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981.
Deji N Kume S Araki S Isshiki K Araki H Chin-Kanasaki M Tanaka Y Nishiyama A Koya D Haneda M Kashiwagi A Maegawa H Uzu T 《Biochemical and biophysical research communications》2012,418(3):559-564
Salt-sensitive hypertension is a characteristic of the metabolic syndrome. Given the links to cardiovascular events, the mechanisms underlying sodium metabolism may represent an important therapeutic target for this disorder. Angiotensin II (AII) is a key peptide underlying sodium retention. However, 5'AMP-activated protein kinase (AMPK) has also been reported to participate in the regulation of ion transport. In this study we examined the relationship between AII and AMPK on the development of hypertension in two salt-sensitive mouse models. In the first model, the mice were maintained on a high-fat diet (HFD) for 12 weeks, in order to develop features similar to the metabolic syndrome, including salt-sensitive hypertension. HFD-induced obese mice showed elevated systolic blood pressure and lower sodium excretion in response to salt loading, along with an increase in AII contents and inactivation of AMPK in the kidney, which were significantly improved by the treatment of an angiotensin II antagonist, losartan, for 2 weeks. To clarify the effects of AII, a second group of mice was infused with AII via an osmotic pump, which led to higher systolic blood pressure, and decreases in urinary sodium excretion and the expression of AMPK, in a manner similar to those observed in the HFD mice. However, treatment with an AMPK activator, metformin, improved the changes induced by the AII, suggesting that AII induced sodium retention works by acting on AMPK activity. Finally, we evaluated the changes in salt-sensitivity by performing 2-week salt loading experiments with or without metformin. AII infusion elevated blood pressure by salt loading but metformin prevented it. These findings indicate that AII suppresses AMPK activity in the kidney, leading to sodium retention and enhanced salt-sensitivity, and that AMPK activation may represent a new therapeutic target for obesity-related salt-sensitive hypertension. 相似文献
982.
Matsushita S Inoue Y Adachi T 《Biochemical and biophysical research communications》2012,420(4):710-713
Actin filaments have a double-helix structure consisting of globular actin molecules. In many mechanical cellular activities, such as cell movement, division, and shape control, modulation of the extensional and torsional dynamics of the filament has been linked to regulatory actin-binding protein functions. Therefore, it is important to quantitatively evaluate extension-torsion coupling of filament to better understand the actin filament dynamics. In the present study, the extension-torsion coupling was investigated using molecular dynamics simulations. We constructed a model for the actin filament consisting of 14 actin subunits in an ionic solvent as a minimal functional unit, and analyzed longitudinal and twisting Brownian motions of the filament. We then derived the expected value of energy associated with extension and torsion at equilibrium, and evaluated the extension-torsion stiffness of the filament from the thermal fluctuations obtained from the MD simulations. The results demonstrated that as the analyzed sampling-window duration was increased, the extension-torsion coupling stiffness evaluated on a nanosecond scale tended to converge to a value of 7.6×10(-11) N. The results obtained from this study will contribute to the understanding of biomechanical events, under mechanical tension and torque, involving extension-torsion coupling of filaments. 相似文献
983.
Yoshizaki T Kusunoki C Kondo M Yasuda M Kume S Morino K Sekine O Ugi S Uzu T Nishio Y Kashiwagi A Maegawa H 《Biochemical and biophysical research communications》2012,417(1):352-357
Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood. In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1β was increased. To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy. Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid). Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress. The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance. 相似文献
984.
Kozako T Matsumoto N Kuramoto Y Sakata A Motonagare R Aikawa A Imoto M Toda A Honda S Shimeno H Soeda S 《FEBS letters》2012,586(7):1067-1072
Vasohibin is thought to be an important negative feedback regulator of angiogenesis that is selectively induced in endothelial cells by VEGF. Here, we assessed the role of vasohibin on HIF-1α expression under oxidative stress induced by hydrogen peroxide (H2O2) in HUVEC. VEGF induced significant cell growth that was associated with an increase in vasohibin expression. Following H2O2-pretreatment, VEGF further increased cell growth but this was contrastingly associated with a decrease in vasohibin expression when compared with VEGF alone. Interestingly, vasohibin inhibited cell proliferation through degradation of HIF-1α expression during H2O2-pretreatment. Furthermore, vasohibin elevated the expression of prolyl hydroxylase (PHD). These results suggest that vasohibin plays crucial roles as a negative feedback regulator of angiogenesis through HIF-1α degradation via PHD. 相似文献
985.
Nakayama H Fukuda S Inoue H Nishida-Fukuda H Shirakata Y Hashimoto K Higashiyama S 《Molecular biology of the cell》2012,23(10):1964-1975
A disintegrin and metalloproteinase (ADAM) is a family of enzymes involved in ectodomain shedding of various membrane proteins. However, the molecular mechanism underlying substrate recognition by ADAMs remains unknown. In this study, we successfully captured and analyzed cell surface transient assemblies between the transmembrane amphiregulin precursor (proAREG) and ADAM17 during an early shedding phase, which enabled the identification of cell surface annexins as components of their shedding complex. Annexin family members annexin A2 (ANXA2), A8, and A9 interacted with proAREG and ADAM17 on the cell surface. Shedding of proAREG was increased when ANXA2 was knocked down but decreased with ANXA8 and A9 knockdown, because of enhanced and impaired association with ADAM17, respectively. Knockdown of ANXA2 and A8 in primary keratinocytes altered wound-induced cell migration and ultraviolet B-induced phosphorylation of epidermal growth factor receptor (EGFR), suggesting that annexins play an essential role in the ADAM-mediated ectodomain shedding of EGFR ligands. On the basis of these data, we propose that annexins on the cell surface function as "shedding platform" proteins to determine the substrate selectivity of ADAM17, with possible therapeutic potential in ADAM-related diseases. 相似文献
986.
We recently identified a novel feeding-modulating peptide, hemolymph major anionic peptide (HemaP), designated Bommo-HemaP (B-HemaP), from hemolymph of the silkworm Bombyx mori. B-HemaP has a unique biological activity in modulating the regular frequency of feeding motivation, which is accompanied by increased foraging behaviors. To confirm the conservation of the HemaP-regulated feeding mechanism in lepidopteran species, we purified and sequenced two candidate peptides from the hemolymph of larvae of the sweet potato hornworm Agrius convolvuli. Unlike B. mori, A. convolvuli had two forms of HemaP, which were designated Agrco-HemaP-1 (A-HemaP-1) and Agrco-HemaP-2 (A-HemaP-2). The amino acid sequence of A-HemaP-2 was identical with that of A-HemaP-1, except for O-glycosylation on the fifth amino acid, threonine, within the N-terminal region. The amino acid sequence of A-HemaP-1/A-HemaP-2 had only 32% identity with B-HemaP. Structural analysis revealed that the carbohydrate moiety of A-HemaP-2 was an α-GalNAc residue. Injection of A-HemaP-1, A-HemaP-2 and recombinant A-HemaP-1 (rA-HemaP-1) individually caused a significant increase in foraging behaviors in A.?convolvuli larvae, and no significant differences were observed among these three A-HemaPs. The CD spectra of these three A-HemaPs were quite similar, and all had α-helix-rich secondary structures. Although A-HemaP-1 and B-HemaP did not exhibit cross-reactivity at any injection doses examined, HemaP might be a conserved molecule among lepidopteran species that can modulate feeding motivation through the fluctuation of peptide levels in hemolymph. 相似文献
987.
Toda N Tago K Marumoto S Takami K Ori M Yamada N Koyama K Naruto S Abe K Yamazaki R Hara T Aoyagi A Abe Y Kaneko T Kogen H 《Bioorganic & medicinal chemistry》2003,11(20):4389-4415
Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM). 相似文献
988.
989.
Treatment with estrogen increases the risk of breast, ovary, and endometrial cancers in women. DNA damage induced by estrogen is thought to be involved in estrogen carcinogenesis. In fact, Y-family human DNA polymerases (pol) eta and kappa, which are highly expressed in the reproductive organs, miscode model estrogen-derived DNA adducts during DNA synthesis. Since the estrogen-DNA adducts are a mixture of 6alpha- and 6beta-diastereoisomers of dG-N(2)-6-estrogen or dA-N(6)-6-estrogen, the stereochemistry of each isomeric adduct on translesion synthesis catalyzed by DNA pols has not been investigated. We have recently established a phosphoramidite chemical procedure to insert 6alpha- or 6beta-isomeric N(2)-(estradiol-6-yl)-2'-deoxyguanosine (dG-N(2)-6-E(2)) into oligodeoxynucleotides. Using such site-specific modified oligomer as a template, the specificity and frequency of miscoding by dG-N(2)-6alpha-E(2) or dG-N(2)-6beta-E(2) were explored using pol eta and a truncated form of pol kappa (pol kappaDeltaC). Translesion synthesis catalyzed by pol eta bypassed both the 6alpha- and 6beta-isomers of dG-N(2)-6-E(2), with a weak blockage at the adduct site, while translesion synthesis catalyzed by pol kappaDeltaC readily bypassed both isomeric adducts. Quantitative analysis of base substitutions and deletions occurring at the adduct site showed that pol kappaDeltaC was more efficient than pol eta by incorporating dCMP opposite both 6alpha- and 6beta-isomeric dG-N(2)-6-E(2) adducts. The miscoding events occurred more frequently with pol eta, but not with pol kappaDeltaC. Pol eta promoted incorporation of dAMP and dTMP at both the 6alpha- and 6beta-isomeric adducts, generating G --> T transversions and G --> A transitions. One- and two-base deletions were also formed. The 6alpha-isomeric adduct promoted slightly lower frequency of dCMP incorporation and higher frequency of dTMP incorporation and one-base deletions, compared with the 6beta-isomeric adduct. These observations were supported by steady-state kinetic studies. Taken together, the miscoding property of the 6alpha-isomeric dG-N(2)-6-E(2) is likely to be similar to that of the 6beta-isomeric adduct. 相似文献
990.
Otomo A Kunita R Suzuki-Utsunomiya K Mizumura H Onoe K Osuga H Hadano S Ikeda JE 《Biochemical and biophysical research communications》2008,370(1):87-92
Loss of function mutations in the ALS2 gene account for a number of juvenile/infantile recessive motor neuron diseases, indicating that its gene product, ALS2/alsin, plays a crucial role in maintenance and survival for a subset of neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 and is implicated in endosome dynamics in cells. However, the role of ALS2 in neurons remains unclear. To elucidate the neuronal ALS2 functions, we investigate cellular phenotypes of ALS2-deficient primary cultured neurons derived from Als2-knockout (KO) mice. Here, we show that ALS2 deficiency results not only in the delay of axon outgrowth in hippocampal neurons, but also in a decreased level of the fluid phase horseradish peroxidase (HRP) uptake, which represents the activity for macropinocytic endocytosis, in cortical neurons. Thus, ALS2 may act as a modulator in neuronal differentiation and/or development through regulation of membrane dynamics. 相似文献