转化生长因子β

TGFβ广泛存在于动物体多种组织和细胞内,由二条相同的、含112个氨基酸的肽链组成,是细胞的多功能双重调节因子。它对不同组织类型的细胞,可促进生长、分化,也可抑制生长、分化,并直接参与组织修复、胚胎发育等过程,调节细胞外基质形成。     

Microbial transformation of 13-ethyl-3-methoxy-8,14-seco-gona-1,3,5(10),9(11)-tetraene-14, 17-dione to its 17-beta hydroxy derivative by Pichia farinosa in pilot plant fermentors

Parameters for microbial transformation of 13-ethyl-3-methoxy-8, 14-seco-gona-1,3,5 (10), 9(11)-tetraene-14,17-dione to its 17 beta-hydroxy derivative by P. farinosa have been standardised in pilot plant fermentors. The yield of the pure crystalline compound was 80%.     

Conjugate hydrocyanation of 17-acetyl-11-carbomethoxygona-1,3,5(10),13(17)-tetraenes

The conjugate hydrocyanation of 17-acetylgona-11-carbomethoxy-1,3,5(10),13(17)-tetraenes using diethylaluminum cyanide (Nagata reaction) is reported. This methodology has allowed the introduction of an angular cyano group at the C-13 position of the steroid skeleton. Subsequent reduction of the nitrile group yielded various functionalized steroids. One of them, 22 bears the natural trans/anti/trans stereochemistry and possesses an hydroxyl and aminomethyl functionalities in the positions 11beta and 13beta, respectively. The characteristic (1)H and (13)C NMR spectroscopic features of the synthesized steroids are reported.     

Placenta defects and embryonic lethality resulting from disruption of mouse hydroxysteroid (17-beta) dehydrogenase 2 gene

Hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2) is a member of aldo-keto reductase superfamily, known to catalyze the inactivation of 17beta-hydroxysteroids to less active 17-keto forms and catalyze the conversion of 20alpha-hydroxyprogesterone to progesterone in vitro. To examine the role of HSD17B2 in vivo, we generated mice deficient in Hsd17b2 [HSD17B2 knockout (KO)] by a targeted gene disruption in embryonic stem cells. From the homozygous mice carrying the disrupted Hsd17b2, 70% showed embryonic lethality appearing at the age of embryonic d 11.5 onward. The embryonic lethality was associated with reduced placental size measured at embryonic d 17.5. The HSD17B2KO mice placentas presented with structural abnormalities in all three major layers: the decidua, spongiotrophoblast, and labyrinth. Most notable was the disruption of the spongiotrophoblast and labyrinthine layers, together with liquid-filled cysts in the junctional region and the basal layer. Treatments with an antiestrogen or progesterone did not rescue the embryonic lethality or the placenta defect in the homozygous mice. In hybrid background used, 24% of HSD17B2KO mice survived through the fetal period but were born growth retarded and displayed a phenotype in the brain with enlargement of ventricles, abnormal laminar organization, and increased cellular density in the cortex. Furthermore, the HSD17B2KO mice had unilateral renal degeneration, the affected kidney frequently appearing as a fluid-filled sac. Our results provide evidence for a role for HSD17B2 enzyme in the cellular organization of the mouse placenta.     

Practical one-pot conversion of 17beta-estradiol to 10beta-hydroxy- (p-quinol) and 10beta-chloro-17beta-hydroxyestra-1,4-dien-3-one

An efficient one-pot procedure for the preparation of 10beta,17beta-dihydroxyestra-1,4-dien-3-one (p-quinol, 1, 75%) is reported, involving oxidation of 17beta-estradiol with potassium permanganate. Similar treatment of 17beta-estradiol with sodium chlorite led to 10beta-chloro-17beta-hydroxyestra-1,4-dien-3-one (2) in 44% yield along with smaller amounts 4-chloro-10beta,17beta-dihydroxyestra-1,4-dien-3-one (3), 2,10beta-dichloro-17beta-hydroxyestra-1,4-dien-3-one (4), and 4,10beta-dichloro-17beta-hydroxyestra-1,4-dien-3-one (5).     

Hypocholesterolemic activity of 17-alpha-methyl-5-alpha-androstane-3-beta, 17-beta-diol, a metabolite of 17-alpha-methyltestosterone

The hypocholesterolemic activities of 17alpha-methyltestosterone and its major identified fecal metabolite, 17alpha-methyl-5alpha-androstane-3,17-diol, were compared in dogs. The dose-response curves indicated that the two compounds had similar effects, although at doses below 1 mg/kg per day the diol appeared to be more active than the parent compound.     

Hemoglobin Tilburg: alpha 2-beta 2 73 (E 17) Asp----Gly. A new hemoglobin with reduced oxygen affinity

A new hemoglobin variant has been found in a Dutch Caucasian girl and detected also in members of three generations of her family. This variant is characterized by the substitution of an aspartic acid at position 73 (E 17) of the beta-chain with a glycine residue. Hemoglobin Tilburg makes up to 42% of the total hemoglobin in the blood of the proposita, it is stable at the isopropanol test, and not associated with significant hematological abnormalities in heterozygous carriers. The oxygen dissociation curve of the purified variant, carried out at different pH values, shows a definite reduction of the affinity for oxygen and a normal alkaline Bohr effect. Three more hemoglobins with a single amino acid substitution at the same site have been previously described: Hb Korle-Bu (Asp----Asn), Hb Mobile (Asp----Val) and Hb Vancouver (Asp----Tyr). In all these proteins the affinity for oxygen is lowered to an extent which is variable and characteristic of each mutant. In this paper we discuss the possible mechanism responsible for the abnormal behaviour of hemoglobins substituted at beta 73.     

Effects of 17-beta estradiol and 4-nonylphenol on phase II electrophilic detoxification pathways in largemouth bass (Micropterus salmoides) liver

The effects of in vivo exposure to a natural and synthetic estrogen upon three hepatic phase II enzyme pathways involved in cellular protection against reactive intermediates were investigated in the largemouth bass (Micropterus salmoides). The pathways analyzed included glutathione S-transferases (GST), glutathione (GSH) biosynthesis and NAD(P)H-dependent quinone reductase (QR). Following exposure to 17-beta estradiol (E2, a model natural estrogen; 2 mg/kg, i.p.) or 4-nonylphenol (NP, a model synthetic estrogen; 5 mg/kg and 50 mg/kg, i.p.), serum vitellogenin concentrations in male fish were markedly increased. Exposure to E2 did not affect steady-state GST-A mRNA expression, although GST catalytic activity toward 1-chloro 2,4-dinitrobenzene (CDNB) was elevated at 48 h post-injection. In addition, the rates of bass liver GST-4-hydroxy-2-nonenal (GST-4HNE) conjugation were elevated by E2 exposure at all timepoints. In contrast, exposure to NP decreased steady-state GST-A mRNA levels, but did not alter GST catalytic activities. Hepatic GSH levels were not significantly affected by exposure to either compound, although a trend towards increased GSH biosynthesis was observed with both compounds. Although bass liver quinone reductase catalyzed 2,6-dichloroindophenol (DCP) reduction, unlike in rodents, these catalytic activities were not inhibited by dicoumarol. Exposure to 5 mg/kg NP significantly increased hepatic QR activities. Collectively, our data suggest that exposure to E2 or NP alters the ability of largemouth bass to biotransform environmental chemicals through glutathione S-transferase and quinone reductase catalytic pathways.