Conformational Change of a Tryptophan Residue in BtuF Facilitates Binding and Transport of Cobinamide by the Vitamin B12 Transporter BtuCD-F.

BtuCD-F is an ABC transporter that mediates cobalamin uptake into Escherichia coli. Early in vivo data suggested that BtuCD-F might also be involved in the uptake of cobinamide, a cobalamin precursor. However, neither was it demonstrated that BtuCD-F indeed transports cobinamide, nor was the structural basis of its recognition known. We synthesized radiolabeled cyano-cobinamide and demonstrated BtuCD-catalyzed in vitro transport, which was ATP- and BtuF-dependent. The crystal structure of cobinamide-bound BtuF revealed a conformational change of a tryptophan residue (W66) in the substrate binding cleft compared to the structure of cobalamin-bound BtuF. High-affinity binding of cobinamide was dependent on W66, because mutation to most other amino acids substantially reduced binding. The structures of three BtuF W66 mutants revealed that tight packing against bound cobinamide was only provided by tryptophan and phenylalanine, in line with the observed binding affinities. In vitro transport rates of cobinamide and cobalamin were not influenced by the substitutions of BtuF W66 under the experimental conditions, indicating that W66 has no critical role in the transport reaction. Our data present the molecular basis of the cobinamide versus cobalamin specificity of BtuCD-F and provide tools for in vitro cobinamide transport and binding assays.

[Gestagenic and contraceptive activity of new synthetic progesterone analogs in experimental animals].

The gestagenic activity of new 17alpha-hydroxyprogesterone analogs was studied in experiments on infantile female rabbits (Clauberg-McPhail assay) and ovariectomized animals (Comer-Allen assay). The new steroidal preparations produced significant secretory transformations in immature rabbit endometrium. The maximum gestagenic activity was observed for butagest, while the minimum effect was produced by duhydrogesterone (dufaston). Butagest, megestrol capronate, and AMOL isopropyl ester showed the ability to maintain pregnancy in ovariectomized female rabbits. The compositions of gestagens (0.8 mg/kg) with ethinylestradiol (0.04 mg/kg) produced high contraceptive effect in rats.

Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons.

We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity.

[Experimental progestogenic activity of novel derivatives of 17alpha-hydroxyprogesterone]. / O gestagennoi aktinosti novykh proizvodnykh 17alpha-gidroksiprogesterona v éksperimente.

Experiments on infantile female rabbits showed that new 17a-hydroxyprogesterone derivatives (AMOL phenyl propionate, AMOL isopropyl ester) possess a pronounced gestagenic activity. In particular, AMOL isopropyl ester is capable of maintaining pregnancy in ovariectomized animals (Corner-Allen assay).

Affinities of gidazepam and its analogs for mitochondrial benzodiazepine receptors.

Mitochondrial benzodiazepine receptors (MBRs) participate in many physiological processes, such as calcium flow regulation, proliferative and respiratory cell functions, mitochondrial steroidogenesis and adaptational reactions to stress. We have found that the selective anxiolytic gidazepam has a higher affinity for CNS MBRs as compared to central benzodiazepine receptors. The ability of gidazepam to bind to MBRs probably underlies a wide spectrum of its pharmacological effects. We have studied affinities of gidazepam analogs for CNS MBRs in search for the ligands possessing higher affinity and selectivity. The experiments were carried out with male Wistar rats weighing between 200-220 g. Affinities of the investigated compounds were assessed on their ability to displace radioligand Ro5-4864 from its specific binding sites on MBRs of rat brain. Within the series of tested compounds three substances comparable on affinity with Ro5-4864 were found. Experimental results have shown that the presence of chlorine atom in o-position of 5-phenyl substituent leads to a 10 to 15-fold increase in affinity for CNS MBRs. We have also found that the essential contribution in affinity of the investigated series is brought by lipophilicity of substituent in IN-position. Our data may be useful in design and synthesis of novel potent selectively acting ligands of CNS MBRs.

[Effect of instenon on the uterine contractile activity]. / Vliianie instenona na sokratitel'nuiu deiatel'nost' matki v éksperimente.

The effect of instenon upon the uterine contractile activity was studied in pregnant rats. The drug administration at a dose resulted in significant suppression of the myometrium contractility. The effect was not decreased when instenon was injected against the background of oxytocin. On the other hand, the concurrent injection of oxytocin upon a single or long-term administration of instenon produced a pronounced stimulating action on the myometrium contractility.

[Effects of verapamil and gynipral on the uterine contractile activity in rats]. / Vliianie verapamila i giniprala na sokratitel'nuiu deiatel'nost' matki krys.

Verapamil and gynipral administered to pregnant rats in doses on a clinical level suppress the uterine contractions, which is manifested by a decrease in the amplitude and frequency of the biopotential. The joint administration of gynipral and verapamil (in half doses) resulted in a pronounced tocolytic effect.

[Current trends in the diagnosis and therapy of colorectal cancer]. / Sovremennye napravleniia v diagnostike i lechenii kolorektal'nogo raka.

The report deals with the 30-year experience gained by the Department in the treatment of nearly 5,500 cases of tumors of large bowel. Radical surgery for colonic tumor was followed by lethality in 3.0 and 5-year survival-80.8%; rectal tumor resection-5.3 and 58.2%, respectively. Individually-tailored modalities have been devised for a spectrum of cases of colonic wall invasion and metastatic lesions in regional lymph nodes. A choice of sparing, extended and combined surgical procedures vis-a-vis these factors has been developed, the latter offering most advantage. Therapeutic strategies for hepatic metastasis have been worked out on individual basis.

[Experimental study of the antitumor properties of acetomepregenol]. / Eksperimental'noe issledovanie protivoopukholevykh svoistv atsetomepregenola.

Antitumor effect on hormone dependent tumors has been demonstrated following oral and parenteral treatment of mice and rats with a gestagenic drug -- acetomepregenol.

[The effect of a peptide preparation made from ovaries on reproductive function]. / Vliianie peptidnogo preparata iz iaichnikov na reproduktivnuiu funktsiiu.

A study was done on the action of the low molecular peptide preparation isolated from cow ovaries by the acetic acid extraction, on the rat ovary function. It was revealed that this preparation: 1) does not possess the gonadotrophic activity; 2) enhances the sensitivity of immature rat ovaries to the human chorionic gonadotrophin; 3) increases the number of ovulating oocytes in neonatal androgenized rats in gonadotrophic stimulation of the ovary function; 4) does not influence the character and duration of the estrous cycle in intact adult rats.

[A rational surgical procedure in diffuse polyposis and multiple primary cancer against a background of polyps of the large intestine]. / Ratsional'naia khirurgicheskaia taktika pri diffuznom polipoze i pervichno-mnozhestvennom rake na fone polipov tolstoi kishki.

Under examination there were 292 patients. An analysis of results of treatment enabled the authors to conclude that surgical treatment of patients with diffuse polyposis of the colon is the method of choice. The method and volume of operations must be determined according to the involvement of the colon in polyposis, the age and state of the patients. The best method of surgery is a one-step radical operation-subtotal resection of the colon. Polyps concomitant to cancer of the colon should be ablated before the main operation since their histological analysis can change the volume of the planned radical operation. When choosing the method of surgical intervention for patients with primary-multiple cancer against the background of polyps the total portion of the colon with polyps should be ablated.

[The effect of calcium antagonists, partusisten, oxytocin and prostenon on uterine contractile activity in pregnant rats]. / Vliianie antagonistov kal'tsiia partusistena, oksitotsina i prostenona na sokratitel'nuiu aktivnost' matki beremennykh krys.

Experiments carried out in pregnant rats show that combination of nifedipine with verapamil or partusystene (in a half dose) depresses contractility in a more pronounced extent than of these drugs in the case of separate application. Calcium antagonist, cardizem does not depress contractility of myometrium.

[The surgical treatment of polyps and early forms of cancer of the large intestine]. / Khirurgicheskoe lechenie polipov i rannikh form raka tolstoi kishki.

The article describes the present-day principles of surgical treatment of polyps and early forms of colorectal carcinoma appearing against their background. The investigation performed has shown that all benign adenomas of the colon can be successfully treated by local dissection. Sessile tumors located on the lower- and middle-ampullar portions of the rectum, are liable to endorectal dissection, in pedicular tumors endoscopic polypectomy is most expedient. In cases with carcinoma against the background of adenoma, the main criterion determining choice of the method of surgical intervention is the degree of ingrowth of the tumor into the colon walls. An analysis of long-term results of treatment shows that in carcinoma of the colon developing against the background of adenoma, local dissection is not inferior in efficiency to typical radical operations.

[The effect of thalicoside on reproductive function in an experiment]. / Vliianie talikozida na reproduktivnuiu funktsiiu v éksperimente.

Talicoside, a triterpene glycoside from Thalictrum minus L., given in an oral dose og 1 mg/kg for 5 days was demonstrated to cause ovulation stimulation induced by intravenously injecting 1.2% solution of copper acetate into the rabbits. The agent enterally administered in a dose of 1 mg/kg to rats for 5 days reduced the levels of luteinizing hormone and elevated serum follicle-stimulating hormone in proestrous and estrous.

[An experimental study of sulprostone as an agent in preparation for abortion]. / Eksperimental'noe issledovanie sul'prostona kak sredstva podgotovki k abortu.

The prostaglandin E sulprostone was studied in experiments on pregnant rats. It was shown to stimulate the bioelectrical activity of the uterus, by increasing the amplitude and frequency of biological potentials. Sulprostone was found to have abortive and embryotoxic effects which were especially pronounced during placentation. The drug induced a slight teratogenic effect.

[Effect of a new prostaglandin aroxaprostol on the contractile activity of the uterus and its abortive action in experimental studies]. / Vliianie novogo prostaglandina aroksaprostola na sokratitel'nuiu aktivnost' matki i ego abortivnyi éffekt v éksperimente.

Experiments with pregnant and nonpregnant rats have shown that aroxaprostol, a group F2 alpha prostaglandin, injected intravenously and intramuscularly in a dose of 50 micrograms/kg, stimulates the uterine bioelectric activity, increasing both the amplitude and frequency of biopotentials, this evidencing intensification of its contractility. Aroxaprostol has shown an abortive effect, that was related to the luteolytic effect of the drug, manifesting by reduction of progesterone level in the ovaries.

[The history of pharmacology in the D. O. Ott Institute of Obstetrics and Gynecology of the Academy of Medical Sciences of the USSR]. / Istoriia farmakologii v Institute akusherstva i ginekologii im. D. O. Otta AMN SSSR.

The history of pharmacology at the Institute of Obstetrics and Gynecology is presented. The Institute was set up in 1797. The founder of the Institute and its first director was N. M. Maksimovich-Ambodik, a brilliant obstetrician and pharmacologist. The activities of D. O. Ott who became the director in 1893 was of great importance for the development of the Institute. In 1948 the Institute was included into the system of the USSR Academy of Medical Sciences. In 1966 the Laboratory of Pharmacology was organized. The main trends of the research performed at the Laboratory and the results are characterized.

[The clinico-pharmacological characteristics of anteovin]. / Kliniko-farmakologicheskaia kharakteristika anteovina.

The clinical and laboratory studies carried out on 160 women showed a high contraceptive effect and good tolerance of anteovine. The contraceptive effect of the biphasic drug is determined by its antiovulatory action concurrent with inhibition of the basal periovulatory secretion of gonadotropins and secretion of sex hormones.

PIP: The results of evaluation of the contraceptive activity of the biphasic oral contraceptive anteovin are presented. 1 package of anteovin consists of 11 white tablets containing 0.05 mg of ethinyl estradiol and 0.05 mg of levonorgestrel and 10 pink tablets of 0.05 mg of ethinyl estradiol and 0.125 mg of levonorgestrel. Anteovin was tested according to the conventional 21-day regimen from day 5 of the cycle for 21 days, followed by 1 7-day rest period. Duration of anteovin administration ranged from 1 to 12 cycles. Anteovin was given to 160 women (aged 17 to 40 years old) who had a history of 618 pregnancies (182 ended by term delivery and 436 ended by induced abortion). During anteovin administration none of the women became pregnant. Side effects of anteovin included mild nausea during first several days in 12 women, breast tenderness in 4, and menstruation disorders in 8. The mechanism of contraceptive effect of anteovin was associated with ovulation inhibition. The changes in the basal temperature had a monophasic characteristic. Colpocytological examination showed decrease in the karyopyknotic and eosinophilic indices to 4-30%. All estrogen fractions (estrone, estradiol and estriol) in the urine showed statistically significant decrease on day 14-16 of the cycle (to 15.8 mcg/day, compared with 41.9 mcg/day in controls). The level of pregnanediol in the urine showed a decrease on day 20-23 of the cycle (0.66 mg/day, compared with 2.98 mg/day in controls). After 6 months of anteovin administration, there was a decrease in the basal and periovulation secretion of follicle-stimulating hormone, luteinizing hormone, and estradiol.