Biomedical subjects
Publications and source records attributed to C V Rao.
The total synthesis of heliannone A (1) and (R,S)-heliannone B (2), two bioactive flavonoids originally isolated from Helianthus annuus cultivars, is described.
Even though there were hints, it was not until 1986 that a number of laboratories worldwide began to demonstrate unequivocally the presence and functions of luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptors in various female and male nongonadal tissues. There was no species specificity but there was tissue specificity in the nongonadal LH/hCG receptor distribution. Nongonadal receptor levels were lower but they were regulated and processed and used signaling mechanisms similarly to gonadal receptors. Although still greater understanding is needed, gains made in the last decade demonstrate that nongonadal actions of LH/hCG are physiologically important and may have relevance to better understanding several diseases and their treatment. A recently developed LH receptor knockout model has begun to reaffirm and extend the importance of nongonadal LH signaling in the body.
The role of human chorionic gonadatropin (hCG) in the maintenance of early pregnancy is well known. Recent data suggests that hCG may play a role in the maintenance of the later stages of pregnancy as well, by directly and indirectly promoting uterine quiescence. If hCG acts as an endogenous tocolytic in normal pregnancy, then it may be an ideal candidate for therapy of preterm labor as well. We present compelling in vitro as well as in vivo data, which support the role of hCG in the maintenance of normal uterine quiescence. Additionally, we will present in vivo and in vitro data that confirms the ability of hCG to directly promote relaxation of uterine contractions. This review provides a basis for future study of the use of hCG in clinical obstetrics. Given the limited effectiveness of tocolytic therapies available at the time, hCG may provide a promising pharmacological approach to the pervasive problem of preterm labor in human pregnancy. While further work is needed, initial data strongly support this novel use of hCG in clinical obstetrics.
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) share a common receptor. LH/hCG receptors, located in the vascular smooth muscle and endothelial cells of uterine blood vessels, are most numerous in smaller intramyometrial vessels and are cyclic in nature. There is a correlation between hCG levels and decreased uterine vascular resistance in humans, and in pseudopregnant rats, hCG decreases uterine blood flow. We found that systemic administration of hCG to cycling rats reduced uterine blood flow within 20 minutes on all days of the estrous cycle when flow was measured via the radioactive microsphere method. This effect was absent in ovariectomized rats. To determine the response to hCG at the microvascular level, we measured uterine arteriolar diameters in vivo via videomicroscopy after direct application or injection of hCG in rats on diestrus-1, diestrus-2, and proestrus. When hCG was suffused over the uterus (20 IU/60 mL), the uterine arterioles in diestrus (1 and 2) rats dilated but in proestrus rats were constricted. Neither response was altered in animals whose ovaries were removed 3 hours previously. An intraperitoneal injection of hCG (50 IU) caused uterine arteriolar constriction in diestrus-2 and proestrus animals but no change in diestrus-1. In ovariectomized rats, uterine arteriolar constriction following hCG injection was absent. Thus, the response of the uterine vasculature is not only cycle day dependent but also dependent on the route of administration. The effect of hCG on uterine blood flow in the rat may be a direct action of hCG, or it could be secondary to the release of other vasoactive substances known to be released by hCG. hCG might also alter blood flow by inducing angiogenesis.
Luteinizing hormone (LH) and its homologue, human chorionic gonadotropin (hCG), are able to elicit multiple effects in the central nervous system (CNS) through binding to their receptors. Specific receptors for LH/hCG have been identified in the hippocampus, dentate gyrus, hypothalamus, cortex, brain stem, area postrema, cerebellum, choroid plexus, ependymal cells, glial cells, neural retina, pituitary gland, and neuron processes of the spinal cord. Neurotropic effects of LH and hCG have been demonstrated in fetal rat brain, where the expression of LH/hCG receptors is developmentally regulated. Administration of hCG has been found to be beneficial in restoration of transected spinal cord function in rats. In adult rat brain, LH and hCG are involved in the feedback regulation of synthesis and secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus and LH in the pituitary gland. LH and hCG also induce several behavioral and other changes that are associated with the hippocampus, which contains the highest density of LH/hCG receptors. Many of the behavioral changes induced by hCG in rats parallel those in pregnant women. Some of these behavioral effects are correlated with changes of eicosanoid metabolism induced by LH and hCG in the brain. The LH/hCG receptors present in the choroid plexus, brain vessels, and perihypophyseal vascular complex may be involved in the modulation of transport of LH, hCG, and GnRH into the CNS. Thus, the CNS is one of the specific target tissues for LH and hCG, by which LH/hCG act as pleiotropic hormones that regulate several reproduction-related as well as reproduction-nonrelated functions in the CNS.
Bacopa monniera Wettst. (BM, syn. Herpestis monniera L; Scrophulariaceae), is an Ayurvedic drug used as a rasayana. Its fresh juice was earlier reported to have significant antiulcerogenic activity. In continuation, methanolic extract of BM (BME) standardized to bacoside-A content (percentage-38.0 +/- 0.9), when given in the dose of 10-50 mg/kg, twice daily for 5 days, showed dose-dependent anti-ulcerogenic on various gastric ulcer models induced by ethanol, aspirin, 2 h cold restraint stress and 4 h pylorus ligation. BME in the dose of 20 mg/kg, given for 10 days, twice daily showed healing effects against 50% acetic acid-induced gastric ulcers. Further work was done to investigate the possible mechanisms of its action by studying its effect on various mucosal offensive acid-pepsin secretion and defensive factors like mucin secretion, mucosal cell shedding, cell proliferation and antioxidant activity in rats. BME 20 mg/kg showed no effect on acid-pepsin secretion, increased mucin secretion, while it decreased cell shedding with no effect on cell proliferation. BME showed significant antioxidant effect per se and in stressed animals. Thus, the gastric prophylactic and curative effects of BME may be due to its predominant effect on mucosal defensive factors.
A new naphthoquinone 1 together with 7-hydroxycadalene (2) and 8-formyl-7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4-naphthoquinone (3) were isolated from the heartwood of Bombax malabaricum. The new naphthoquinone was characterized as 7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4-naphthoquinone (1) based on spectral and chemical studies.
A number of technological innovations are yielding unprecedented data on the networks of biochemical, genetic, and biophysical reactions that underlie cellular behavior and failure. These networks are composed of hundreds to thousands of chemical species and structures, interacting via nonlinear and possibly stochastic physical processes. A central goal of modern biology is to optimally use the data on these networks to understand how their design leads to the observed cellular behaviors and failures. Ultimately, this knowledge should enable cellular engineers to redesign cellular processes to meet industrial needs (such as optimal natural product synthesis), aid in choosing the most effective targets for pharmaceuticals, and tailor treatment for individual genotypes. The size and complexity of these networks and the inevitable lack of complete data, however, makes reaching these goals extremely difficult. If it proves possible to modularize these networks into functional subnetworks, then these smaller networks may be amenable to direct analysis and might serve as regulatory motifs. These motifs, recurring elements of control, may help to deduce the structure and function of partially known networks and form the basis for fulfilling the goals described above. A number of approaches to identifying and analyzing control motifs in intracellular networks are reviewed.
The data in this report clearly indicate that the form (structure) in which selenium is used is the most critical determinant of success in future clinical trials. Synthetic organoselenium compounds can be tailored to achieve greater chemopreventive efficacy with minimal toxic side effects by structural modifications. We demonstrated that 1,4-phenylenebis(methylene)selenocyanate is a powerful chemopreventive agent against the development of experimental colon, mammary, lung, and oral carcinogenesis. On the basis of metabolism studies of organoselenium compounds and those reported in the literature, our working hypothesis is that aromatic selenol intermediates are important entities in cancer chemoprevention. In addition, we suggest that 1,4-phenylenebis(methylene)selenocyanate not only serves as a chemopreventive agent, but it may be valuable in preventing metastatic diseases in future studies in the clinic.
The functional receptors that bind human CG (hCG) and LH have recently been identified in a number of nongonadal human tissues. The current experiments tested the hypothesis that human ejaculated sperm may also contain them. The data revealed that they, indeed, do as determined by the presence of receptor messenger RNA and receptor protein that can bind (125)I-hCG. The receptors were functional, as indicated by an increase in cyclic AMP levels and activation of sperm protein kinase A following treatment with hCG or LH. Treatment with these hormones, on the other hand, had no effect on sperm protein kinase C activity. Now that the functional LH/hCG receptors are found in human sperm, it is important to determine whether hCG treatment could improve the outcome of infertility procedures.
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LH/hCG receptors were disrupted by gene targeting in embryonic stem cells. The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testosterone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdominal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round spermatid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in testes. However, it caused a dramatic decrease in StAR and estrogen receptor-alpha (ERalpha) mRNA levels and an increase in ERbeta mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phenotype and biochemical changes were a consequence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained infertile. It is anticipated that the LH receptor knockout animals will increase our current understanding of gonadal and nongonadal actions of LH and hCG.
Two new 2'-oxygenated flavones, 5,2',6'-trihydroxy-7-methoxyflavone (3) and skullcapflavone I 2'-O-beta-D-(4"-E-cinnamyl) glucopyranoside (5), together with three known flavones, 7-O-methylwogonin (1), skullcapflavone I (2) and skullcapflavone I 2'-O-beta-D-glucopyranoside (4) were isolated from the whole plant of Andrographis elongata, and the structures were elucidated by FAB-MS and one- and two-dimensional (1D- and 2D)-NMR spectral studies including 1H-1H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and rotating frame Overhauser enhancement spectroscopy (ROESY) experiments, and chemical studies.
Metabolic epidemiological studies in humans and laboratory animal models demonstrate that consumption of diets high in fat and low in fiber excrete increased levels of 1,2-diacyl-sn-glycerol (DAG) and secondary bile acids such as deoxycholic acid (DA) and lithocholic acid that have been shown to promote colon carcinogenesis. The secondary bile acids and DAG have been shown to activate protein kinase C (PKC) and induce colonic cell proliferation. A large body of evidence indicates that iNOS, an inducible isoform of nitric oxide synthase, is over-expressed in human colon adenomas and in chemically-induced colon tumors of laboratory animals. However, the precise cascade of intracellular events that leads to the iNOS over-expression remains to be fully explored. In this study, we investigated the relationship between induction of iNOS and activation of the PKC pathway by DAG and DC, in an in vitro system using the rat intestinal cell line, RIE-1. As an initial step, we determined whether lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) modulate iNOS protein expression in RIE-1 cells. Treatment of RIE-1 cells with LPS and PMA for 4 h significantly elevated the iNOS protein expression. The induction of iNOS by the treatment with LPS/PMA was concentration- and time-dependent. Treatment with LPS/DAG or LPS/DC also caused iNOS over-expression in a concentration- and time-dependent fashion suggesting that DAG and DC induce iNOS activity in intestinal cells. Pretreatment with specific PKC inhibitors, bisindolylmaleimide I or Gö 6976, inhibited LPS/PMA, LPS/DAG, or LPS/DC-induced iNOS expression and activity. Extracts of the cells treated with LPS/PMA, LPS/DAG or LPS/DC had a high iNOS activity compared to that of control (p<0.04 to p<0.0001). Taken together, our data suggest a possible role of colon tumor promoters, DAG and DC, for iNOS over-expression through activation of the PKC pathway.
Centella asiatica is commonly mentioned as a Rasayana in Ayurveda, an ancient system of Indian medicine for various ailments including abdominal disorders. Rasayanas have been advocated for use in rejuvenation therapy. The present study was conducted to evaluate the possible anti-ulcerogenic activity of fresh juice of C. asiatica (CAJ) against ethanol-, aspirin-, cold-restraint stress- and pyloric ligation induced gastric ulcers in rats. The drug given orally in doses of 200 and 600 mg/kg twice daily for five days, showed significant protection against all the above experimental ulcer models and the results were comparable with those elicited by sucralfate (SF, 250 mg/kg, p.o., BD x 5 days). CAJ showed little or no effect on offensive acid-pepsin secretion. However, at 600 mg/kg CAJ significantly increased gastric juice mucin secretion and increased the mucosal cell glycoproteins signifying increase in cellular mucus. It also decreased cell shedding indicating fortification of mucosal barrier. Thus, the ulcer protective effect of CAJ may be due to strengthening of the mucosal defensive factors.
Convolvulus pluricaulis is an indigenous plant commonly mentioned in Ayurveda, an ancient system of Indian medicine, as a rasayana which is mainly advocated for use in rejuvenation therapy. The present study was conducted to evaluate the potential anti-ulcerogenic effect of juice of fresh whole plants of C. pluricaulis (CPJ) against various experimental gastric ulcer models induced by ethanol, aspirin, 2 hr cold restraint stress and 4 hr pyloric ligation in rats. The drug was given orally twice daily for five days in the doses of 375 and 750 mg/kg body weight. CPJ showed anti-ulcerogenic effect at both doses in all the experimental gastric ulcer models and was comparable to the reference drug sucralfate (250 mg/kg). Gastric juice secretion and mucosal studies were undertaken to find out the possible mechanism of action of antiulcer effect by studying its effects both on offensive and defensive mucosal factors. The antiulcerogenic effect of CPJ was found to be due to augmentation of mucosal defensive factors like mucin secretion, lifespan of mucosal cells and glycoprotiens rather than on the offensive factors like acid-pepsin.
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Studies with plantain banana (Musa sapientum var. paradisiaca) have indicated its ulcer protective and healing activities through its predominant effect on various mucosal defensive factors [Sanyal et.al, Arch Int Pharmacodyn, 149 (1964) 393; 155 (1965) 244]. Oxidative stress and Helicobactorpylori colonization are considered to be important factors in the pathogenesis of gastric ulcers. In the present study methanolic extract of plantain banana pulp (BE) was evaluated for its (i) antiulcer and antioxidant activities in 2 hr cold restraint stress and (ii) anti-H.pylori activity in vitro. The extract (BE, 50 mg/kg, twice daily for 5 days) showed significant antiulcer effect and antioxidant activity in gastric mucosal homogenates, where it reversed the increase in ulcer index, lipid peroxidation and super oxide dismutase values induced by stress. However it did not produce any change in catalase values, which was significantly decreased by stress. Further, in the in vitro study. BE (0.32-1,000 microg/ml) did not show any anti-H.pylori activity. The results suggest absence of anti-H. pyloric activity of methanolic extract of banana in vitro and its antioxidant activity may be involved in its ulcerprotective activity.