Thin-layer chromatographic separation of regioselective and stereospecific androgen metabolites.
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Androstenedione↗
Biomedical subjects
A K Agrawal
Publications and source records attributed to A K Agrawal.
Neurobehavioral, neurochemical and electrophysiological studies in 6-hydroxydopamine lesioned and neural transplanted rats.
Unilateral injection of 6-hydroxydopamine (6-OHDA) into the caudate nucleus of rat caused degeneration of dopaminergic terminals, evidenced by significant (P < 0.05) elevation of spontaneous and drug-induced motor behaviour, enhanced DA receptor binding and significant increase in the neuronal firing rate of caudate neurons, suggesting supersensitivity of dopaminergic receptors. Eight weeks following the transplantation of embryonic cell suspensions from caudate at the lesioned site, a significant restoration of the enhanced 3H spiperone binding and neuronal activity of caudate neurons was observed in comparison with lesioned rats. These results clearly demonstrate that transplanted embryonic neuronal tissue at the lesioned site is capable of restoring the neuronal deficits caused by 6-OHDA as evidenced by significant amelioration in neurochemical, behavioral and electrophysiological alterations.
Action Potentials↗
Gender differences in drug metabolism regulated by growth hormone.
Gender differences in drug metabolism in rats have been known for more than 60 years when it was first reported that the much shorter duration of drug action in the male was due to the effects of testicular androgens. More recent studies have demonstrated that this sexual dimorphism in rat drug metabolism results from the differential expression of a possible dozen, or so sex-dependent hepatic forms of cytochrome P450. Moreover, it is the sexually dimorphic plasma profiles of growth hormone, and not androgens, that directly regulate the expression of these individual forms of hepatic cytochrome P450. Male rats secrete growth hormone in an "on-off" episodic rhythm in which interpulse periods contain no detectable levels of the hormone. Growth hormone secretion in the female rat is also pulsatile, but can be characterized as "continuous" since hormone levels are always present in the circulation. It would appear that the duration of the interpulse period is at least one "signal" in the growth hormone profile regulating hepatic expression of the sex-dependent forms of cytochrome P450, and thus establishing the gender differences in drug metabolism. The exaggerated gender differences in rat drug metabolism (i.e. 300-500%) have made it the standard, and understandably an ideal model in which to investigate the mechanisms regulating these dimorphisms. However, it is also possible that these studies have limited value when extrapolated to other species, such as humans, in which the magnitude of the sexual differences are much smaller, and the dimorphism may be reversed (F > M). In this regard, the mouse model, in which the sexual differences (F > M) in drug metabolizing enzyme activities vary by only 40-100%, are also regulated by sex-dependent plasma growth hormone profiles, and may be more representative of the vast majority of outbred species in which only subtle gender differences occur in drug metabolism.
Animals↗
Neonatal phenobarbital-induced defects in age- and sex-specific growth hormone profiles regulating monooxygenases.
Growth hormone was secreted in sexually dimorphic patterns in both 65- and 150-day-old rats (i.e., "on-off" pulsatile for males and "continuous" pulsatile for females), but as a result of a 200-400% increase in pulse levels the mean concentration of hormone in the circulation was about two times as great in the younger animals. Neonatal exposure to phenobarbital at anticonvulsant therapeutic doses for the rat reduced the pulse amplitudes of circulating growth hormone in both the 65- and 150-day-old males but only in the 65-day-old females. As expected, neonatal administration of the barbiturate produced an almost immediate increase in the activities of the hepatic monooxygenases, as measured by hexobarbital metabolism, which declined to noninduction levels after treatment ceased. Contrary to the well-known transient effects of phenobarbital, at around the time of sexual maturity when gender-dependent differences in hepatic monooxygenases appear (males > females), we observed a second "round" of enzyme induction that persisted in both sexes for the remainder of the study (180 days). Because growth hormone is the primary regulator of sex-dependent hepatic monooxygenases, we have proposed that the abnormal plasma growth hormone profiles produced by neonatal phenobarbital are responsible for the permanent induction of hepatic monooxygenases.
Aging↗
Altered platelet functions in non-insulin-dependent diabetes mellitus (NIDDM).
We have studied platelet aggregation and membrane fluidity, along with various biochemical parameters, in 19 non-insulin-dependent diabetes mellitus (NIDDM) patients prior to control of blood sugar, 11 patients after control of blood sugar, and 26 normal subjects. Platelet cholesterol: phospholipid ratio and basal levels of)[Ca+] were comparable between normal and uncontrolled NIDDM. Basal levels of malonaldehyde (MDA) and the levels of [Ca++]i, as well as MDA after the addition of arachidonic acid, were 2.5-fold, 5-fold, and 2.5-fold higher, respectively, in the uncontrolled NIDDM group than normals. Platelet aggregation in response to ADP (0.25 microM), epinephrine (1.25 microM), and arachidonic acid (0.25 mM) was significantly higher in uncontrolled NIDDM than in normals (75%, 40% and 52%, respectively). Platelet fluorescence polarization was also higher in NIDDM patients indicating decreased membrane fluidity in such patients as compared to normals. After control of blood sugar in 11 NIDDM patients, agonist-stimulated platelet aggregation and other biochemical parameters were comparable to normals.
Adult↗
Modulation of acrylamide-induced neurochemical and behavioral deficits by cerebellar transplants in rats.
Acrylamide (30 mg/kg body wt.) administered intraperitoneally daily to young adult male rats, five times a week for 3 consecutive weeks, affected the cerebellar functions, as exhibited by a significant reduction in rotarod performance, spontaneous locomotor activity, glutathione-S-transferase activity, and 3H-flunitrazepam binding in cerebellum. Transplantation of dissociated fetal cerebellar cells (E14) to cerebellum resulted in a significant recovery in behavioral and neurochemical parameters evaluated 9 weeks after transplantation. Light- and electron-microscopic studies confirmed the viability and specificity of cerebellar grafts.
Acrylamides↗
Evaluation of Manning's criteria in the diagnosis of irritable bowel syndrome.
Six symptoms of Manning et al are widely used in clinical practice to diagnose irritable bowel syndrome (IBS). We studied 123 patients to evaluate the diagnostic value of Manning's criteria, using a preformed bowel symptom questionnaire which included these six symptoms. This study included 65 patients with IBS, 35 patients with non-ulcer dyspepsia, 23 patients with organic diseases of colon and 45 healthy controls. Sensitivity of presence of three or more symptoms of Manning's criteria discriminating irritable bowel syndrome from all other groups was 66.1%. Manning's criteria discriminated irritable bowel syndrome from organic diseases of colon with specificity and positive predictive value of 66.9% and 82.6%. When irritable bowel syndrome was compared with non-ulcer dyspepsia and healthy controls, specificities of Manning's criteria were 91.4% and 93.3% and positive predictive values 93.4% and 93.4% respectively.
Adolescent↗
Phencyclidine binds to blood platelets with high affinity and specifically inhibits their activation by adrenaline.
The ion channel probe phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] selectively inhibited aggregation, secretion and ultrastructural changes in platelets induced by adrenaline, but did not affect activation induced by other common platelet agonists such as alpha-thrombin, ADP, collagen or ionophore A23187. [3H]PCP bound to platelets with high affinity (Kd 134 +/- 33 nM; 3600 +/- 1020 sites/platelet), as did the thienyl analogue [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine). PCP binding to platelets was increased 3-4-fold in N-methylglucamine buffer in the absence of Na+ ions. Binding was unaffected by haloperidol and was only weakly inhibited (EC50 10-20 microM), without significant stereoselectivity by the two sets of stereoselective ligands, dexoxadrol/levoxadrol and (+)MK801/(-)MK801. Binding of PCP was not competed for by adrenaline or yohimbine. Only the high-affinity binding of [3H]PCP to platelets was blocked by prior treatment of the platelets with the covalent affinity probe Metaphit, and these platelets no longer aggregated in response to adrenaline although they responded normally to alpha-thrombin, ADP and collagen. These results suggest that platelets contain high-affinity receptors for PCP that can modulate adrenaline-induced platelet activation.
Binding, Competitive↗
Ultrasonographic patterns of hepatobiliary mass lesions.
The study deals with an analysis of ultrasonographic (USG) patterns in 100 consecutive patients with hepatobiliary mass lesions. Amoebic liver abscess, carcinoma (CA) gall bladder and secondaries in liver comprised nearly 70% of cases. USG appearances in liver abscess, hepatoma, secondaries in liver and CA gall bladder were variable, but were characteristic in hydatid disease and congenital polycystic disease. Two patients with cholangiocarcinoma revealed dilated biliary channels with an intraluminal mass in common bile duct.
Adenoma, Bile Duct↗
Endoscopic sphincterotomy: preliminary experience at a university hospital.
Endoscopic sphincterotomy (ES) was attempted in 38 patients with biliary calculi. There were 21 patients (55.3%) with common bile duct (CBD) stones following cholecystectomy, 14 patients (36.8%) with intact gall bladder and 3 patients with retained CBD stones along with T tube in the early post-operative period. Endoscopic sphincterotomy was possible in all but one patient and duct clearance was attained in 34 (89.4%) patients. Spontaneous clearance of calculi occurred in 31 (81.6%) patients while 3 patients required instrumental extraction. Four patients failed to clear stones and required surgical intervention. Complications occurred in 4 (10.5%) patients--haemorrhage in two, pancreatitis and cholangitis in one each. One patient died of bleeding on the 4th day following ES while hemostasis was achieved in other after two units of blood. Other complications were managed conservatively without any mortality. Endoscopic sphincterotomy appears to be a simple, effective and safe therapeutic modality for the management of biliary calculi.
Adolescent↗
Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.
Binding of glutamate and muscimol (an agonist for GABAA receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the N-methyl-D-aspartate (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.
Ammonia↗
Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.
Plasma growth hormone (GH) profiles are sexually differentiated in many species and regulate the sex-dependence of peripubescent growth rates and liver function, including steroid hydroxylase cytochrome P450 expression, by mechanisms that are poorly understood. By use of an external pump to deliver to hypophysectomized rats pulses of rat GH of varying frequency and amplitude, a critical element for liver discrimination between male and female GH patterns was identified. Liver expression of the male-specific steroid 2 alpha (or 16 alpha)-hydroxylase P450, designated CYP2C11, was stimulated by GH at both physiological and nonphysiological pulse amplitudes, durations, and frequencies, provided that an interpulse interval of no detectable GH was maintained for at least 2.5 hr. This finding suggests that hepatocytes undergo an obligatory recovery period after stimulation by a GH pulse. This period may be required to reset a GH-activated intracellular signaling pathway or may relate to the short-term absence of GH receptors at the hepatocyte surface after a cycle of GH binding and receptor internalization. These requirements were distinguished from those necessary for the stimulation by GH of normal male growth rates in hypophysectomized rats, indicating that different GH responses and, perhaps, different GH-responsive tissues recognize distinct signaling elements in the sexually dimorphic patterns of circulating GH.
Activity Cycles↗
Differential effects of neonatally administered glutamate on the ultradian pattern of circulating growth hormone regulating expression of sex-dependent forms of cytochrome P450.
Neonatal male rats were treated with monosodium glutamate (MSG) at either 0.5, 1.0, 2.0, 3.0 or 4.0 mg/g body weight on alternate days during the first 9 days of life. As adults, rats were catheterized to obtain unstressed, serial blood samples for the determination of ultradian patterns of circulating growth hormone. In addition, the levels of drug-metabolizing enzymes (i.e. hexobarbital hydroxylase, cytochromes P450 and b5, NADPH-cytochrome P450 reductase and ethoxyresorufin O-deethylase) as well as sex-dependent forms of cytochrome P450 [i.e. male-dependent cytochromes P450 2c (IIC11), 2a (IIIA2) and RLM2 (IIA2) and female-dependent cytochromes P450 2d (IIC12) and 3 (IIA1)] and/or their catalytic activities were measured in the hepatic microsomes of the treated rats. The results demonstrated a dose-dependent, graded response to MSG treatment. As the dose of MSG increased from 0.5 to 4.0 mg, there was a concurrent decline in the amplitudes of the characteristically masculine, episodic bursts of growth hormone, until at the highest dose (4 mg), the pulses were no longer detectable. Associated with this dose-dependent alteration in the ultradian pattern of growth hormone secretion was a measurable change in the activities of the sex-dependent hepatic enzymes. As the pulse heights of the hormone declined to 10-20% of their normal amplitudes, the levels of the male-dependent enzymes (i.e. the drug-metabolizing enzymes, as well as the male forms of cytochrome P450 and their specific steroid hydroxylases) were maintained, and in some cases, exceeded the levels normally found in males. However, as the hormone pulse heights declined, there appeared an accompanying increase in the activities of some of the female-dependent enzymes. Finally, with the loss of all detectable levels of circulating growth hormone, the normal masculine profile of hepatic enzymes was reversed to an apparently normal (with the exception of cytochrome P450 2d) feminine profile. Summarizing, the results indicate that (1) neonatal administration of MSG can produce dose-dependent, graded, long-term developmental defects in the ultradian rhythm of circulating growth hormone and associated sex-dependent hepatic enzymes, and (2) while the male-dependent hepatic enzymes can be maintained at normal or even higher levels in the face of an up to 90% reduction in the pulse heights of plasma growth hormone, the activities of the female-dependent enzymes may begin to increase.
Animals↗
Sex- and dose-dependent effects of neonatally administered aspartate on the ultradian patterns of circulating growth hormone regulating hexobarbital metabolism and action.
Rats, neonatally treated with monosodium aspartate (MSA), exhibited developmental defects through adulthood that were characterized by stunted growth, obesity, and reduced size of the liver, kidney, adrenals, and pituitary. Adult male and female rats treated with 4 mg of MSA had no detectable plasma growth hormone as determined from serial blood samples taken every 15 min for 8 consecutive hr. Associated with this loss of circulating growth hormone in the males was a dramatic decline in in vivo and in vitro hexobarbital metabolism and hepatic cytochrome P450 to female levels. The loss of plasma growth hormone in the females had no effect on the already low levels of hepatic monooxygenases. At 2 mg/g body weight, MSA produced both sex- and dose-dependent effects that were far more subtle than the full-blown obesity and growth retardation associated with the larger 4-mg dose. While the mean concentration of circulating growth hormone was reduced 70 to 90% in 2-mg-MSA-treated rats, the sexually dimorphic, ultradian patterns of growth hormone secretion were undisturbed. Affected males continued to secrete a pulse of growth hormone every 3 hr, albeit at greatly reduced amplitudes, interposed by normally undetectable baselines. Similarly, 2-mg-MSA-treated females had greatly reduced mean levels of plasma growth hormone, but with the usual secretion of multiple pulses never dropping to baseline. Surprisingly, the sex-dependent, hepatic monooxygenases, which are normally regulated by the ultradian secretions of growth hormone, were unaffected by the 2-mg MSA treatment. Our results suggest that while an ultradian pulse of circulating growth hormone is necessary for the characteristically male profile of hepatic monooxygenases, neither the amplitude of the secretory peaks nor their total growth hormone content is critical.
Animals↗
Renaturalizing the sexually dimorphic profiles of circulating growth hormone in hypophysectomized rats.
Hypophysectomy resulted in a total elimination of measurable circulating growth hormone with an associated loss of body weight gain. The typical sexually dimorphic plasma growth hormone patterns: pulsatile profiles in male rats and tonic-like secretion in female rats, were lost. The male- and female-dependent profiles of plasma growth hormone, monitored from serial blood collections, were restored by administering the hormone through a single electrically controlled external pump attached to an indwelling catheter, and by implanting osmotic pumps intraperitoneally, respectively. Restoring the natural patterns of plasma growth hormone in animals devoid of pituitaries, re-initiated body growth. However, the body weight gains in both sexes of hypophysectomized rats were much greater when rat growth hormone was introduced to the animals in a masculine (pulsatile) pattern that appeared to be independent of pulse frequency, rather than in a continuous feminine profile. Subcutaneous injections, the most commonly reported method of administration, produced low-amplitude, long-lasting plasma peaks that were not as effective as pulse infusion in restoring growth. The procedure allows manipulation of the hormone profile (i.e. number of pulses/day, pulse amplitude, and through duration in the pulsatile pattern, and plasma concentration in the tonic pattern) in order to identify, and thus study the presumed salient components of the pattern regulating growth hormone responses.
Animals↗
Single cell protein production by Aspergillus niger and its evaluation.
An efficient cellulolytic mold, Aspergillus niger AS-101 was used to produce single cell protein from alkalitreated corn cobs. Microbial biomass obtained after 6 days of fermentation was evaluated for its various quality components. Single cell protein product contained 30.4% crude protein and had an essential amino acid profile featuring a high lysine content and appreciable amounts of methionine and tryptophane. Product contained 12.9% fat which was comprised of all essential fatty acids. Product has 77% of in vitro dry matter digestibility, hence can be used to supplement the feed components of ruminents and other monogastric animals.
Amino Acids, Essential↗
General and kinetic properties of endoglucanase from Aspergillus niger.
Endoglucanase of Aspergillus niger AS-101 was partially purified by ammonium sulphate fractionation and molecular sieving on Sephadex G-200. The enzyme was found to be unstable on storage, however, it received some protection on the addition of BSA, glycerol or sodium azide. Glycerol also protected the enzyme from inactivation due to freezing and thawing. Studies on the effect of thiol group reagents revealed the involvement of -SH group(s) at the active site of enzyme. The enzyme was a metallo-protein or it required certain metal ions for activation. A variety of modulators such as macroionic compounds and metal ions showed varying effects on the purified endoglucanase.
Aspergillus niger↗
Gastro-esophageal reflux disease (GERD): an appraisal of different tests for diagnosis.
Fifty symptomatic patients with GERD, 20 each of non ulcer dyspepsia (NUD) & duodenal ulcer (DU) and 10 healthy controls were subjected to various tests employed for diagnosis of GERD. Among these endoscopy and histology had highest sensitivities (92% & 91% respectively) followed by Bernstein's test (overall 88%; early positivity 72%) and oesophagography (70%). The specificities of various tests were: endoscopy (86%), histology (82%) and Bernstein's test (overall 80%; early positive 94%). The false positivity was mainly in DU subjects where majority (greater than 84%) had two or more of these tests offitive. Any two of the three tests (endoscopy, histology & Bernstein's test) in combination had a sensitivity of 80-91% and a specificity of 90-92%. Our observations suggest that these tests, particularly in combination, are useful in establishing the diagnosis of GERD and that subclinical oesophagitis in DU might be responsible for the false positivity of these tests.
Adolescent↗