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Biological Actions (biological + action)
Selected AbstractsElectronic structure and physicochemical properties of selected penicillinsINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 3 2007Catalina Soriano-Correa Abstract Traditionally, penicillins have been used as antibacterial agents due to their characteristics and widespread applications with few collateral effects, which have motivated several theoretical and experimental studies. Despite the latter, their mechanism of biological action has not been completely elucidated. We present a theoretical study at the Hartree,Fock and density functional theory (DFT) levels of theory of a selected group of penicillins such as the penicillin-G, amoxicillin, ampicillin, dicloxacillin, and carbenicillin molecules, to systematically determine the electron structure of full ,-lactam antibiotics. Our results allow us to analyze the electronic properties of the pharmacophore group, the aminoacyl side-chain, and the influence of the substituents (R and X) attached to the aminoacyl side-chain at 6, (in contrast with previous studies focused at the 3, substituents), and to corroborate the results of previous studies performed at the semiempirical level, solely on the ,-lactam ring of penicillins. Besides, several density descriptors are determined with the purpose of analyzing their link to the antibacterial activity of these penicillin compounds. Our results for the atomic charges (fitted to the electrostatic potential), the bond orders, and several global reactivity descriptors, such as the dipole moments, ionization potential, hardness, and the electrophilicity index, led us to characterize: the active sites, the effect of the electron-attracting substituent properties and their physicochemical features, which altogether, might be important to understand the biological activity of these type of molecules. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source] Hepatocyte Growth Factor Contributes to Fracture Repair by Upregulating the Expression of BMP Receptors,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2005Yuuki Imai MD Abstract Hepatocyte growth factor (HGF) is activated and the expression of BMP receptors (BMPRs) is induced around the fracture site during the early phase of fracture repair. HGF facilitates the expression of BMPRs in mesenchymal cells. This study suggests that HGF contributes to fracture repair by inducing the expression of BMPRs. Introduction: The precise mechanisms that control the upregulation of BMP, BMPRs, and other molecules involved in bone repair are not completely understood. In this study, we hypothesized that HGF, activated through the action of thrombin on the HGF activator, may enhance BMP action through the local induction of BMP or BMPRs. Materials and Methods: Callus samples from tibial fractures in mice were harvested for immunohistochemical analysis of HGF and phosphorylated c-Met, for in situ hybridization of BMPRs, and for real-time RT-PCR analysis for the expression of HGF, c-Met, and BMPRs. To study the changes in gene expression of BMPRs in response to HGF, C3H10T1/2 cells were cultured with or without HGF and harvested for real-time RT-PCR and for Western blot analysis. To evaluate the contribution of HGF to the biological action of BMP2, C3H10T1/2 cells and primary muscle-derived mesenchymal cells were precultured with HGF and cultured with BMP2. In addition, the expression of the luciferase gene linked to the Id1 promoter containing the BMP responsive element and alkaline phosphatase (ALP) activity were assayed. Results: Positive immunostaining of HGF and phosphorylated c-Met was detected around the fracture site at 1 day after the fracture was made. mRNA expression of BMPRs was increased 1 day after fracture and localized in mesenchymal cells at the fracture site. From an in vitro study, the expression of mRNA for BMPRs was elevated by treatment with HGF, but the expression of BMP4 did not change. Western blot analysis also showed the upregulation of BMPR2 by HGF treatment. The results from the luciferase and ALP assays indicated increased responsiveness to BMPs by treating with HGF. Conclusions: This study indicates that HGF is activated and expressed at the fracture site and that HGF induces the upregulation of BMPRs in mesenchymal cells. Furthermore, HGF may facilitate BMP signaling without altering the expression of BMP molecules. [source] Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegansAGING CELL, Issue 4 2009Jeong-Hoon Hahm Summary G-proteins, including GPA-3, play an important role in regulating physiological responses in Caenorhabditis elegans. When confronted with an environmental stimulus such as dauer pheromone, or poor nutrients, C. elegans receives and integrates external signals through its nervous system (i.e. amphid neurons), which interprets and translates them into biological action. Here it is shown that a suppressed neuronal cGMP level caused by GPA-3 activation leads to a significant increase (47.3%) in the mean lifespan of adult C. elegans through forkhead transcription factor family O (FOXO)-mediated signal. A reduced neuronal cGMP level was found to be caused by an increased cGMP-specific phosphodiesterase activity at the transcriptional level. Our results using C. elegans mutants with specific deficits in TGF-, and FOXO RNAi system suggest a mechanism in that cGMP, TGF-,, and FOXO signaling interact to differentially produce the insulin-like molecules, ins-7 and daf-28, causing suppression of the insulin/IGF-1 pathway and promoting lifespan extension. Our findings provide not only a new mechanism of cGMP-mediated induction of longevity in adult C. elegans but also a possible therapeutic strategy for neuronal disease, which has been likened to brain diabetes. [source] Prostaglandin EP2 receptor expression is increased in Barrett's oesophagus and oesophageal adenocarcinomaALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010P. JIMÉNEZ Aliment Pharmacol Ther,31, 440,451 Summary Background, Accumulating evidence suggests that cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is involved in oesophageal adenocarcinogenesis. PGE2 exerts its biological action by binding to specific receptors (EP1, EP2, EP3 and EP4). Aim, To investigate which PGE2 receptor subtypes regulate PGE2 signals in the oesophageal adenocarcinoma sequence. Methods, Expression was determined in oesophageal biopsies from 85 patients with oesophagitis, Barrett's metaplasia, intraepithelial neoplasia, oesophageal adenocarcinoma and normal oesophagus. Levels of mRNA and protein expression were determined by quantitative PCR, immunohistochemistry and western-blot. Expression of EP receptors was also determined in response to acid and bile exposure in the Barrett's adenocarcinoma cell line OE33. Results, All four EP receptors subtypes were expressed in human oesophageal tissues. COX-2 and, especially, EP2 were increased in the Barrett's metaplasia-intraepithelial neoplasia-adenocarcinoma sequence. Expression of the EP4 receptor protein was increased in oesophageal adenocarcinoma. In contrast, expression levels of COX-1 and EP3 receptor were decreased along the sequence. No differences in EP1 expression were found. Treatment with the bile acid deoxycholate increased COX-2, EP1, EP2 and EP4 expression in OE33 cells. Conclusions, Our data suggest that in addition to COX-2, EP2 and EP4 receptors could be a selective target in the prevention and/or treatment of the Barrett's-associated adenocarcinoma. [source] Crystallization and preliminary crystallographic analysis of a novel haemolytic lectin from the mushroom Laetiporus sulphureusACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2004José M. Mancheño The novel haemolytic lectin from the parasitic mushroom Laetiporus sulphureus (LSL) is a homotetramer (,140,kDa) composed of subunits associated by non-covalent bonds. It exhibits haemagglutination and haemolytic activities, both of which are inhibited by N -acetyllactosamine. The structural similarity found between LSL and the bacterial pore-forming toxins mosquitocidal toxin (MTX2) from Bacillus sphaericus and ,-toxin from Clostridium septicum points to a mechanism of biological action involving the formation of pores in the target membranes. LSL has been crystallized using the hanging-drop vapour-diffusion method at 291,K. Diffraction-quality hexagonal crystals have unit-cell parameters a = b = 101.8, c = 193.9,Å and belong to space group P6322. A 2.7,Å native data set was collected with an Rmerge of 9.2%. [source] Macrophage-stimulating protein is a neurotrophic factor for embryonic chicken hypoglossal motoneuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2002Oliver Schmidt Abstract Macrophage-stimulating protein (MSP) exerts a variety of biological actions on many cell types, but has no known functions in the brain. MSP is structurally related to hepatocyte growth factor (HGF), another pleiotropic factor whose many functions include promoting neuronal survival and growth. To investigate whether MSP is also capable of acting as a neurotrophic factor, we purified hypoglossal motoneurons from the embryonic chicken hindbrain because these neurons are known to express the MSP receptor tyrosine kinase RON. MSP promoted the in vitro survival of these neurons during the period of naturally occurring neuronal death and enhanced the growth of neurites from these neurons. MSP mRNA was detected in the developing tongue whose musculature is innervated by hypoglossal neurons. Our study demonstrates that MSP is a neurotrophic factor for a population of developing motoneurons. [source] Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patientsINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Srilatha Swami Abstract Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE2 by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment. © 2008 Wiley-Liss, Inc. [source] Renin-angiotensin system revisitedJOURNAL OF INTERNAL MEDICINE, Issue 3 2008F. Fyhrquist Abstract. New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2,8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3,8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1,7 (Ang 1,7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed. [source] Hydroxytyrosol induces antioxidant/detoxificant enzymes and Nrf2 translocation via extracellular regulated kinases and phosphatidylinositol-3-kinase/protein kinase B pathways in HepG2 cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 7 2010María Angeles Martín Abstract Hydroxytyrosol (HTy) is a natural polyphenol abundant in olive oil, which possesses multiple biological actions. Particularly, HTy has cytoprotective activity against oxidative-stress-induced cell damage, but the underlying mechanisms of action remain unclear. Here, we have investigated the molecular mechanism involved in the protection exerted by HTy on tert -butyl hydroperoxide-induced damage in human HepG2 liver cells. Treatment of HepG2 cells with HTy increased the expression and the activity of glutathione-related enzymes such as glutathione peroxidase, glutathione reductase and glutathione S -transferase. HTy also induced the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Moreover, two important signalling proteins involved in Nrf2 translocation, the protein kinase B and the extracellular regulated kinases, were also activated by HTy. Further studies with specific inhibitors confirmed that both molecular pathways are critical for the nuclear translocation of Nrf2, the increased enzyme expression and activity and the beneficial effect against oxidative stress induced by HTy. In conclusion, together with the inherent radical scavenging activity of HTy, our results provide an additional mechanism of action to prevent oxidative stress damage through the modulation of signalling pathways involved in antioxidant/detoxifying enzymes regulation. [source] Protective effect of resveratrol on markers of oxidative stress in human erythrocytes subjected to in vitro oxidative insultPHYTOTHERAPY RESEARCH, Issue S1 2010Kanti Bhooshan Pandey Abstract Resveratrol is a natural polyphenolic compound found largely in the skin of red grapes. Growing evidence suggests that resveratrol may play an important role in the prevention of many human diseases. Many of the biological actions of this polyphenol have been attributed to its antioxidant properties. The present study was undertaken to evaluate the effect of resveratrol on intracellular reduced glutathione (GSH) and membrane sulphydryl groups in erythrocytes subjected to oxidative stress in vitro by incubating with t-BHP (10 µm). The study was aimed to test the efficacy of the antioxidant effect of resveratrol on human erythrocytes. Subjecting erythrocytes to oxidative stress (in vitro) by incubating them with t-BHP (10 µm) caused a significant decrease in the intracellular GSH level and membrane ,SH content compared with basal values. Incubation of erythrocytes/membranes with resveratrol (1,100 µm final conc) resulted in significant protection against the t-BHP-induced oxidative stress as evidenced by the increase in GSH level and membrane ,SH content. It was observed that the effect of resveratrol is dose/concentration and time-dependent. Since resveratrol is naturally present in many fruits and vegetables, a diet rich in resveratrol may provide protection against degenerative diseases. Copyright © 2009 John Wiley & Sons, Ltd. [source] Flavonoids from Chinese Viscum coloratum: antiarrhythmic efficacy and ionic mechanismsPHYTOTHERAPY RESEARCH, Issue 12 2006Chu Wen-Feng Abstract Viscum coloratum flavonoids (VCF) have been demonstrated to produce a variety of biological actions. An accumulating line of evidence supported the view that VCF may exert protective effects on the cardiovascular system. The aim of the study was to assess the antiarrhythmic activity as well as the electrophysiological properties of VCF. The antiarrhythmic effects of VCF were observed in a rat model of arrhythmia induced by aconitine. VCF significantly and dose-dependently increased the dosage of aconitine required to induce the arrhythmia indexes. Electrophysiological experiment revealed that VCF shortened APD through inhibition of ICa-L. Copyright © 2006 John Wiley & Sons, Ltd. [source] O -Glycosylated 24,kDa human growth hormone has a mucin-like biantennary disialylated tetrasaccharide attached at Thr-60PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 13 2009Juan J. Bustamante Abstract MS was used to characterize the 24,kDa human growth hormone (hGH) glycoprotein isoform and determine the locus of O -linked oligosaccharide attachment, the oligosaccharide branching topology, and the monosaccharide sequence. MALDI-TOF/MS and ESI-MS/MS analyses of glycosylated 24,kDa hGH tryptic peptides showed that this hGH isoform is a product of the hGH normal gene. Analysis of the glycoprotein hydrolysate by high-performance anion-exchange chromatography with pulsed amperometric detection and HPLC with fluorescent detection for N -acetyl neuraminic acid (NeuAc) yielded the oligosaccharide composition (NeuAc2, N -acetyl galactosamine1, Gal1). After ,-elimination to release the oligosaccharide from glycosylated 24,kDa hGH, collision-induced dissociation of tryptic glycopeptide T6 indicated that there had been an O -linked oligosaccharide attached to Thr-60. The sequence and branching structure of the oligosaccharide were determined by ESI-MS/MS analysis of tryptic glycopeptide T6. The mucin-like O -oligosaccharide sequence linked to Thr-60 begins with N -acetyl galactosamine and branches in a bifurcated topology with one appendage consisting of galactose followed by NeuAc and the other consisting of a single NeuAc. The oligosaccharide moiety lies in the high-affinity binding site 1 structural epitope of hGH that interfaces with both the growth hormone and the prolactin receptors and is predicted to sterically affect receptor interactions and alter the biological actions of hGH. [source] Peptide products of the afp-6 gene of the nematode Ascaris suum have different biological actionsTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 5 2007Joanne Y. Yew Abstract Matrix-assisted laser desorption/ionization time-of-flight and tandem time-of-flight (MALDI-TOF and MALDI-TOF/TOF) mass spectrometry were used to sequence and localize three novel, related neuropeptides in the nervous system of the nematode Ascaris suum, AMRNALVRFamide (AF21), NGAPQPFVRFamide (AF22), and SGMRNALVRFamide (AF23). The amino acid sequences were used to clone a novel neuropeptide gene (afp-6) that encodes a precursor bearing a single copy of each of the peptides. In situ hybridization and immunocytochemistry revealed that both the transcript and the peptides are expressed in a single cell in the ventral ganglion. Pharmacological studies of intact nematodes injected with these peptides, as well as physiological studies of responses to them in muscle tissue, motor neurons, and the pharynx, reveal that these peptides have potent bioactivity in the locomotory and feeding systems. Further exploration of their effects may contribute to our understanding of neuropeptide modulation of behavior and also to the development of compounds with anthelmintic relevance. J. Comp. Neurol. 502:872,882, 2007. © 2007 Wiley-Liss, Inc. [source] Not just angiogenesis,wider roles for the angiopoietinsTHE JOURNAL OF PATHOLOGY, Issue 4 2003Pamela F Jones Abstract Since the discovery of the angiopoietins, much interest has been focused on their biological actions and their potential use as therapeutic targets. It is generally accepted that the angiopoietins play an important role in angiogenesis and hence are described as angiogenic factors. However, it is becoming increasingly clear that this is not their only role and it is likely that the angiopoietins have important roles in a wider range of biological and pathological functions. Copyright © 2003 John Wiley & Sons, Ltd. [source] Essential fatty acids: biochemistry, physiology and pathologyBIOTECHNOLOGY JOURNAL, Issue 4 2006Undurti N. Das Dr. Abstract Essential fatty acids (EFAs), linoleic acid (LA), and ,-linolenic acid (ALA) are essential for humans, and are freely available in the diet. Hence, EFA deficiency is extremely rare in humans. To derive the full benefits of EFAs, they need to be metabolized to their respective long-chain metabolites, i.e., dihomo-,-linolenic acid (DGLA), and arachidonic acid (AA) from LA; and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ALA. Some of these long-chain metabolites not only form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), but also give rise to lipoxins (LXs) and resolvins that have potent anti-inflammatory actions. Furthermore, EFAs and their metabolites may function as endogenous angiotensin-converting enzyme and 3-hdroxy-3-methylglutaryl coenzyme A reductase inhibitors, nitric oxide (NO) enhancers, anti-hypertensives, and anti-atherosclerotic molecules. Recent studies revealed that EFAs react with NO to yield respective nitroalkene derivatives that exert cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors. The metabolism of EFAs is altered in several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, schizophrenia, Alzheimer's disease, atherosclerosis, and cancer. Thus, EFAs and their derivatives have varied biological actions and seem to be involved in several physiological and pathological processes. [source] Cyclopentenone Eicosanoids as Mediators of Neurodegeneration: A Pathogenic Mechanism of Oxidative Stress-Mediated and Cyclooxygenase-Mediated NeurotoxicityBRAIN PATHOLOGY, Issue 2 2005Erik S. Musiek The activation of cyclooxygenase enzymes in the brain has been implicated in the pathogenesis of numerous neurodegenerative conditions. Similarly, oxidative stress is believed to be a major contributor to many forms of neurodegeneration. These 2 distinct processes are united by a common characteristic: the generation of electrophilic cyclopentenone eicosanoids. These cyclopentenone compounds are defined structurally by the presence of an unsaturated carbonyl moiety in their prostane ring, and readily form Michael adducts with cellular thiols, including those found in glutathione and proteins. The cyclopentenone prostaglandins (PGs) PGA2, PGJ2, and 15-deoxy-,12,14 PGJ2, enzymatic products of cyclooxygenase-mediated arachidonic acid metabolism, exert a complex array of potent neurodegenerative, neuroprotective, and anti-inflammatory effects. Cyclopentenone isoprostanes (A2/J2 -IsoPs), products of non-enzymatic, free radical-mediated arachidonate oxidation, are also highly bioactive, and can exert direct neurodegenerative effects. In addition, cyclopentenone products of docosahexaenoic acid oxidation (cyclopentenone neuroprostanes) are also formed abundantly in the brain. For the first time, the formation and biological actions of these various classes of reactive cyclopentenone eicosanoids are reviewed, with emphasis on their potential roles in neurodegeneration. The accumulating evidence suggests that the formation of cyclopentenone eicosanoids in the brain may represent a novel pathogenic mechanism, which contributes to many neurodegenerative conditions. [source] Robert F. Furchgott, Nobel laureate (1916,2009) , a personal reflectionBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009William Martin Robert F. Furchgott, pharmacologist and joint winner of the Nobel Prize for Medicine or Physiology (1998) died on the 12th of May 2009 aged 92. By unlocking the astonishingly diverse biological actions of nitric oxide, Furchgott leaves behind a rich legacy that has both revolutionized our understanding of human physiology and stimulated new and exciting opportunities for drug development in a wide range of pathological conditions. In this article, William Martin, who worked with Furchgott for 2 years (1983,1985), following the exciting discovery of endothelium-derived relaxing factor/nitric oxide, pays tribute to his close friend and colleague. [source] Structure,Activity Studies on Suramin Analogues as Inhibitors of NAD+ -Dependent Histone Deacetylases (Sirtuins)CHEMMEDCHEM, Issue 10 2007Johannes Trapp Dr. Abstract Suramin is a symmetric polyanionic naphthylurea originally used for the treatment of trypanosomiasis and onchocerciasis. Suramin and diverse analogues exhibit a broad range of biological actions in,vitro and in,vivo, including, among others, antiproliferative and antiviral activity. Suramin derivatives usually target purinergic binding sites. Class,III histone deacetylases (sirtuins) are amidohydrolases that require nicotinamide adenine dinucleotide (NAD+) as a cofactor for their catalytic mechanism. Deacetylation of the target proteins leads to a change in conformation and alters the activity of the proteins in question. Suramin was reported to inhibit human sirtuin,1 (SIRT1). We tested a diverse set of suramin analogues to elucidate the inhibition of the NAD+ -dependent histone deacetylases SIRT1 and SIRT2 and discovered selective inhibitors of human sirtuins with potency in the two-digit nanomolar range. In addition, the structural requirements for the binding of suramin derivatives to sirtuins were investigated by molecular docking. The recently published X-ray crystal structure of human SIRT5 in complex with suramin and the human SIRT2 structure were used to analyze the interaction mode of the novel suramin derivatives. [source] MODULATORY EFFECT OF NARINGENIN ON N -METHYL- N, -NITRO- N -NITROSOGUANIDINE- AND SATURATED SODIUM CHLORIDE-INDUCED GASTRIC CARCINOGENESIS IN MALE WISTAR RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008Ekambaram Ganapathy SUMMARY 1Naringenin is a flavanone that is believed to have many biological actions, including as an anti-oxidant, free radical scavenger and an antiproliferative agent. The global incidence of gastric carcinoma is increasing rapidly, more than for any other cancer. Therefore, in the present study, we tested the effects of naringenin on gastric carcinogenesis induced by N -methyl- N,-nitro- N -nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl) in rats. 2Male Wistar rats were divided into five groups and treated over a period of 20 weeks as follows: (i) a control group given corn oil (1 mL/rat, p.o.) daily 20 weeks; (ii) 200 mg/kg, p.o., MNNG on Days 0 and 14 with S-NaCl (1 mL/rat) administered twice a week for the first 3 weeks; (iii) 200 mg/kg, p.o., MNNG on Days 0 and 14, with naringenin (200 mg/kg, p.o., daily) treatment for the entire 20 weeks; (iv) 200 mg/kg, p.o., MNNG on Days 0 and 14, with naringenin treatment (200 mg/kg, p.o., daily) initiated from 6 to 20 weeks; (v) 200 mg/kg, p.o., naringenin alone daily for 20 weeks. 3In Group II rats in which gastric cancer was inducted with MNNG and S-NaCl, there was a significant increase in hydrogen peroxide and lipid peroxidation levels, with decreases in reduced glutathione, oxidized glutathione, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase. In addition, in Group II rats with gastric cancer, there were significant increases in the activity of cytochrome P450, cytochrome b5 and NADPH cytochrome c reductase, with concomitant decreases in the activity of the phase II enzymes glutathione S-transferase and UDP-glucuronosyl transferase. Naringenin treatment (Groups III and IV) restored enzyme activity to near control levels. 4These results indicate that naringenin has a chemopreventive action against MNNG-induced gastric carcinoma in experimental rats. [source] Ghrelin: more than a natural GH secretagogue and/or an orexigenic factorCLINICAL ENDOCRINOLOGY, Issue 1 2005E. Ghigo Summary Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ,the' or just ,a' GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives. [source] | ||||||||||||||||||||||||||||