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111.
Wei‐Guang Wang Zhao‐Yuan Wu Rui Chen Hai‐Zhou Li Hong‐Mei Li Yuan‐Dan Li Rong‐Tao Li Huai‐Rong Luo 《化学与生物多样性》2013,10(6):1061-1071
Four highly acylated diterpenoids, designated as pierisformotoxins A–D ( 1 – 4 , resp.), along with 26 known compounds, were isolated from the flowers of Pieris formosa. Among them, pierisformotoxins A and B ( 1 and 2 , resp.) were new highly acylated grayanane diterpenoids, of which the five‐membered ring A has undergone an oxidative cleavage between C(3) and C(4), followed by lactonization, to give rise to a five‐membered lactone ring between C(3) and C(5), differing from the previously reported grayanane diterpenoids with a 5/7/6/5 ring system. Results of the cAMP‐regulation‐activity assay showed that pierisformotoxin C ( 3 ) at 10 μM (inhibitory ratio (IR): 10.1%) or 2 μM (9.8%), and pierisformotoxin B ( 2 ) at 50 μM (13.9%) significantly decreased the cAMP level in N1E‐115 neuroblastoma cells (p<0.05). 相似文献
112.
Michal Ciolkowski Monika Rozanek Maria BryszewskaBarbara Klajnert 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(10):1982-1987
In this study the ability of three polyamidoamine (PAMAM) dendrimers with different surface charge (positive, neutral and negative) to interact with a negatively charged protein (porcine pepsin) was examined. It was shown that the dendrimer with a positively charged surface (G4 PAMAM-NH2), as well as the dendrimer with a neutral surface (G4 PAMAM-OH), were able to inhibit enzymatic activity of pepsin. It was also found that these dendrimers act as mixed partially non-competitive pepsin inhibitors. The negatively charged dendrimer (G3.5 PAMAM-COOH) was not able to inhibit the enzymatic activity of pepsin, probably due to the electrostatic repulsion between this dendrimer and the protein. No correlation between changes in enzymatic activity of pepsin and alterations in CD spectrum of the protein was observed. It indicates that the interactions between dendrimers and porcine pepsin are complex, multidirectional and not dependent only on disturbances of the secondary structure. 相似文献
113.
Kevin R.W. Ngoei Dominic C.H. Ng Paul R. Gooley David P. Fairlie Martin J. Stoermer Marie A. Bogoyevitch 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(6):1077-1088
Based on bioinformatics interrogation of the genome, > 500 mammalian protein kinases can be clustered within seven different groups. Of these kinases, the mitogen-activated protein kinase (MAPK) family forms part of the CMGC group of serine/threonine kinases that includes extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs), and p38 MAPKs. With the JNKs considered attractive targets in the treatment of pathologies including diabetes and stroke, efforts have been directed to the discovery of new JNK inhibitory molecules that can be further developed as new therapeutics. Capitalizing on our biochemical understanding of JNK, we performed in silico screens of commercially available chemical databases to identify JNK1-interacting compounds and tested their in vitro JNK inhibitory activity. With in vitro and cell culture studies, we showed that the compound, 4′-methyl-N2-3-pyridinyl-4,5′-bi-1,3-thiazole-2,2′-diamine (JNK Docking (JD) compound 123, but not the related compound (4′-methyl-N ~ 2 ~ -(6-methyl-2-pyridinyl)-4,5′-bi-1,3-thiazole-2,2′-diamine (JD124), inhibited JNK1 activity towards a range of substrates. Molecular docking, saturation transfer difference NMR experiments and enzyme kinetic analyses revealed both ATP- and substrate-competitive inhibition of JNK by JD123. In characterizing JD123 further, we noted its ATP-competitive inhibition of the related p38-γ MAPK, but not ERK1, ERK2, or p38-α, p38-β or p38-δ. Further screening of a broad panel of kinases using 10 μM JD123, identified inhibition of kinases including protein kinase Bβ (PKBβ/Aktβ). Appropriately modified thiazole diamines, as typified by JD123, thus provide a new chemical scaffold for development of inhibitors for the JNK and p38-γ MAPKs as well as other kinases that are also potential therapeutic targets such as PKBβ/Aktβ. 相似文献
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115.
Ryunosuke Ohkawa Hann Low Nigora Mukhamedova Ying Fu Shao-Jui Lai Mai Sasaoka Ayuko Hara Azusa Yamazaki Takahiro Kameda Yuna Horiuchi Peter J. Meikle Gerard Pernes Graeme Lancaster Michael Ditiatkovski Paul Nestel Boris Vaisman Denis Sviridov Andrew Murphy Alan T. Remaley Dmitri Sviridov Minoru Tozuka 《Journal of lipid research》2020,61(12):1577
Lipoproteins play a key role in transport of cholesterol to and from tissues. Recent studies have also demonstrated that red blood cells (RBCs), which carry large quantities of free cholesterol in their membrane, play an important role in reverse cholesterol transport. However, the exact role of RBCs in systemic cholesterol metabolism is poorly understood. RBCs were incubated with autologous plasma or isolated lipoproteins resulting in a significant net amount of cholesterol moved from RBCs to HDL, while cholesterol from LDL moved in the opposite direction. Furthermore, the bi-directional cholesterol transport between RBCs and plasma lipoproteins was saturable and temperature-, energy-, and time-dependent, consistent with an active process. We did not find LDLR, ABCG1, or scavenger receptor class B type 1 in RBCs but found a substantial amount of ABCA1 mRNA and protein. However, specific cholesterol efflux from RBCs to isolated apoA-I was negligible, and ABCA1 silencing with siRNA or inhibition with vanadate and Probucol did not inhibit the efflux to apoA-I, HDL, or plasma. Cholesterol efflux from and cholesterol uptake by RBCs from Abca1+/+ and Abca1−/− mice were similar, arguing against the role of ABCA1 in cholesterol flux between RBCs and lipoproteins. Bioinformatics analysis identified ABCA7, ABCG5, lipoprotein lipase, and mitochondrial translocator protein as possible candidates that may mediate the cholesterol flux. Together, these results suggest that RBCs actively participate in cholesterol transport in the blood, but the role of cholesterol transporters in RBCs remains uncertain. 相似文献
116.
Natascha Verhagen Attila Teleki Christoph Heinrich Martin Schilling Andreas Unsöld Ralf Takors 《Biotechnology and bioengineering》2020,117(11):3239-3247
The improvement of cell specific productivities for the formation of therapeutic proteins is an important step towards intensified production processes. Among others, the induction of the desired production phenotype via proper media additives is a feasible solution provided that said compounds adequately trigger metabolic and regulatory programs inside the cells. In this study, S-(5′-adenosyl)- l -methionine (SAM) and 5′-deoxy-5′-(methylthio)adenosine (MTA) were found to stimulate cell specific productivities up to approx. 50% while keeping viable cell densities transiently high and partially arresting the cell cycle in an anti-IL-8-producing CHO-DP12 cell line. Noteworthy, MTA turned out to be the chemical degradation product of the methyl group donor SAM and is consumed by the cells. 相似文献
117.
Hideaki Tagashira Chen Zhang Ying-mei Lu Hideyuki Hasegawa Hiroshi Kanai Feng Han Kohji Fukunaga 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
We previously reported that the σ1-receptor (σ1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how σ1R stimulation with the selective σ1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through σ1R localized in the sarcoplasmic reticulum (SR).Methods
We first confirmed anti-hypertrophic effects of SA4503 (0.1–1 μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0 mg/kg) and the σ1R antagonist NE-100 (1.0 mg/kg) orally to TAC mice for 4 weeks (once daily).Results
σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72 h impaired phenylephrine (PE)-induced Ca2 + mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca2 + mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72 h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function.Conclusions
σ1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca2 + mobilization and ATP production via σ1R stimulation.General significance
Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction. 相似文献118.
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