Role Of Prostaglandins Research Articles

Gastroprotection of Suaveolol, Isolated from Hyptis suaveolens, against Ethanol-Induced Gastric Lesions in Wistar Rats: Role of Prostaglandins, Nitric Oxide and Sulfhydryls

Hyptis suaveolens is a medicinal plant that is, according to traditional medicine, considered useful in the treatment of gastric ulcers. Although its gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim of the present study was to identify at least one active compound potentially responsible for the gastroprotective activity of H. suaveolens by using a bioassay guided study with an ethanol-induced gastric ulcer experimental model in rats. The results show that the hexane extract had protective activity (close to 70% when using doses between 10 and 100 mg/kg), and that the compound suaveolol, isolated from this extract, was one of the active gastroprotective agents. This is the first report about the gastroprotective activity of suaveolol. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 12.6, 21.3, 39.6 and 70.2% gastroprotection respectively. The effect elicited by suaveolol (at 100 mg/kg) was attenuated by pretreatment with either NG-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of this compound involves NO, prostaglandins and sulfhydryl groups.

Study of long effects of administration of aspirin (acetylsalicylic acid) on bone in broiler chickens

Tibial dyschondroplasia (TD) is considered to be a major production-related health and welfare problem in meat-type chickens and turkeys. One cause of such poultry leg problems is traced to a defect arising in the growing end of leg bones which partially fail to become bone, making the ends prone to breakage and infection. In this study, we investigate the possible role of prostaglandins and their deleterious effects on TD in broiler chickens, experimentally receiving dietary administration of aspirin. Fourteen male Ross chickens aged 1 day were divided into two groups to receive either only water or aspirin (400 mg/L) in the drinking water. Chickens were observed for clinical signs of lameness twice daily. None of the chickens in treatment and control groups showed clinical signs of lameness. However, histopathologic observations of tibiotarsal bones in treatment group showed vascular abnormality along with degenerative changes in chondrocytes at growth pales, attributed to over mineralization of the bone. In addition, alkaline phosphatase activity in treatment groups was decreased, suggesting TD in chickens receiving aspirin. In conclusion, our study showed that dietary administration of aspirin at dose of 400 mg/L for 21 days induced histopathological changes in broiler chickens. Inhibition of prostaglandins seems to contribute majorly with disruption of normal chondrocyte differentiation in growth plates of tibiotarsal bones in chickens receiving aspirin.

β1‐Adrenoceptor antibody‐induced increase in soluble CD40 ligand release in chronic periodontitis patients: role of prostaglandin E2

In this paper, we demonstrate that circulating antibodies from chronic periodontitis patients reacting with atrial β(1)-adrenoceptors (β(1)-ARs) act as an inducer of soluble CD40 ligand (sCD40L) release and prostaglandin E(2) (PGE(2)) generation. By enzyme-linked immunosorbent assay using β(1) synthetic peptide (with an amino acid sequence identical to the second loop of human myocardial β(1)-ARs) as a coating antigen, we demonstrated reactivity against the second extracellular loop on human myocardial β(1)-ARs. This autoantibody present in the serum of chronic periodontitis patients was significantly correlated with the release of sCD40L and PGE(2). The release of sCD40L was blunted by atenolol, SP600125 and β(1) synthetic peptide, and PGE(2) generation was inhibited by DuP 697 and slightly by FR122049. The effects of the antibody incubated with isolated rat atria upregulated sCD40L release with an increase of PGE(2) production and c-Jun N-terminal kinase phosphorylation. These results indicate that in chronic periodontitis patients, there is a positive association between sCD40L release and PGE(2) generation via the action of β(1)-AR antibodies.

Arachidonate Cascade in the Intensive Insulin Therapy for Critically Ill Patients with Sepsis: Roles of Prostaglandins on Hyperglycemia-Impaired Immunity

Intensive insulin therapy to control blood glucose level increases survival among critically ill patients in intensive care unit and hospital. Hyperglycemia is potentially harmful because it acts as a procoagulant, induces insulin resistance, causes apoptosis, impairs neutrophil function, increases the infection rate and is associated with the risk of morbidity and mortality. Hyperglycemia and insulin resistance are virtually universally in sepsis, which is the leading cause of death in critically ill patients. Initially, sepsis is characterized by a hyper-inflammatory response; but as sepsis persists, there is a shift toward an anti-inflammatory immunosuppressive state. The intensive insulin therapy also reduces the infection rate and the mortality in septic patients. Arachidonate cascade is one of the factors associated with hyperglycemia, sepsis and infection. The cascade is involved in the upregulation of proinflammtory cytokines and the dysfunction of immune cells. Especially, we focused on prostaglandin D2 (PGD2), which is produced from innate and adaptive immune cells. PGD2 is non-enzymatically metabolized to 15-deoxy-Δ12,14-PGJ2, (15d-PGJ2). 15d-PGJ2 is an endogenous ligand for the nuclear receptor, peroxysome proliferators-activated receptor γ (PPARγ) and induces apoptosis in the both immune cells. This review presents plausible roles of arachidonate cascade in hyperglycemia-impaired immunity. Furthermore, we shed light on therapeutic potentials of PPARγ ligands for critically ill patients under the insulin resistant state.

Role of prostaglandin E2 in the experimental L-carnitine-induced endometriosis-like inflammatory model

Purpose Ectopic implantation of endometrium leading to endometriosis has been correlated with various immune and non-immune parameters. Inflammatory cytokines including IL-2, IFN-γ, TNF-α, increase in serum and peritoneal fluid of endometriotic patients, while elevated levels of prostaglandins PGE1 and PGE2 have been accused of facilitating the inflammation process. Using the experimental model of L-carnitine (L-Cn)-induced endometriosis, the aim of this study was to explore the role of PGE1 and PGE2 in endometriosis development and define whether L-Cn had a direct effect on endometrial cells. Methods During treatment with L-Cn, experimental mice were injected with indomethacin or specific PGE1 and PGE2 analogs and their effect on the L-Cn-induced inflammatory state was examined. Primary uterine cells or human endometrial adenocarcinoma cell lines were used to assess the direct or indirect effect of L-Cn. Results The seven-day treatment of virgin females with L-Cn induced obvious endometrial abnormalities with accumulation of CD90 and CD11 cells. Administration of indomethacin alleviated some of the L-Cn-induced effects, but could not inverse the phenotype. Interestingly, 11-deoxy-PGE1 aggravated the L-Cn-induced effects, whereas 17-phenyl-trimor-PGE2 reversed them. In vitro experiments showed that the effect of L-Cn depended on the nature of endometrioma cells. L-Cn could aggravate the inflammatory state of Ishikawa-inoculated mice, but could alleviate symptoms from MFE-319 inoculated females. Conculsions Although PGE2 appeared to play a key role in the L-Cn-induced uterus inflammation, the actual role of L-Cn depends on the nature of endometrioma cells and can aggravate or protect from inflammation according to the induced regulatory pathways.

Editorial introductions

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce one of the Section Editors for this issue. SECTION EDITORS David H. AlpersDavid H. AlpersDavid H. Alpers received his bachelor and medical degrees from Harvard University, was a medical house officer at the Massachusetts General Hospital, and a research fellow at NIH under Gordon Tomkins. After a fellowship in gastroenterology at the Massachusetts General Hospital and serving as a junior faculty member at Harvard Medical School, he served as chief of the GI Division at Washington University School of Medicine from 1969–1997. His laboratory research was focused on the regulation of protein synthesis in the GI tract, and on the biology of proteins unique to the GI mucosa, including especially intestinal alkaline phosphatase, gastric intrinsic factor, and the intrinsic factor-cobalamin receptor (cubilin). He has published over 220 peer reviewed scientific papers related to this work. Dr Alpers has had many editorial responsibilities, including associate editor of the J Clin Invest, editor of the Am J Physiol Gastrointest Liver Physiol (1991–97), editorial board of the J Biol Chem (1998–2003), Editor of Small Intestine and Nutrition sections of Current Opinion in Gastroenterology (1997-present), and Associate Editor of the Am J Clin Nutr (2008-present). He is Associate Editor of the Textbook of Gastroenterology (5th edition), T. Yamada (editor-in-chief), and coauthor (with W Stenson, B Taylor, and DM Bier) of the Manual of Nutritional Therapeutics (5th edition). He served as director of the Undergraduate Teaching Project of the American Gastroenterological Association from 1985–2001, and was president of the AGA in 1990–91. He received the Julius Friedenwald medal of the AGA for lifetime contributions to the field of gastroenterology. Currently he serves as William B Kountz Professor of Medicine and Geriatrics and is Co-director for the Center for Human Nutrition and the Center for Clinical Research Unit at Washington University School of Medicine. William F. StensonWilliam F. StensonDr Stenson graduated from the Washington University School of Medicine and was a medical resident at Barnes Hospital in St Louis, USA. This was followed by a gastroenterology fellowship and laboratory training in immunology with Dr Charles Parker, both at Washington University. After training he joined the gastroenterology faculty at Washington University and has spent his entire career there. He is currently the Nicholas V Costrini Professor of Gastroenterology and Inflammatory Bowel Disease. His clinical interests have focused on inflammatory bowel disease, celiac disease and nutrition. His laboratory interests include intestinal inflammation and the epithelial response to injury. The role of prostaglandins in these processes has been a particular interest. He has published more than a hundred scientific articles. He is the co-author of the Manual of Nutritional Therapeutics which is now in its fifth edition. He is a member of the Digestive Disease Commission and was the chairman of the Gastrointestinal Mucosal Pathobiology Study Section for the NIH.

Effects of naproxen on the hypobaric hypoxia-induced immune changes in male rats

Some cell-mediated immune responses are altered in hypobaric hypoxic (HH) condition in rats. Prostaglandins (PGs) are increased in hypobaric hypoxia and non-steroidal anti-inflammatory drugs are used to facilitate acclimatization in high altitude by inhibiting PGs. The present study explores the role of PGs in hypobaric hypoxia-induced immune responses by inhibiting its synthesis with different doses of naproxen. The rats were exposed to HH condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days. The phagocytic activity of circulating blood WBC, measured by fluorescein isothiocyanate-tagged bacterial cell, was increased in HH and this change was blocked after administration of naproxen. There was reduction of natural killer cell cytotoxicity of splenic mononuclear cell and delayed type of hypersensitivity responses to bovine serum albumin in rats exposed to HH condition but these immune responses were blocked after administration of naproxen in HH condition. The leukocytes adhesive inhibition index was not altered in HH condition and after administration of naproxen in HH condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HH condition and this elevated CORT concentration was blocked after administration of naproxen in HH condition. The observed HH-induced immune changes are inhibited by naproxen in a dose-dependent manner. The study indicates that hypobaric hypoxia-induced immune changes are mediated by PGs.

Role of prostaglandins in neuroinflammatory and neurodegenerative diseases.

Increasing data demonstrates that inflammation participates in the pathophysiology of neurodegenerative diseases. Among the different inflammatory mediators involved, prostaglandins play an important role. The effects induced by prostaglandins might be mediated by activation of their known receptors or by nonclassical mechanisms. In the present paper, we discuss the evidences that link prostaglandins, as well as the enzymes that produce them, to some neurological diseases.

Brainstem Neuropeptides and Vagal Protection of the Gastric Mucosal Against Injury: Role of Prostaglandins, Nitric Oxide and Calcitonin-Gene Related Peptide in Capsaicin Afferents

Earlier experimental studies indicated that the integrity of vagal pathway was required to confer gastric protection against damaging agents. Several peptides located in the brainstem initially identified to influence vagal outflow to the stomach, as assessed by electrophysiological approach or by vagal dependent alterations of gastric secretory and motor function, were investigated for their influence in the vagal regulation of the resistance of the gastric mucosa to injury. Thyrotropin releasing hormone (TRH), or its stable TRH analog, RX-77368, injected at low doses into the cisterna magna or the dorsal motor nucleus (DMN) was the first peptide reported to protect the gastric mucosa against ethanol injury through stimulation of vagal cholinergic pathways, inducing the release of gastric prostaglandins/nitric oxide (NO) and the recruitment of efferent function of capsaicin sensitive afferent fibers containing calcitonin-gene related peptide (CGRP). Activation of endogenous TRH-TRH1 receptor signaling located in the brainstem plays a role in adaptive gastric protection against damaging agents. Since then, an expanding number of peptides, namely peptide YY, CGRP, adrenomedullin, amylin, glugacon-like peptide, opioid peptides acting on µ, δ1 or δ2 receptors, nocicpetin, nocistatin, ghrelin, leptin and TLQP-21, a peptide derived from VGF prohormone, have been reported to act in the brainstem to afford gastric protection against ethanol injury largely through similar peripheral effectors mechanisms than TRH. Therefore gastric prostaglandins and CGRP/NO pathways represent a common final mechanism through which brain peptides confer vagally mediated gastroprotection against injury. A better understanding of brain circuitries through which these peptides are released will provide new strategies to recruit integrated and multifaceted gastroprotective mechanisms.

In VivoChemical Screening for Modulators of Hematopoiesis and Hematological Diseases

In vivo chemical screening is a broadly applicable approach not only for dissecting genetic pathways governing hematopoiesis and hematological diseases, but also for finding critical components in those pathways that may be pharmacologically modulated. Both high-throughput chemical screening and facile detection of blood-cell-related phenotypes are feasible in embryonic/larval zebrafish. Two recent studies utilizing phenotypic chemical screens in zebrafish have identified several compounds that promote hematopoietic stem cell formation and reverse the hematopoietic phenotypes of a leukemia oncogene, respectively. These studies illustrate efficient drug discovery processes in zebrafish and reveal novel biological roles of prostaglandin E2 in hematopoietic and leukemia stem cells. Furthermore, the compounds discovered in zebrafish screens have become promising therapeutic candidates against leukemia and included in a clinical trial for enhancing hematopoietic stem cells during hematopoietic cell transplantation.

Effect of Phenylbutazone on Pentylenetetrazole-Induced Seizure in Mice

Problem statement: The Cyclooxygenases (COXs), the key enzymes that convert arachidonic acid to Prostaglandins (PGs), had been implicated in physiological and pathophysiological functions in the CNS. Non-Stesoidal Anti-Inflammatory Drugs (NSAIDs), COX inhibitors, were used largely to treat febrile condition, pain state and for prevention of and therapeutics of many diseases. However the role of PGs and NSAIDs in the seizure activity has been disputed. The aim of this study was to evaluation the effect of intraperitoneally injection of different doses of Phenylbutazone on PTZ-induced seizure threshold in mice. Approach: Mice were divided into 9 groups randomly: The first group received saline normal (ip) (control group); the second group received Carboxy Methyl Cellulose (CMC) 0.5% (ip) (vehicle group) and the next groups received respectively different doses of Phenylbutazone (5, 10, 20, 40, 60, 80 and 100 mg kg-1 ip) 45 min before determination of seizure threshold induced by PTZ. Results: Results showed that PTZ-induced seizure threshold in control mice was 34.75±1.54 mg kg-1. Intraperitoneal injection of Phenylbutazone showed significant (p<0.05) increase of PTZ-induced seizure threshold in a dose dependently manner compared with control group. Conclusion: Phenylbutazone has anticonvulsant effects on mice. Nevertheless, new studies must be carried out in order to determine the beneficial effects of NSAIDs in treatment of epilepsy.

The role of prostaglandin E2 in endometriosis

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E2 is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E2 increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E2 affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.

Role of Prostaglandins in Venous Thrombus Resolution in a Murine Model of Thrombosis

Role of Prostaglandins in Venous Thrombus Resolution in a Murine Model of Thrombosis

Insight: Prolonged Vaginal Bleeding during Central Precocious Puberty Therapy with a Long-acting Gonadotropin-Releasing Hormone Agonist: A Proposed Mechanism and Management Plan

We have previously described our data collected after administration of gonadotropin releasing hormone-agonist (GnRH-a) to delay sexual maturation, in premenarchal girls suffering from idiopathic central precocious puberty. 1 We have explained the recurrent episodes of bleeding due to discontinuation of the estrogen support of the proliferative and stable endometrium. The recognition in recent years of the extra-pituitary functions of GnRH-a, the ability of GnRH to stimulate prostaglandin production and the known role of prostaglandins in irregular vaginal bleeding prompted us to seek alternative explanations to our data. We suggest considering a potential clinical use of combination therapies of GnRH agonists and prostanoid receptor antagonists to treat central precocious puberty.

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems.

Role of Prostaglandin D Receptor CRTH2 in Sustained Eosinophil Accumulation in the Airways of Mice with Chronic Asthma

The prostaglandin D₂ (PGD₂)/CRTH2 pathway is important for eosinophil trafficking in vitro; however, genetic deficiency of CRTH2 does not suppress in vivo eosinophilic airway inflammation in acute models of asthma, and the role of CRTH2 in the pathogenesis of asthma is still ambiguous. Therefore, in the present study we explored whether the PGD₂/CRTH2 pathway could affect the phenotypes of chronic asthma. Either CRTH2-deficient (CRTH2–/–) or wild-type mice were sensitized and exposed to ovalbumin (OVA) for 3 days (acute model) or 6 weeks (chronic model). While the magnitude of the acute eosinophilic inflammation was equivalent between CRTH2–/– and wild-type mice, the number of inflammatory cells and eosinophils in bronchoalveolar lavage fluid after chronic OVA exposure was significantly reduced in CRTH2–/– mice (18.0 ± 2.6 × 10⁴ cells and 2.0 ± 0.5 × 10⁴ cells) compared to wild-type mice (27.9 ± 2.5 × 10⁴ cells and 6.8 ± 1.1 × 10⁴ cells, p < 0.001). On the contrary, no difference was observed between CRTH2–/– and wild-type mice in terms of airway hyperresponsiveness or remodeling (goblet cell hyperplasia) in the chronic model of asthma. In conclusion, CRTH2 that mediates PGD₂ activity is essential for sustained eosinophilic inflammation in the airways, and its antagonists could exert an anti-inflammatory effect in chronic asthma.

Abstract LB-250: Establishment of a positive feedback between PGE2 and COX2 diverts DC differentiation into MDSCs and sustains their immunosuppressive functions in ovarian cancer

Abstract Myeloid-derived suppressor cells (MDSCs) are essential players in cancer-associated immune dysfunction. We report that the differentiation and functional stability of human monocytic MDSCs is driven by a single cancer-associated inflammatory mediator, prostaglandin E2 (PGE2), and depends on the establishment of a positive feedback between PGE2 and the key regulator of PGE2 synthesis, COX-2. PGE2 abrogates the differentiation of CD1a+ DC from monocytes, redirecting it towards CD14+CD33+CD34+ cells expressing all MDSC-associated suppressive factors: IDO, arginase, NOS2 and IL-10, and inducing their CTL-suppressive functions. Moreover, PGE2 promotes the expression of endogenous COX2 and autocrine secretion of PGE2 in MDSCs, establishing a positive feedback loop that stabilizes the MDSC phenotype. Undisturbed COX2 activity and persistent production of PGE2 by MDSCs, isolated from cancer patients, was required for their continued expression of CXCR4 and responsiveness to CXCL12. Moreover, PGE2 also proved to be the key factor promoting the production of CXCL12 in cancer microenvironment, a chemokine exerting multiple tumor-promoting effects either directly by acting on cancer cells or indirectly by inducing angiogenesis and recruiting other immunosuppressive cells, i.e. Tregs and pDCs. In accordance with the physiological role of PGE2 in the development and functional stability of human cancer -associated MDSCs, we observed that the frequencies of CD11b+ CD33+ MDSCs in the ovarian cancer (OvCa) ascites closely correlate with the local production of PGE2 and expression of COX2, while the OvCa ascites environment can promote the induction of MDSCs from differentiating monocytes in a COX2-dependent manner. Importantly. disruption of COX2-PGE2 feedback in fully-developed MDSCs isolated from cancer patients, using COX2 inhibitors or inhibitors of EP2/EP4-dependent PGE2 signaling, eliminates the production of all other suppressive factors and terminates the CTL-suppressive function of MDSCs as well as eliminates both the expression of CXCR4 on MDSCs and the production of CXCL12, highlighting the key role of PGE2 in the tumor-accumulation of immunosuppressive cells. The currently demonstrated key role of the positive COX2-PGE2 feedback loop in the differentiation and functional stability of MDSCs facilitates the targeting of MDSCs in cancer immunotherapy and facilitates the development of additional MDSC-targeting therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-250. doi:10.1158/1538-7445.AM2011-LB-250

The effects of prostaglandins E1, E2, F1alpha and F2alpha on guinea-pig ileal and colonic peristalis.

Prostaglandins (PGE1, E2, F1alpha and F2alpha) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds has no significant effect.

Possible role of prostaglandins in post-tetanic potentiation at the nerve-muscle junction in the longitudinal muscle strip of guinea-pig ileum.

The effect of tetanic stimulation on the twitch responses of the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum to electrical stimulation was investigated in the presence of naloxone. Under this condition, or after the addition of PGE2, twitch contractions were maximal and no potentiation of twitches following tetanus was observed. In the presence of indomethacin (1 mumol litre-1) twitches were diminished and post-tetanic potentiation (PTP) was manifested. PTP was seen with indomethacin concentrations of 1 to 20 mumol litre-1 or after simultaneous addition of diphloretin phosphate (16 mumol litre-1). Thus it seems unlikely that the effect of prostaglandins released during tetanic stimulation would be of key importance for the manifestation of PTP. Rather it is thought that a decrease in the release of acetylcholine from motor nerve terminals, and consequently smaller twitches in the presence of indomethacin, offer favourable conditions for PTP.

Gastroprotective Effect of l-Phenyl-3-(4-hydroxy-3,5-di-tert-butylphenyl)prop-2-en- 1 -one in Rats

1-Phenyl-3-(4-hydroxy-3,5-di-tert-butylphenyl)prop-2-en-1-one (PHP), an antioxidant, has been studied for gastroprotective activity in-vitro and in-vivo, more specifically for its capacity to inhibit in-vitro iron- and copper-driven oxidant damage at acidic pH values mimicking intragastric conditions in the clinical setting. Our studies showed significant inhibition of both iron- and copper-driven oxidant damage at pH 3.5 and 5.3. Intragastric and intraperitoneal administration of PHP (250 mg kg(-1)) reduced gastric mucosal haemorrhagic lesions in stress-induced and ethanol-induced rat models. The gastroprotective effect of PHP against ethanol was reversed significantly by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis, indicating a possible role of prostaglandins in its gastroprotective effect. Treatment of PHP replenished reduced levels of gastric mucosal non-protein sulphydryls in ethanol-treated rats, suggesting the mediation of its effect through sulphydryls. These results indicate that PHP was active at acidic pH. This is an interesting observation because highly acidic pH is known to be important in the development of gastric ulcers. Our study suggests that PHP might protect gastric mucosa by its capacity to scavenge free radicals.