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Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis 总被引:2,自引:0,他引:2
Cheng CY Silvestrini B Grima J Mo MY Zhu LJ Johansson E Saso L Leone MG Palmery M Mruk D 《Biology of reproduction》2001,65(2):449-461
The three currently available male contraceptive approaches are 1) the barrier method such as the condom, 2) hormonal methods by disrupting the pituitary-testicular axis so as to impair spermatogenesis, and 3) immunological methods by preparing vaccines against male-specific antigens. We hereby describe an alternative approach in which attachments of developing germ cells onto the seminiferous epithelium are disrupted, thereby inducing their premature release into the tubular lumen. This in turn leads to infertility. A panel of analogues based on the core structure of 1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid was synthesized. These compounds were subjected to an in vivo screening assay assessing their effects in inducing the expression of testin, a testicular marker whose expression correlates with the integrity of Sertoli-germ cell junctions. An induction of testin expression in the testis signifies a disruption of Sertoli-germ cell junctions that is followed by depletion of germ cells from the seminiferous epithelium. Two compounds, namely 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF-2785), were identified that caused detachment of germ cells, in particular round and elongated spermatids, from the epithelium inducing their premature release into the tubular lumen as confirmed by histological analysis. Adult rats receiving several oral doses of either one of these compounds became infertile within 3-7 wk after the epididymal sperm reserve was exhausted. Depending on the dosing of the administered compound, rats became infertile for 4-14 wk before their fertility gradually bounced back, illustrating the reversibility and efficacy of these new compounds. Also, these compounds did not appear to impair the hypothalamus-pituitary-testicular axis because the serum levels of LH, FSH, and testosterone of the treated animals did not change significantly when compared to control rats. In addition, results of serum microchemistry illustrate that liver and kidney function was not affected in animals treated with both compounds. 相似文献
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L Saso M G Leone M Y Mo E Grippa C Y Cheng B Silvestrini 《Biochemistry. Biokhimii?a》1999,64(7):839-844
Changes in serum and cerebrospinal fluid (CSF) proteins following generalized acute inflammation induced by fermented yeast in the rat was examined by concanavalin A-blotting, immunoblotting, and radioimmunoassay. Using alpha2-macroglobulin (alpha2-M) and hemopexin (HPX) as marker proteins, the concentration alpha2-M was found to increase in serum and CSF by 150- and 5-fold, respectively, whereas the concentration of HPX increased by about 4-fold in both fluids following yeast-induced inflammation. The lesser increase in alpha2-M in the CSF versus the systemic circulation is not likely to be the result of changes in the permeability of the blood--brain barrier, since no change in the total protein content of CSF was detected in inflamed rats when compared to control animals. These results, however, illustrate the regulation of the same protein, such as alpha2-M, in two separate organs within the same animal can be drastically different. These results also suggest a possible protective role of alpha2-M in the brain during acute inflammation. Moreover, these observations are consistent with the previous observation that there is a differential response in the level of alpha2-M between the testis and the systemic circulation during inflammation. 相似文献
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Terpredoxin (Tdx) is a 105-residue bacterial ferredoxin consisting of a single polypeptide chain and a single Fe2S2 prosthetic group. Tdx was first identified in a strain of Pseudomonas sp. capable of using alpha-terpineol as sole carbon source. The Tdx gene, previously cloned from the plasmid-encoded terp operon, that carries genes encoding for proteins involved in terpineol catabolism, has been subcloned and expressed as the holoprotein in E. coli. Physical characterization of the expressed Tdx has been performed, and a model for the solution structure of oxidized Tdx (Tdxo) has been determined. High-resolution homo- and heteronuclear NMR data have been used for structure determination in diamagnetic regions of the protein. The structure of the metal binding site (which cannot be determined directly by NMR methods due to paramagnetic broadening of resonances) was modeled using restraints obtained from a crystal structure of the homologous ferredoxin adrenodoxin (Adx) and loose restraints determined from paramagnetic broadening patterns in NMR spectra. Essentially complete 1H and 15N NMR resonance assignments have been made for the diamagnetic region of Tdxo (ca. 80% of the protein). A large five-stranded beta-sheet and a smaller two-stranded beta-sheet were identified, along with three alpha-helices. A high degree of structural homology was observed between Tdx and two other ferredoxins with sequence and functional homology to Tdx for which structures have been determined, Adx and putidaredoxin (Pdx), a homologous Pseudomonas protein. 1H/2H exchange rates for Tdx backbone NH groups were measured for both oxidation states and are rationalized in the context of the Tdx structure. In particular, an argument is made for the importance of the residue following the third ligand of the metal cluster (Arg49 in Tdx, His49 in Pdx, His56 in Adx) in modulating protein dynamics as a function of oxidation state. Some differences between Tdx and Pdx are detected by UV-visible spectroscopy, and structural differences at the C-terminal region were also observed. Tdx exhibits only 2% of the activity of Pdx in turnover assays performed using the reconstituted camphor hydroxylase system of which Pdx is the natural component. 相似文献
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The mammalian retina contains numerous morphological and physiological subtypes of amacrine cells necessary for integrating and modulating visual signals presented to the output neurons. Among subtypes of amacrine cells grouped by neurotransmitter phenotypes, the glycinergic and gamma-aminobutyric acid (GABA)ergic amacrine cells constitute two major subpopulations. To date, the molecular mechanisms governing the specification of subtype identity of amacrine cells remain elusive. We report here that during mouse development, the Barhl2 homeobox gene displays an expression pattern in the nervous system that is distinct from that of its homologue Barhl1. In the developing retina, Barhl2 expression is found in postmitotic amacrine, horizontal and ganglion cells, while Barhl1 expression is absent. Forced expression of Barhl2 in retinal progenitors promotes the differentiation of glycinergic amacrine cells, whereas a dominant-negative form of Barhl2 has the opposite effect. By contrast, they exert no effect on the formation of GABAergic neurons. Moreover, misexpressed Barhl2 inhibits the formation of bipolar and Müller glial cells, indicating that Barhl2 is able to function both as a positive and negative regulator, depending on different types of cells. Taken together, our data suggest that Barhl2 may function to specify the identity of glycinergic amacrine cells from competent progenitors during retinogenesis. 相似文献
130.
Young?Sik?Kim Chong?Ho?Lee Phillip?C.?Wankat Yoon?Mo?KooEmail author 《Biotechnology and Bioprocess Engineering》2004,9(5):362-368
A new one-column chromatography process, analogous to a four-zone simulated moving bed (SMB), was presented. The basic principle
of the process was identical to that of a four-zone SMB. The process consisted of one chromatographic column and four tanks,
instead of the four columns in the four-zone SMB (1-1-1-1), and has been used for the separation of two amino acids, phenylalanine
and tryptophan, using an ion exchange resin. The operating parameters for the one-column process and four-zone SMB were obtained
from equilibrium theory. Computer simulations were used to compare the performances of the new one column process to that
of the general four-zone SMB, using Aspen Chromatography™ v 11.1. The differences between the one-column and SMB processes in terms of the purities and yields of phenylalanine and
tryptophan were less than 4 and about 6%, respectively. The lower purities of the one-column process were due to the loss
of the developed concentration profiles in the column when the liquid was stored in tanks. The one-column process gave great
flexibility, and would be useful for reconstructing an existing conventional chromatography process to one of a SMB. 相似文献