The effect of prostaglandins A2,E1,E2,15 methyl E2, 16, 16 dimethyl E2 and F2α on erythropoiesis

Prostaglandins A₂, E₁, E₂, methylated E₂s and F₂α affected erythropoiesis and/or erythropoietin (Ep) production. This action is indicated in the exhypoxic, polycythemic mouse where radioiron incorporations into RBC increased after administration of these compounds. The kidney and liver have been indicated through previous studies, to actively participate in Ep production. By the removal of one of these active sites in a murine system treated with prostaglandins it is shown that a response is reflected in Ep levels. Interference of the action of prostaglandins (PG) is altered by the removal of one of these target sites of Ep production. The erythropoietic responses elicited by PGA₂, E₁, and perhaps the methylated PGE₂s act through the liver whereas PGE₂ may operate through a renal pathway for its response. PGF_2α reveals no effect on erythropoietic activity and is no different than that observed for vehicle-treated controls. The prostaglandins tested appear to act primarily through the kidney or liver but the possibility exists that some yet undetermined organ site may also be involved.     

The solution structure of the human retinoic acid receptor-β DNA-binding domain

Summary The three-dimensional structure of the DNA-binding domain of the human retinoic acid receptor- (hRAR-) has been determined by nuclear magnetic resonance spectroscopy in conjunction with distance geometry, restrained molecular dynamics and iterative relaxation matrix calculations. A total of 1244 distance restraints were obtained from NOE intensities, of which 448 were intra-residue and 796 inter-residue restraints. In addition 23 and 30 dihedral angle restraints were obtained from J-coupling data. The two zinc-finger regions of the 80-amino acid residue protein are followed by two -helices that cross each other perpendicularly. There is a short stretch of b-sheet near the N-terminus. The -helical core of the protein is well determined with a backbone root-mean-square deviation (r.m.s.d.) with respect to the average of 0.18 Å and 0.37 Å when the side chains of residues 31, 32, 36, 61, 62, 65 and 69 are included. The r.m.s.d. for the backbone of residues 5–80 is 0.76 Å. For the first finger (residues 8–28), the r.m.s.d. of the backbone is 0.79 Å. For the second finger (residues 44–62) the r.m.s.d. is 0.64 Å. The overall structure is similar to that of the corresponding domain of the glucocorticoid receptor, although the C-terminal part of the protein is different. The second -helix is two residues shorter and is followed by a well-defined region of extended backbone structure.     

Prostaglandin E2 suppresses β1-integrin expression via E-prostanoid receptor in human monocytes/macrophages

β₁-Integrins mediate cell attachment to different extracellular matrix proteins, intracellular proteins, and intercellular adhesions. Recently, it has been reported that prostaglandin E₂ (PGE₂) has anti-inflammatory properties such as inhibition of the expression of adhesion molecules or production of chemokines. However, the effect of PGE₂ on the expression of β₁-integrin remains unknown. In this study, we investigated the effects of PGE₂ on the expression of β₁-integrin in the human monocytic cell line THP-1 and in CD14⁺ monocytes/macrophages in human peripheral blood. For this, we examined the role of four subtypes of PGE₂ receptors and E-prostanoid (EP) receptors on PGE₂-mediated inhibition. We found that PGE₂ significantly inhibited the expression of β₁-integrin, mainly through EP₄ receptors in THP-1 cells and CD14⁺ monocytes/macrophages in human peripheral blood. We suggest that PGE₂ has anti-inflammatory effects, leading to the inhibited expression of β₁-integrin in human monocytes/macrophages, and that the EP₄ receptor may play an important role in PGE₂-mediated inhibition.     

Amyloid-β peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A2

Oligomeric amyloid-β peptide (Aβ) is known to induce cytotoxic effects and to damage cell functions in Alzheimer's disease. However, mechanisms underlying the effects of Aβ on cell membranes have yet to be fully elucidated. In this study, Aβ 1-42 (Aβ₄₂) was shown to cause a temporal biphasic change in membranes of astrocytic DITNC cells using fluorescence microscopy of Laurdan. Aβ₄₂ made astrocyte membranes became more molecularly-disordered within the first 30 min to 1 h, but gradually changed to more molecularly-ordered after 3 h. However, Aβ₄₂ caused artificial membranes of vesicles made of rat whole brain lipid extract to become more disordered only. The trend for more molecularly-ordered membranes in astrocytes induced by Aβ₄₂ was abrogated by either an NADPH oxidase inhibitor, apocynin, or an inhibitor of cytosolic phospholipase A₂ (cPLA₂), but not by an inhibitor of calcium-independent PLA₂ (iPLA₂). Apocynin also suppressed the increased production of superoxide anions (O₂⁻) and phosphorylation of cPLA₂ induced by Aβ₄₂. In addition, hydrolyzed products of cPLA₂, arachidonic acid (AA), but not lysophosphatidylcholine (LPC) caused astrocyte membranes to become more molecularly-ordered. These results suggest (1) a direct interaction of Aβ₄₂ with cell membranes making them more molecularly-disordered, and (2) Aβ₄₂ also indirectly makes membranes become more molecularly-ordered by triggering the signaling pathway involving NADPH oxidase and cPLA₂ in astrocytes.     

前列腺素E2受体亚型1(EP1)研究进展

前列腺素E₂(prostaglandinE₂,PGE₂)是花生四烯酸代谢产生的重要脂质分子,在多种生理和病理活动中发挥重要作用。非甾体抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)主要通过抑制PGE₂的生成而被广泛用于各类炎症性疾病的治疗和发热、疼痛症状的缓解。PGE₂功能的发挥主要依赖于与4种不同的G蛋白耦联受体相结合,其中PGE₂受体亚型1 (PGE₂receptor1,EP1)的分布相对比较局限,且PGE₂与EP1的亲和力相对较低。尽管如此,EP1在心血管、泌尿、消化等系统的生理功能维持和稳态调节方面却发挥重要作用。此外,EP1广泛参与炎症反应、痛觉维持和多系统的病理生理学功能调节。本文拟就近年来有关EP1在生理和病理生理学方面的功能和研究现状,以及与之相关药物的研究进展进行简要综述。     

Prostaglandin D2, another renal prostaglandin?

Prostaglandin (PG) D₂ was biosynthesized by rabbit renal papillae incubates in vitro. Quantification of the renal prostaglandins by gas chromatography-mass spectroscopy demonstrated that the concentration of PGD₂ generated by renal papillae was to the amount of PGE₂ or about 1 μg/g tissue/30 min. Infusion of the sodium salt of PGD₂ into the renal artery of the dog produced a dose related increase in renal blood flow and urine flow, free water clearance, sodium excretion and potassium excretion without changes in systemic hemodynamics. At low doses PGD₂ increased renal blood flow to all cortical zones. Higher concentrations of PGD₂ produced a shift in the intrarenal distribution of blood flow toward the juxtamedullary nephrons.     

Synthesis of 11β-3H-prostaglandin E2

11β-³H-Prostaglandin E₂ was synthesized by the stereoselective reduction of the PGD₂ derivative $\text{2}$ using sodium borotritide.     

Lysophosphatidic acid induces increased BACE1 expression and Aβ formation

The abnormal production and accumulation of β-amyloid peptide (Aβ), which is produced from amyloid precursor protein (APP) by the sequential actions of β-secretase and γ-secretase, are thought to be the initial causative events in the development of Alzheimer's disease (AD). Accumulating evidence suggests that vascular factors play an important role in the pathogenesis of AD. Specifically, studies have suggested that one vascular factor in particular, oxidized low density lipoprotein (oxLDL), may play an important role in regulating Aβ formation in AD. However, the mechanism by which oxLDL modulates Aβ formation remains elusive. In this study, we report several new findings that provide biochemical evidence suggesting that the cardiovascular risk factor oxLDL may contribute to Alzheimer's disease by increasing Aβ production. First, we found that lysophosphatidic acid (LPA), the most bioactive component of oxLDL induces increased production of Aβ. Second, our data strongly indicate that LPA induces increased Aβ production via upregulating β-secretase expression. Third, our data strongly support the notion that different isoforms of protein kinase C (PKC) may play different roles in regulating APP processing. Specifically, most PKC members, such as PKCα, PKCβ, and PKCε, are implicated in regulating α-secretase-mediated APP processing; however, PKCδ, a member of the novel PKC subfamily, is involved in LPA-induced upregulation of β-secretase expression and Aβ production. These findings may contribute to a better understanding of the mechanisms by which the cardiovascular risk factor oxLDL is involved in Alzheimer's disease.     

Central cardiovascular activity of prostaglandin E2, prostagladin F2∝ and prostacyclin

Prostacyclin (PGI₂), prostaglandin E₂ (PGE₂) and prostaglandin F_2∝ (PGF_2∝) were tested here in unanesthetized male Sprague-Dawley rats for their effects on the cardiovascular system as mediated by the Central nervous system. Cannulae were chronically implanted into the third cerebral ventricle, femoral arteries and femoral veins of rats. Both PGE₂ and PGF_2∝ induced increased arterial blood pressure and tachycardia by an action on the central nervous system. The changes seen with PGE₂ were larger than those observed with PGF_2∝. Only transient depressor effects were seen with PGI₂ and these changes appeared to be due to the leakage of the substance into the peripheral vascular system.     

Comparison of the effects of prostaglandins D2, F2α and E1 on spontaneous contractions of rabbit oviduct

The effects of PGD₂, PGF_2α and PGE₁ were studied on the circular muscle of post-ovulatory rabbit oviducts $\text{in vitro}$. PGE₁ inhibited spontaneous contractile activity. Lower concentrations of PGD₂ and PGF_2α were stimulatory and higher concentrations were inhibitory. Since PGD₂ may be produced in the oviduct, any hypothesis concerning the role of prostaglandins in the control of oviductal motility and ovum transport should include PGD₂ as well as PGFs and PGEs.     

芽孢杆菌E2菌株纤维素酶性质的研究

芽孢杆菌EZ菌在55C下生长良好．在培养液中能大量积累胞外纤维素酶(190m㈣／L培养液),所产生的纤维素酶为单一的羧甲基纤维素酶((CMCase)。羧甲基纤维素钠(CMC—Na)为其专一性底物。该酶作用的pH为4．5 8．0;最适pH为6．5 7．0;在pH4.0- 8．0范围内较稳定。酶作用的最适温度为55C、;在60C、处理 10、30、60、90以及120分钟后,残余酶活分别为95％、80.3％、41．4％,19.3％和7.0%;在65C和70C处理10分钟后残余酶活分别为59％N 19％。M2+、Ca2+对酶促反应稍有促进作用;Ag-、Mn2-、Cu2-、Fe2-和Zn2+有明显的抑制作用。     

Synthesis of prostaglandin E2 and prostaglandin F2α by toadfish red blood cells

Saline washed red blood cells of the toadfish convert [1-¹⁴C] arachidonic acid to products that cochromatograph with prostaglandin E₂ and prostaglandin F_2α. This synthesis is inhibited by indomethacin (10 μg/ml). Conversion of arachidonic acid to prostaglandin E₂ was confirmed by mass spectrometry. When saline washed toadfish red blood cells were incubated with a mixture of [1-¹⁴C]-arachidonic acid and [5,6,8,9,11,12,14,15,-³H]-arachidonic acid, comparison of the isotope ratios of the radioactive products indicated that prostaglandin F_2α was produced by reduction of prostaglandin E₂. The capacity of toadfish red blood cells to reduce prostaglandin E₂ to prostaglandin F_2α was confirmed by incubation of the cells with [1-¹⁴C] prostaglandin E₂.     

The effects of prostaglandins E2 and F2α on synaptosomal accumulation and release of 3H-norepinephrine

Prostaglandins (PG) of both the E and F series may serve as modulators of norepinephrine (NE) release from peripheral sympathetic neurons. We have studied the effects of PGE₂ and PGF_2α on the accumulation and release of ³H-NE in the CNS using synaptosomes isolated from rat hypothalami.The release of ³H-NE from synaptosomes superfused with Krebs-Ringer bicarbonate buffer was multiphasic with an initial fast release phase followed by a slower release. Raising KC1 concentration of the superfusion medium to 56mM during the slow release phase is known to stimulate ³H-NE release. PGE₂ (1 × 10^?6M) attenuated ³H-NE release during the fast phase and reduced the amount of ³H-NE released due to KC1 stimulation. At lower concentrations of PGE₂ there was no change in the release profile. PGF_2α was without effect on ³H-NE release at all concentrations tested.The accumulation of ³H-NE was significantly diminished by PGE₂ at a concentration of 1 × 10^?6M, while a lower concentration (1 × 10^?7M) was ineffective. PGF_2α had no effect on ³H-NE accumulation at all concentrations investigated.