Biomedical subjects
Publications and source records attributed to S Batra.
The synthesis of isoxazole-based derivatives utilizing Baylis-Hillman chemistry and results of their preliminary bioevaluation as hypolipidemic agents in triton model are described.
For the extrapolation of data obtained from experimental animals to the human situation, it is important to know the similarities and differences between human and animal species. Some important characteristics of nitric oxide synthase (NOS) in myometrium and vagina from human and rat were compared. NOS-activity was measured by the formation of 14C-citrulline from 14C-arginine and the expression of NOS isoforms was examined by Western blotting. NOS activity in human uterus and vagina was significantly lower than in the tissues from rat. In contrast to the rat where NOS activity was predominantly found in the cytosolic fractions, NOS activity in particulate and cytosolic fractions from both human myometrium and vagina was similar. Data from Western blots confirmed that eNOS and nNOS isoforms were concentrated in the particulate and cytosolic fractions, respectively. Estrogen treatment of rats resulted in a down regulation of uterine cytosolic NOS activity. A down regulation of NOS in the cytosolic fraction was also seen in the human pregnant myometrium as compared with the nonpregnant myometrium. The vaginal NOS activity was considerably higher than the uterus in both species. In spite of some clear-cut qualitative and other differences between human and rat tissues, there are some interesting similarities. Downregulation in pregnancy of human uterine NOS is probably due to, at least in part, the influence of estrogen and progesterone.
OBJECTIVES: To compare maternal and fetal outcomes in patients with non-operated valvular heart disease and patients who had surgery before or during pregnancy. METHODS: The 308 women with valvular heart disease who delivered in this hospital in the last 8 years were divided into three groups. The 218 (70.7%) women in group 1 had no surgical intervention; the 42 (13.6%) women in group 2 underwent balloon mitral valvotomy during pregnancy; and the 48 (15.5%) women in group 3 had surgical intervention before pregnancy (35 had balloon mitral valvotomy, eight had mitral valve replacement, and five had mitral valve repair). Maternal and fetal outcomes were compared for these three groups. RESULTS: The antenatal events differed significantly: 175 (80.3%), 40 (94.2%), and 46 (95.8%) patients in groups 1, 2 and 3, respectively, had uneventful pregnancies. In group 1, 14 (6.4%) patients had congestive heart failure (P>0.05) and 24 (11%) patients had cardiac arrhythmias, which was statistically significant. The rate of preterm deliveries did not differ significantly among the three groups. The groups did not differ in mean birth weight, mode of delivery, low birth weight, Apgar scores less than 8, stillbirths, neonatal death, or congenital anomalies. CONCLUSIONS: Mitral valve surgery before or during pregnancy did not significantly improve maternal and fetal outcomes but decreased adverse events such as congestive heart failure and cardiac arrhythmias. It should be therefore performed only in selected cases.
OBJECTIVES: To observe the effect of the antioxidant lycopene on the occurrence of pre-eclampsia and intrauterine growth retardation in primigravida women. METHODS: A total of 251 primigravida women were enrolled in this prospective, randomized controlled study in the second trimester. A total of 116 women were given oral lycopene (Group I) in a dose of 2 mg twice daily while 135 women were given a placebo (Group II) in the same dose until delivery. The criteria for recruitment included gestational age of 16-20 weeks, singleton pregnancy, absence of any medical complication and willingness on the part of the women to participate in the study. The women were followed-up until delivery for development of pre-eclampsia, mode of delivery and fetal outcome. RESULTS: The two groups were comparable in their maternal characteristics. Pre-eclampsia developed in significantly less women in the lycopene group than in the placebo group (8.6% vs. 17.7%, P=0.043 by chi-square test). Mean diastolic blood pressure was significantly higher in the placebo group (92.2+/-5.98 mmHg vs. 86.7+/-3.80 mmHg, P=0.012). Mean fetal weight was significantly higher in the lycopene group (2751.17+/-315.76 g vs. 2657+/-444.30 g, P=0.049). The incidence of intrauterine growth retardation was significantly lower in the lycopene group than in the placebo group (12% vs. 23.7%, P=0.033). CONCLUSIONS: The results of the present study suggest that the antioxidant lycopene reduces the development of pre-eclampsia and intrauterine growth retardation in primigravida women.
The use of the triterpenoid lupeol as a scaffold for the synthesis of lupeol-based libraries is described. Lupeol was anchored to a solid support (Rink amide/Sieber Amide) through aliphatic dicarboxylic acid moieties, which also served as a site for introducing diversity. The resulting polymer linked 3beta-O (resin-alkanoyl)-lup-20(29)-ene 3 was used to generate key intermediates 3beta-O (resin-alkanoyl)-30-bromo-lup-20(29)-ene 4 and 3beta-O (resin-alkanoyl)-30-amino-lup-20(29)-ene 6 for the generation of libraries based on disubstituted lupeol derivatives. A 96-member library was screened for its in-vitro antimalarial activity against Plasmodium falciparum.
The 3-substituted phenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries on solid phase through automation. Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions. With an objective of lead generation all the three libraries were evaluated for their antithrombin activity in vivo.
Four sets of mixture based nonapeptide libraries derived from an antifungal hexapeptide pharmacophore Arg-D-Trp-D-Phe-Ile-D-Phe-His-NH(2) (II) have been synthesized. The three C-terminal positions 7, 8 and 9 were subject to randomization using 19 genetically coded amino acids. They were then screened for their antifungal activity against Candida albicans and Cryptococcus neoformans in order to quantify inhibition at each step of the nonapeptide sublibrary deconvolution. The studies led to the identification of several novel nonapeptides with potent antifungal activity. Two of the nonapeptides exhibited approximately 17-fold increase in the activity in comparison to the lead hexapeptide motif His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH(2) (I) against C. albicans.
OBJECTIVES: To analyze the maternal and perinatal outcome in varying degrees of anemia. METHODS: A total of 447 pregnant women were divided into group I (Hb>11 g%, n=123 women), group II (Hb 9-10.9 g%, n=214 women), group III (Hb 7-8.9 g%, n=79 women) group IV (Hb<7 g%, n=31 women). Their maternal and perinatal outcome, mode of delivery, duration of labor and postpartum complications were noted and analyzed using multiple logistic regression to calculate odds ratios (95% CI) for duration of labor, mode of delivery and low birth babies. Chi square or Fisher's exact test was employed for difference in proportions and Student's t-test for testing difference between means. RESULTS: Mean age (27+/-4.25 years) and number of women with parity >3 were highest in group IV. The patients with Hb<8.9 g% had a 4-6-fold higher risk of prolonged labor compared to Hb>11 g%. The odds ratios for abnormal delivery (cesarean and operative vaginal deliveries) showed a 4.8-fold higher risk (95% CI 1.82, 12.7) in patients with Hb </=7.5 g%. The mean birth weight was maximum in the 9.6-10.5 g% category that fell with both increasing and decreasing hemoglobin values, being lowest in Group IV. Women in Group II had lowest number of low birth weight and IUGR babies, no stillbirths and neonatal deaths, lowest induction and operative delivery rates. CONCLUSIONS: Mild anemia fared best in maternal and perinatal outcome. Severe anemia was associated with increased low birth weight babies, induction rates, operative deliveries and prolonged labor.
The stereocontrolled reduction of 3-aryl-5-acetylisoxazolines (1) to the corresponding alcohols (2 and 3) in the presence of four different yeast strains, recognized as Baker's yeast (commercial), Candida krusei (ATCC 14243), Pichia farinosa (NRRL Y110) and Sacchromyces sp. (soil isolate) have been attempted. The C. krusei was found to be diastereoselective for the (R)-1 while the Sacchromyces sp. led to complete reduction to yield the RS- and SS-alcohol in 1:1 ratio at 10 g/L scale.
OBJECTIVES: To assess endothelial function and vascular mechanical properties in normotensive pregnant women with high resistance in the uteroplacental circulation. DESIGN: Cross-sectional prospective study. SETTING: Doppler ultrasound laboratory at university department of obstetrics and gynaecology referral centre for high risk pregnancies. PARTICIPANTS: Forty-two caucasian normotensive pregnant women: 23 with uncomplicated pregnancies and 19 with bilateral uterine artery notches. METHODS: Flow-mediated dilatation of the brachial artery was measured by ultrasonography at 25 gestational weeks. Concentrations of nitrite and nitrate in the plasma were established at 25 and 32 gestational weeks. The elastic properties of the common carotid artery, abdominal aorta and popliteal artery were measured with an ultrasonic echo-tracking system. RESULTS: Flow-mediated dilatation at two minutes after cuff deflation was significantly lower in the bilateral notch group compared with the control group, 8.3% and 13.7%, respectively (P = 0.0007). The ability to sustain vasodilatation was reduced in the bilateral notch group (P = 0.02). Lower values of nitrite and nitrate in the plasma were found at 32 gestational weeks in the bilateral notch group than in the control group (mean 24.76 microM/L (SD 5.6) and 30.93 microM/L (8.2), respectively; P = 0.008). Nitrite and nitrate levels tended to be lower in the bilateral notch group even at 25 gestational weeks (29.45 microM/L (8.3) and 35.73 microM/L (11.0) in the bilateral notch and control group, respectively; P = 0.09). There was no difference in aortic, carotid or popliteal elasticity between the two groups. CONCLUSIONS: Healthy normotensive pregnant women with bilateral uterine artery notches show impaired endothelial function, but no differences in vascular mechanical properties.
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Potent enzyme inhibitors have long been recognized as powerful tools for assessing the physiological roles of enzymes and have led to the therapeutic drugs able to modulate their activities in vivo. However, to be valuable tools such inhibitors should be selective so that they do not interfere with other members of the particular enzyme family. Combinatorial chemistry has proven to be a novel approach for the identification of molecules with a desired selectivity profile from the libraries of several million compounds. In recent years it has been extensively used in conjunction with computational methods for the development of potent inhibitors of therapeutically interesting targets. This review describes the various structurally diverse enzyme inhibitors identified by screening combinatorial libraries of peptides and small organic molecules.
The effects of estrogen (E2), progesterone (P) and E2 and P (E2 + P) were examined on nitric oxide synthase (NOS) activity in both cytosolic and particulate fractions isolated from the rat uterus, vagina, cervix and cerebral cortex. Additionally plasma nitrate + nitrite (NO3 + NO2) levels were measured in control and hormone treated rats. Cytosolic NOS was the predominant form being approximately 80% of the total in all four tissues. NOS activity in both fractions from all tissues was highly Ca-dependent (> 90%). Among the reproductive tract tissues, the highest activity was found in the cervix, which was nearly 5- and 2-fold higher than the uterus and vagina, respectively. NOS activity in the cerebral cortex was by far the highest being 5-fold higher than in the cervix. In contrast to the cortex, E2 treatment downregulated cytosolic NOS in all reproductive tract tissue, but this was statistically significant in only uterus. When compared with E2 treated rats, P increased cytosolic NOS in uterus, vagina, and particulate NOS in the cervix. The data do not give any indication whatsoever of differential effects of P in the uterus and cervix.
The three separate proteins that make up anthrax toxin-protective antigen (PA), edema factor (EF) and lethal factor (LF) act in binary combinations to produce two distinct reactions in experimental animals: edema (PA+EF) and death (PA+LF). PA is believed to interact with a membrane receptor and, after proteolytic processing, to mediate endocytosis and subsequent translocation of EF or LF into the cytosol. Residues W346, M350, and L352 in loop 3 of domain 2 have been implicated to induce a conformational change when the pH is lowered from 7.4 to 6.5. Modification of the residues Trp (346), Met (350), and Leu (352) to alanine individually and all the three residues together to alanine residues resulted in the loss of cytotoxic activity in combination with LF. The mutant proteins were able to bind to the cell surface receptor, become cleaved by trypsin, bind LF, and oligomerize. These residues might play an important role in the membrane insertion of PA and/or translocation of LF/EF into the cytosol.
In continuation of an ongoing program on developing nonsteroidal pregnancy interceptives to be used as a menses regulating agent, a new class of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones series has been investigated for pregnancy interceptive activity in the hamster and rat. The compounds were administered (subcutaneous) on days 4-8 (hamster) and 5-9 (rat) post coitum (PC). The animals were laparotomized on days 12 (hamster) and 16 (rat) PC. To derive percent efficacy, the total number of implantation was divided by the number of normal and resorbed implantations. Among the 14 compounds evaluated, three were found to intercept pregnancy by 100%. Another compound was active by 75%, whereas the rest were inactive. None of the active compounds were, however, active in rat with this schedule. Results indicate that the observed species- and schedule-specific activity owes its origins to differences in the implantation physiology and early post-implantation development between the two species. The study, nevertheless, offers an insight to the new class of compounds for this activity.
A new series of compounds belonging to N,N'- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2-5a-f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity.
Anthrax is primarily a disease of herbivores caused by gram-positive, aerobic, spore-forming Bacillus anthracis. Humans are accidental hosts through the food of animal origin and animal products. Anthrax is prevelant in most parts of the globe, and cases of anthrax have been reported from almost every country. Three forms of the disease have been recognized: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). The major virulence factors of Bacillus anthracis are a poly-D glutamic acid capsule and a three-component protein exotoxin. The genes coding for the toxin and the enzymes responsible for capsule production are carried on plasmid pXO1 and pXO2, respectively. The three proteins of the exotoxin are protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). The toxins follow the A-B model with PA being the B moeity and LF/EF, the alternative A moeities. LF and EF are individually nontoxic, but in combination with PA form two toxins causing different pathogenic responses in animals and cultured cells. PA + LF forms the lethal toxin and PA + EF forms the edema toxin. During the process of intoxication, PA binds to the cell surface receptor and is cleaved at the sequence RKKR (167) by cell surface proteases such as furin generating a cell-bound, C-terminal 63 kDa protein (PA63). PA63 possesses a binding site to which LF or EF bind with high affinity. The complex is then internalized by receptor-mediated endocytosis. Acidification of the vesicle leads to instertion of PA63 into the endosomal membrane and translocation of LF/EF across the bilayer into the cytosol where they exert their toxic effects. EF has a calcium- and calmodulin-dependent adenylate cyclase activity. Recent reports indicate that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and 2), and this cleavage inactivates MAPKK1 and thus inhibits the mitogen-activated protein kinase signal transduction pathway. We describe in detail the studies so far done on unraveling the molecular mechanisms of pathogenesis of Bacillus anthracis.
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