factor receptor 1 (FGFR-1), platelet-derived growth factor receptor b (PDGFR-b). In contrast to emodin, aloe-emodin did not inhibit Kit activity at all. Emodin also blocked the cellular kinase activities of Kit and its down-stream p44/42 mitogen activated protein kinase (MAPK) in MO7e cells and human primary melanocytes. Emodin strongly suppressed the melanin synthesis triggered by stem cell factor (SCF) treatment. Also, emodin showed almost no toxicity up to 10 microM on cultured melanocytes as reported previously by other researchers. The results indicate that emodin is a good candidate for the development of antipigmentation agents since it can radically block the differentiation and proliferation of pigment cells by reducing Kit signaling.

A novel sphingosylphosphorylcholine and sphingosine-1-phosphate receptor 1 antagonist, KRO-105714, for alleviating atopic dermatitis.

BACKGROUND: Atopic dermatitis (eczema) is a type of inflammation of the skin, which presents with itchy, red, swollen, and cracked skin. The high global incidence of atopic dermatitis makes it one of the major skin diseases threatening public health. Sphingosylphosphorylcholine (SPC) and sphingosine-1-phosphate (S1P) act as pro-inflammatory mediators, as an angiogenesis factor and a mitogen in skin fibroblasts, respectively, both of which are important biological responses to atopic dermatitis. The SPC level is known to be elevated in atopic dermatitis, resulting from abnormal expression of sphingomyelin (SM) deacylase, accompanied by a deficiency in ceramide. Also, S1P and its receptor, sphingosine-1-phosphate receptor 1 (S1P1) are important targets in treating atopic dermatitis. RESULTS: In this study, we found a novel antagonist of SPC and S1P1, KRO-105714, by screening 10,000 compounds. To screen the compounds, we used an SPC-induced cell proliferation assay based on a high-throughput screening (HTS) system and a human S1P1 protein-based [35S]-GTPγS binding assay. In addition, we confirmed the inhibitory effects of KRO-105714 on atopic dermatitis through related cell-based assays, including a tube formation assay, a cell migration assay, and an ELISA assay on inflammatory cytokines. Finally, we confirmed that KRO-105714 alleviates atopic dermatitis symptoms in a series of mouse models. CONCLUSIONS: Taken together, our data suggest that SPC and S1P1 antagonist KRO-105714 has the potential to alleviate atopic dermatitis.

KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia.

KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (Ki=3.85 nM) for human dopamine D3 receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (Ki=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT1A receptor (Ki=6.4 nM). KKHA-761 exhibited D3 and 5-HT1A receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [35S]GTPrS binding. The in vivo pharmacological profile of KKHA-761 was compared with both typical and atypical antipsychotics including clozapine and haloperidol. Apomorphine-induced dopaminergic behavior, cage climbing, in mice was potently blocked by a single administration (i.p.) of KKHA-761 (ID50=4.06 mg/kg) or clozapine (ID50=4.0 mg/kg). Cocaine- or MK-801-induced hyperactivity in animals was markedly inhibited by KKHA-761 or clozapine. In addition, KKHA-761 significantly reversed the disruption of prepulse inhibition (PPI) produced by apomorphine in mice, indicating the antidopaminergic or antipsychotic activity of KKHA-761 in mice. However, KKHA-761 was inactive in the forced swimming behavioral despair model in mice, suggesting lack of antidepressant properties. KKHA-761 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT, in mice, whereas clozapine enhanced it. Moderate doses of both KKHA-761 and clozapine did not increase serum prolactin levels in rats. Lower doses of, however, haloperidol significantly increased prolactin secretion. KKHA-761 did not induce cataleptic response up to 20 mg/kg, but significant catalepsy was shown at lower doses of clozapine and haloperidol. Furthermore, KKHA-761 showed a low incidence of rotarod ataxia (TD50=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D3 and serotonin 5-HT1A receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.

Inhibition of c-Kit signaling by diosmetin isolated from Chrysanthemum morifolium.

The interaction of stem cell factor (SCF) with its cognate receptor c-Kit is closely associated with the survival and maturation of melanocytes. To investigate novel depigmentation agents, we screened 2,000 plant extracts for c-Kit inhibitors to identify active small molecules by using time-resolved fluorescence enzyme assays. For the active extracts identified as inhibitors of c-Kit enzyme, we evaluated the effects of the active extracts and isolated flavonoids on c-Kit phosphorylation in MO7e/melanocytes. Anti-melanogenic activity was also examined in melanocytes and melanoderm model. The flavonoids such as diosmetin, apigenin, acacetin and luteolin isolated from Chrysanthemum morifolium were found to be active in inhibiting c-Kit both at enzyme and cellular levels. In addition, these flavonoids attenuated SCF-induced proliferation of human primary melanocytes without toxicity and suppressed ultraviolet (UV) B irradiation-mediated melanin synthesis significantly. Among the active flavonoids, diosmetin was found to inhibit SCF-induced melanogenesis in a human melanoderm model. These results strongly suggest that C. morifolium extract and diosmetin have potential to suppress SCF-/UVB-induced melanogenesis, and could be developed as anti-pigmentation agents.

Naphthofuroquinone derivatives: inhibition of receptor tyrosine kinases.

A series of dinaphtho[1,2-b;2',3'-d]furan-7,12-dione derivatives were synthesized and evaluated for inhibitory activities against receptor tyrosine kinases. The naphthofuroquinone compounds with dialkylaminoethoxy group at C(5)-position (7, 8, 10, and 11) manifested strong inhibitory activities against epidermal growth factor receptor and vascular endothelial growth factor receptor. Docking study of 11 with EGFR was also performed.

Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110.

1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.