153 research outputs found
Associations between LDL/HDL-cholesterol ratio and thoracic and abdominal aortic atherosclerosis assessed by MRI
Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor
慢性アレルギー疾患に関わるヒスタミン受容体の構造解明 --新規アトピー性皮膚炎・喘息治療薬の開発に貢献--. 京都大学プレスリリース. 2023-10-23.Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H₄ receptor (H₄R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H₄R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344[7.39], which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H₄R and subtype selectivity of histamine receptors, and show that the H₄R structures may be valuable in rational drug design of drugs targeting the H₄R
Associations between LDL/HDL-cholesterol ratio and thoracic and abdominal aortic atherosclerosis assessed by MRI
The inhibitory effects of a RANKL-binding peptide on articular and periarticular bone loss in a murine model of collagen-induced arthritis: a bone histomorphometric study
Showing the effects of OP3-4 on the proliferation and differentiation of cartilage cell line ATDC5. A Results of proliferation assay on day 1 with the noninduction medium. B Alcian blue-positive area ratio in the cartilage induction medium on day 10. **p <0.01 vs. vehicle control, #p <0.05 vs. 100 ÎźM OP3-4. (JPEG 384 kb
Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex
熱、炎症などに関与するプロスタグランジン受容体EP3シグナリング複合体の可視化 --緑内障、高眼圧症治療薬の合理的設計に貢献--. 京都大学プレスリリース. 2022-09-15.Prostaglandin receptors have been implicated in a wide range of functions, including inflammation, immune response, reproduction, and cancer. Our group has previously determined the crystal structure of the active-like EP3 bound to its endogenous agonist, prostaglandin E₂. Here, we present the single-particle cryoelectron microscopy (cryo-EM) structure of the human EP3-Gi signaling complex at a resolution of 3.4 Å. The structure reveals the binding mode of Gi to EP3 and the structural changes induced in EP3 by Gi binding. In addition, we compare the structure of the EP3-Gi complex with other subtypes of prostaglandin receptors (EP2 and EP4) bound to Gs that have been previously reported and examine the differences in amino acid composition at the receptor-G protein interface. Mutational analysis reveals that the selectivity of the G protein depends on specific amino acid residues in the second intracellular loop and TM5
ノウコウソク ノ チリョウ セイセキ ワ ナゼ コウジョウ シナイ ノカ : 10ネンカン ノ ヤマガタケン ノウソッチュウ トウロク データ カラ ノ ヨゴ フリョウ インシ ノ ケントウ
We studied ten years of stroke data registered with the Yamagata Society on Treatment for Cerebral Stroke(YSTCS). The subjects included 16,407 cases of acute-phase cerebral infarction that were registered with the YSTCS during the ten years between 2002 and 2011. The cases were divided into two groups: the early phase group(2002-2006)and the late phase group(2007-2011). The clinical diagnoses included atherothrombotic cerebral infarction(AT)(n=7,196; 43.9%), cardiogenic cerebral embolism(CE)(n=4,011; 24.4%), and lacunar infarction(LI)(n=4,703; 28.7%). The average age of the early phase group was 72.7±11.43 years, while that of the late phase group was 75.0±11.35 years; the difference was statistically significant. The proportion of CE cases increased in the late phase, while that of LI decreased. This phenomenon was more marked in cases involving patients of ≥80 years of age. In both the early and late phase groups, the AT and CE cases showed a significantly high proportion of poor outcomes. However, when age adjustment was implemented in the late phase group, the treatment outcomes improved across all clinical entities. A multiple logistic regression analysis revealed a significant association between old age, female sex, severe symptoms at onset, CE, a previous history of stroke, and a poor prognosis. It is clear that developments in medicine have not kept pace with the advancement in the age at onset. The improvement of the outcomes of treatment for cerebral infarction requires further developments in acute-phase therapies and the primary prevention of cardiogenic cerebral embolism, many cases of which are severe
Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation
BACKGROUND: Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. METHODS AND FINDINGS: Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE(2) stimulation increased EP4 protein expression (1.4 ± 0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4 ± 0.03- and 1.7 ± 0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE(-/-) mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4(+/-)/ApoE(-/-) mice exhibited significantly less AAA formation than EP4(+/+)/ApoE(-/-) mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl(2) application was also reduced in EP4(+/-) mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6 ± 0.06- and 0.7 ± 0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. CONCLUSION: An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA
Heterophilic binding of the adhesion molecules poliovirus receptor and immunoglobulin superfamily 4A in the interaction between mouse spermatogenic and sertoli cells
金沢大学医薬保健研究域医学系The cell adhesion protein immunoglobulin superfamily 4A (IGSF4A) is expressed on the surfaces of spermatogenic cells in the mouse testis. During spermatogenesis, IGSF4A is considered to bind to the surface of Sertoli cells in a heterophilic manner. To identify this unknown partner of IGSF4A, we generated rat monoclonal antibodies against the membrane proteins of mouse Sertoli cells grown in primary culture. Using these monoclonal antibodies, we isolated a clone that immunostained Sertoli cells and reacted with the product of immunoprecipitation of the homogenate of mouse testis with anti-IGSF4A antibody. Subsequently, to identify the Sertoli cell membrane protein that is recognized by this monoclonal antibody, we performed expression cloning of a cDNA library from the mouse testis. As a result, we identified poliovirus receptor (PVR), which is another IGSF-type cell adhesion molecule, as the binding partner of IGSF4A. The antibodies raised against PVR and IGSF4A immunoprecipitated both antigens in the homogenate of mouse testis. Immunoreactivity for PVR was present in Sertoli cells but not in spermatogenic cells at all stages of spermatogenesis. Overexpression of PVR in TM4, a mouse Sertoli cell line, increased more than three-fold its capacity to adhere to Tera-2, which is a human cell line that expresses IGSF4A. These findings suggest that the heterophilic binding of PVR to IGSF4A is responsible, at least in part, for the interaction between Sertoli and spermatogenic cells during mouse spermatogenesis. © 2007 by the Society for the Study of Reproduction, Inc.Embargo Period 12 month
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