Publications (134) View all
-
Article: Antiproliferative, apoptotic and antimutagenic activity of isolated compounds from Polyalthia cerasoides seeds.
[show abstract] [hide abstract]
ABSTRACT: Phytochemical investigation of the petroleum ether extract fraction of Polyalthia cerasoides seeds led to the isolation of two phytosterols (alpha-spinasterol and spinasterol) and a clerodane di-terpenoid. The structures of these compounds were elucidated using IR, (1)H-NMR, (13)C-NMR and Mass spectral analysis. Further, these compounds were tested for antiproliferative action against CACO-2 cell line and apoptotic action was determined by nuclear staining and DNA fragmentation analysis. The results showed that the compounds exhibited antiproliferative action at various concentrations with an IC(50) value of 28.6+/-4.34nM/ml, 57.7+/-6.81nM/ml and 60.0+/-7.10nM/ml for clerodane diterpenoid, spinasterol and alpha-Spinasterol respectively. Furthermore, the isolated compounds were screened for antimutagenic effect against methylmethane sulfonate (MMS) induced mutation. Phytosterols showed protective effect, whereas clerodane diterpenoid was less effective to MMS induced chromosomal aberrations. Our research contributes to the characterization of phytochemical constituents and to understand the ability of these compounds to antiproliferative and antimutagenic responses from the seed extracts.Phytomedicine: international journal of phytotherapy and phytopharmacology 10/2009; 17(7):513-8. · 2.17 Impact Factor -
Article: Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis.
[show abstract] [hide abstract]
ABSTRACT: In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. The purpose of this study is to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI) and, if so, the potential mechanism responsible for the benefit. To study this, adult male rats were exposed to 5-Gy whole body irradiation followed by cecal ligation and puncture (CLP, a model of sepsis) 48 h thereafter. Human ghrelin (30 nmol/rat) or vehicle (saline) was infused intravenously via an osmotic minipump immediately after radiation exposure. Blood and tissue samples were collected at 20 h after RCI (68 h after irradiation or 20 h after CLP) for various measurements. To determine the longterm effect of human ghrelin after RCI, the gangrenous cecum was removed at 5 h after CLP and 10-d survival was recorded. In addition, vagotomy or sham vagotomy was performed in sham and RCI animals immediately prior to ghrelin administration, and various measurements were performed at 20 h after RCI. Our results showed that serum levels of ghrelin and its gene expression in the stomach were decreased markedly at 20 h after RCI. Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems.Molecular Medicine 09/2009; 15(11-12):407-14. · 3.76 Impact Factor -
Article: Human adrenomedullin and its binding protein attenuate organ injury and reduce mortality after hepatic ischemia-reperfusion.
[show abstract] [hide abstract]
ABSTRACT: To determine whether administration of a vasoactive peptide, human adrenomedullin (AM), in combination with its binding protein (ie, AMBP-1), prevents or minimizes hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury results from tissue hypoxia and subsequent inflammatory responses. Even though numerous pharmacological modalities and substances have been studied to reduce I/R-induced mortality, none have been entirely successful. We have shown that administration of AM/AMBP-1 produces significant beneficial effects under various pathophysiological conditions. However, it remains unknown if human AM/AMBP-1 has any protective effects on hepatic I/R-induced tissue damage and mortality. Seventy percent hepatic ischemia was induced in male adult rats by placing a microvascular clip across the hilum of the left and median lobes for 90 minutes. After removing the clip, human AM alone, human AMBP-1 alone, human AM in combination with human AMBP-1 or vehicle was administered intravenously over a period of 30 minutes. Blood and tissue samples were collected 4 hours after reperfusion for various measurements. In additional groups of animals, the nonischemic liver lobes were resected at the end of 90-minute ischemia. The animals were monitored for 7 days and survival was recorded. After hepatic I/R, plasma levels of AM were significantly increased, whereas AMBP-1 levels were markedly decreased. Likewise, gene expression of AM in the liver was increased significantly, whereas AMBP-1 expression was markedly decreased. Administration of AM in combination with AMBP-1 immediately after the onset of reperfusion down-regulated inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. On the other hand, administration of human AM alone or human AMBP-1 alone after hepatic I/R failed to produce significant protection. Human AM/AMBP-1 may be a novel treatment to attenuate tissue injury after an episode of hepatic ischemia.Annals of surgery 03/2009; 249(2):310-7. · 7.90 Impact Factor -
Article: Pivotal role of the alpha(2A)-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis.
[show abstract] [hide abstract]
ABSTRACT: Norepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-alpha production in Kupffer cells (KCs) through the activation of the alpha(2)-AR. It is important to know which of the three alpha(2)-AR subtypes (i.e., alpha(2A), alpha(2B) or alpha(2C)) is responsible for the upregulation of TNF-alpha production. The aim of this study was to determine the contribution of alpha(2A)-AR in this process. Adult male rats underwent CLP and KCs were isolated 2 h later. Gene expression of alpha(2A)-AR was determined. In additional experiments, cultured KCs were incubated with NE with or without BRL-44408 maleate, a specific alpha(2A)-AR antagonist, and intraportal infusion of NE for 2 h with or without BRL-44408 maleate was carried out in normal animals. Finally, the impact of alpha(2A)-AR activation by NE was investigated under inflammatory conditions (i.e., endotoxemia and CLP). Gene expression of the alpha(2A)-AR subtype was significantly upregulated after CLP. NE increased the release of TNF-alpha in cultured KCs, which was specifically inhibited by the alpha(2A)-AR antagonist BRL-44408. Equally, intraportal NE infusion increased TNF-alpha gene expression in KCs and plasma TNF-alpha which was also abrogated by co-administration of BRL-44408. NE also potentiated LPS-induced TNF-alpha release via the alpha(2A)-AR in vitro and in vivo. This potentiation of TNF-alpha release by NE was mediated through the alpha(2A)-AR coupled Galphai protein and the activation of the p38 MAP kinase. Treatment of septic animals with BRL-44408 suppressed TNF-alpha, prevented multiple organ injury and significantly improved survival from 45% to 75%. Our novel finding is that hyperresponsiveness to alpha(2)-AR stimulation observed in sepsis is primarily due to an increase in alpha(2A)-AR expression in KCs. This appears to be in part responsible for the increased proinflammatory response and ensuing organ injury in sepsis. These findings provide important feasibility information for further developing the alpha(2A)-AR antagonist as a new therapy for sepsis.PLoS ONE 02/2009; 4(5):e5504. · 4.09 Impact Factor -
Article: Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response.
[show abstract] [hide abstract]
ABSTRACT: In sepsis, phagocytosis and the killing of bacteria by phagocytes are important. Similarly, the clearance of accumulating apoptotic cells is critical in maintaining normal immunity. Upon maturation, peritoneal macrophages (PM) become a major source of proinflammatory cytokines, while losing their efficacy of phagocytosis. However, the underlying mechanism remains unknown. Here we investigated the differential effects of apoptotic thymocytes (AoTC) on TNF-alpha release in immature thioglycolate-elicited PM (TGPM) and mature resident PM (RPM) in vitro by culturing them with or without AoTC and/or LPS. MFG-E8 expression was assessed using Western blotting and the ability to engulf AoTC was determined histologically. Cytokine secretion was measured by ELISA. MAP kinase phosphorylation was assessed using Western blotting. Mature RPM express <50% of TGPM MFG-E8 levels and have a 30% lower capacity to clear AoTC. The proinflammatory response (TNF-alpha release) to LPS is 5 times higher, and the capability to phagocytose is decreased along with further down-regulation of MFG-E8 after LPS-stimulation. RPMs also lack phagocytosis-induced inhibition of TNF-alpha release after LPS stimulation. LPS-induced phosphorylation of ERK1/2, p38 and JNK is more enhanced in RPM compared to TGPM. MFG-E8-mediated apoptotic cell phagocytosis results in an inhibition of MAPK and NFkappaB signaling pathways. Differential MAPK activation may play a role in the enhanced LPS responsiveness of RPM and the lack of MFG-E8 impedes post-phagocytic suppression of LPS-response through the inhibition of those signaling pathways. These results provide a potential mechanistic insight into the benefit of promoting apoptotic cell clearance via MFG-E8 under inflammatory conditions.International Journal of Molecular Medicine 12/2008; 22(6):743-8. · 1.98 Impact Factor
