Mechanistic Pathways and Molecular Targets of Plant-Derived Anticancer ent-Kaurane Diterpenes.

Since the first discovery in 1961, more than 1300 ent-kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon. Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe the anticancer potential and mechanism of action of ent-kaurane compounds in a series of cancer cell lines. Oridonin is one of the prime anticancer ent-kaurane diterpenoids that is currently in a phase-I clinical trial in China. In this review, we have extensively summarized the anticancer activities of ent-kaurane diterpenoids according to their plant sources, mechanistic pathways, and biological targets. Literature analysis found that anticancer effect of ent-kauranes are mainly mediated through regulation of apoptosis, cell cycle arrest, autophagy, and metastasis. Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4. The most common metastatic target proteins of ent-kauranes are MMP-2, MMP-9, VEGF, and VEGFR whereas LC-II and mTOR are key regulators to induce autophagy.

Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling.

Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/ß-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases.

Flexicaulin A, An ent-Kaurane Diterpenoid, Activates p21 and Inhibits the Proliferation of Colorectal Carcinoma Cells through a Non-Apoptotic Mechanism.

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia), a genus of the Lamiaceae (formerly Labiatae) family, has been reported as a rich source of natural diterpenes. In the current study, we evaluated the in vitro anti-proliferative property of flexicaulin A (FA), an Isodon diterpenoid with an ent-kaurane structure, in human carcinoma cells, by means of cell viability assay, flow cytometric assessment, quantitative polymerase chain reaction array, Western blotting analysis, and staining experiments. Subsequently, we validated the in vivo antitumor efficacy of FA in a xenograft mouse model of colorectal carcinoma. From our experimental results, FA appears to be a potent antitumor molecule, since it significantly attenuated the proliferation of human colorectal carcinoma cells in vitro and restricted the growth of corresponsive xenograft tumors in vivo without causing any adverse effects. Regarding its molecular mechanism, FA considerably elevated the expression level of p21 and induced cell cycle arrest in the human colorectal carcinoma cells. While executing a non-apoptotic mechanism, we believe the antitumor potential of FA opens up new horizons for the therapy of colorectal malignancy.

In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence.

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1-19), including 11 novel ones (5 and 10-19) from another Miliusa plant ( M. balansae), and synthesized additional derivatives to elucidate the structure-activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5-40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1-3 (GI50 0.03-4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

Perspectives of Plant Natural Products in Inhibition of Cancer Invasion and Metastasis by Regulating Multiple Signaling Pathways.

BACKGROUND: Metastasis is often derived from increased invasion and migration of tumor cells, and is the most frequent cause of cancer-associated death. Either the prophylactic or therapeutic treatment of metastatic cancer remains very challenging today by virtue of the complex histopathology and genetic or epigenetic variations. Medicinal scientists had discovered many potential anti-invasive and anti-metastatic compounds from plant materials. However, data on currently available plant-based compounds inhibiting cancer invasion and metastasis is relatively scanty and no published article has been found with updated information in this unique and important aspect. METHODS: We obtained relevant information from a structured search of 327 peer-reviewed articles, including both research- and review-based papers, related to the use of plant materials in cancer treatments, particularly for the suppression of invasion and metastasis. RESULTS: We have categorized the plant-based products with anti-invasive or anti-metastatic properties into alkaloids, flavonoids, terpenes, quinones, phenolics, xanthone and sulfur-containing compounds, and complemented with their chemical structures, sources of isolation and biological targets in the present review article. CONCLUSION: We aim to provide readers a convenient way in reviewing the potential anti-invasive and anti-metastatic plant-based products with links to different mechanistic pathways, and to inspire researchers with updated information for the development of new anticancer remedies.

The Use of Naphthoquinones and Furano-naphthoquinones as Antiinvasive Agents.

BACKGROUND: Cancer is a leading cause of mortality in the world and metastasis is to blame. A number of naphthoquinones (NQs) have shown ability to reduce cancer stemness and metastatic potential. Furano-naphthoquinones (FNQs), which is a class of NQ characterized by the incorporation of an additional furan ring, have demonstrated improved anti-cancer potency as compared to the other classes of NQs. OBJECTIVE: In this study, the natural origins, synthetic routes and derivatives of migrastatic NQs were reviewed. The anti-invasive and anti-metastatic mechanisms of NQs and the more powerful FNQs in targeting cancer were also discussed. METHODS: The articles related to the anti-invasive mechanisms of NQs were comprehensively reviewed. The plant origins, synthetic routes and antitumor effects of more than 360 FNQs were also covered and presented according to their chemical structures. RESULTS: Anti-cancer NQs inhibit cancer invasion by acting on epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and signal transducer and activator of transcription 3 (STAT3) signaling. BBI608, a natural FNQ, has entered phases I and II clinical trials. It has been regarded as a potential candidate for new-generation lead compound acting directly on CSCs to overcome the problem of chemotherapy resistance. Apart from the plant-derived FNQs, there are a number of synthetic FNQs that were found to intervene in cancer invasion and metastasis. CONCLUSION: The anti-invasive mechanisms of NQs have been thoroughly studied. FNQs generally show higher anti-cancer activity than that of NQs. The mechanisms of action of FNQs are worth further investigation.

Resveratrol Ameliorates the Severity of Fibrogenesis in Mice with Experimental Chronic Pancreatitis.

SCOPE: Resveratrol is generally considered beneficial to health-span and longevity since this dietary stilbenoid has been scrutinized for its activating property on the "rescue gene" sirtuin-1 that promotes cellular survival under stress. In addition to its antiaging property, our previous in vitro studies revealed that resveratrol notably inhibits the production of extracellular matrix (ECM) proteins in pancreatic stellate cells (PSCs), the classic effector cells against pancreatic injury. OBJECTIVE: We aim to extrapolate resveratrol intervention to the management of fibrogenesis in mice with chronic pancreatitis. METHODS AND RESULTS: C57/BL6 mice are given repetitive injections of cerulein (50 µg kg-1  h-1 ) for 6 weeks for the induction of chronic pancreatitis. We demonstrate that the oral administration of resveratrol (20 mg kg-1  d-1 ) effectively attenuated PSC activation, ECM deposition, fibrogenesis, and acinar atrophy in the pancreatitic parenchyma of cerulein-induced mice, as the damage index score was improved by 45.5%. The enhanced cell survival and preserved acinar integrity by resveratrol plausibly involves a perpetuated nuclear accumulation of Mist1 and a negative modulation of the Akt and p38 MAPK pathways. CONCLUSION: We suggest that resveratrol is potentially a nutraceutical for the mitigations of pancreatic fibrosis in chronic pancreatitis for which no effective therapeutic measure is currently available.

Efficient Semisynthesis of (-)-Pseudoirroratin A from (-)-Flexicaulin A and Assessment of Their Antitumor Activities.

Accumulating evidence indicates that natural ent-kaurane diterpenoids show great potential for medical treatment of different pathological conditions including cytotoxicity, antibacterial, and anti-inflammatory activity. Among a variety of diterpenoids tested, (-)-pseudoirroratin A displayed a promising antitumor property in vitro and in vivo. However, this diterpenoid could merely be isolated in a limited amount from a rare source of Isodon pseudoirrorata. To overcome such scanty source, we developed a novel, facile, and efficient semisynthetic strategy to prepare (-)-pseudoirroratin A from natural (-)-flexicaulin A, which can be expediently obtained from I. flexicaulis in a great quantity. The three-dimensional structure and the absolute configuration of our synthetic diterpenoid have been determined and confirmed with the X-ray crystallographic analysis. More importantly, we demonstrated for the first time that pseudoirroratin A exerted significant cytotoxicity against human colorectal carcinoma cells via an induction of apoptosis, as well as a remarkable suppression on tumor growth in a colon cancer xenograft mouse model.

Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis.

Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance. In the present study, upon the oral administration of dihydro-resveratrol (10-50 mg/kg), the severity of acute pancreatitis in the cerulein-treated rats was significantly ameliorated as evidenced by decreased α-amylase activities in the plasma and lessened oedema formation in the pancreatic parenchyma. In addition, the generation of intracellular reactive oxidative products, including malondialdehyde and protein carbonyls, was accordingly reduced, so as the production of pro-inflammatory cytokines. While inhibiting the activities of NADPH oxidase and myeloperoxidase, the depletion of glutathione was considerably restored. Importantly, the attenuation of pancreatic oxidative damage by dihydro-resveratrol was associated with a down-regulation of the nuclear factor-kappaB and phosphatidylinositol 3'-kinase-serine/threonine kinase signalling pathways. Furthermore, we demonstrated that the solubility of dihydro-resveratrol was at least 5 times higher than trans-resveratrol whilst exhibiting a much lower cytotoxicity. Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans-resveratrol due to the lack of proper microbial strains.

Eruberin A, a Natural Flavanol Glycoside, Exerts Anti-Fibrotic Action on Pancreatic Stellate Cells.

BACKGROUND: Eruberin A (2, 3-dehydroflavonoid), a flavanol glycoside isolated from Pronephrium penangianum, has been used as a blood-nourishing folk medicine for centuries; however, it indeed possesses a variety of other health-promoting benefits including anti-fibrotic bioactivity. Activation of pancreatic stellate cells (PSCs) is the key initiating step in pancreatic fibrosis, which is a characteristic feature associated with chronic pancreatitis and pancreatic adenocarcinoma. METHODS: The anti-fibrotic effect of eruberin A and the underlying mechanisms of its anti-fibrotic action in LTC-14 cells, which retained essential characteristics and morphological features of primary PSCs, were examined by means of real-time polymerase chain reactions, Western blotting and immunostaining. RESULTS: The application of eruberin A (20 µg/ml) effectively inhibited the expression levels of fibrotic mediators namely alpha-smooth muscle actin, fibronectin and type I-collagen, so as the sonic hedgehog signaling pathway components post transforming growth factor-beta (5 ng/ml) stimulation. Eruberin A treatment also led to a notable decrease in the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT). CONCLUSION: Our results demonstrated that eruberin A significantly suppressed the expression levels of fibrotic mediators in PSCs, and we suggest that its anti-fibrotic mechanism was associated with an attenuation of the PI3K/AKT/NF-κB signaling pathway.

Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells.

BACKGROUND: Pancreatic fibrosis is a prominent histopathological characteristic of chronic pancreatitis and plausibly a dynamic process of transition to the development of pancreatic ductal adenocarcinoma. Conversely, the activation of pancreatic stellate cells (PSCs) has been recently suggested as the key initiating step in pancreatic fibrosis. As natural polyphenols had been largely applied in complementary therapies in the past decade, in this study, we aimed to investigate which groups of phenolic compounds exert promising inhibitory actions on fibrogenesis as there are few effective strategies for the treatment of pancreatic fibrosis to date. METHODS: We examined the anti-fibrotic effects of a variety of herbal constituents using a cellular platform, the LTC-14 cells, which retained essential characteristics and morphologies of primary PSCs, by means of various biochemical assays including cell viability test, real-time polymerase chain reaction and Western blotting analysis. RESULTS: Among a number of commonly used herbal constituents, we found that the application of rhein, emodin, curcumin and resveratrol significantly suppressed the mRNA and protein levels of several fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in LTC-14 cells against transforming growth factor-beta stimulation. Though the values of cytotoxicity varied, the mechanism of the anti-fibrotic action of these four phenolic compounds was principally associated with a decrease in the activation of the nuclear factor-kappaB signaling pathway. CONCLUSIONS: Our findings suggest that the mentioned phenolic compounds may serve as anti-fibrotic agents in PSC-relating disorders and pathologies, particularly pancreatic fibrosis.

Anti-fibrotic effect of trans-resveratrol on pancreatic stellate cells.

Trans-resveratrol, also known as 3,5,4'-trihydroxy-trans-stilbene, is a natural stilbenoid found at high concentration in skins of red grapes and berries. Over the recent years, it has been reported with a variety of beneficial effects such as antioxidant, anti-aging and anti-inflammatory bioactivities; thus often utilized as an active substance in human and veterinary therapeutics. In the current study, we aimed to delineate the mechanism of its anti-fibrotic action by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction and Western blotting analyses in a cellular model, the LTC-14 cells, which retain essential characteristics and morphological features of primary pancreatic stellate cells (PSCs). Our results demonstrated that the application of trans-resveratrol as low as 10 µM notably suppressed the mRNA and protein levels of different fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in the LTC-14 cells stimulated with transforming growth factor-beta, a well recognized pro-fibrotic inducer. Importantly, the mechanism of the anti-fibrotic action of trans-resveratrol was associated with a decrease in nuclear factor-kappaB activation and protein kinase B phosphorylation. In conclusion, our finding suggests that trans-resveratrol may serve as a therapeutic or an adjuvant agent in anti-fibrotic approaches and/or PSC-relating pathologies.

Traditional Chinese medicine formulas for irritable bowel syndrome: from ancient wisdoms to scientific understandings.

Traditional Chinese Medicine (TCM) serves as the most common alternative therapeutic approach for Western medicine and benefits IBS patients globally. Due to the lack of scientific evidence in the past, TCM formulas were not internationally well recognized as promising IBS remedies. In this review, firstly, we present the etiology and therapy of IBS in terms of traditional Chinese medical theory. Secondly, we summarize the clinical randomized controlled trials (RCTs) of TCM formulas for IBS patients that are available in the literature (from 1998 to September 2013), in which 14 RCTs conducted of high quality were discussed in detail. Of the 14 selected trials, 12 of those concluded that TCM formulas provided superior improvement in the global symptoms of IBS patients over the placebo or conventional medicines. As well, all 14 RCTs suggested that TCM formulas have good safety and tolerability. Last but not least, we explore the pharmacological mechanisms of the anti-IBS TCM formulas available in the literature (from 1994 to September, 2013). Collectively, in combating IBS symptoms, most TCM formulas exert multi-targeting actions including the regulation of neurotransmitters and hormones in the enteric nervous system (ENS), modulation of smooth muscle motility in the gastrointestinal (GI) tract, modulation of the hypothalamic-pituitary-adrenal (HPA) axis, attenuation of intestinal inflammation and restoration of intestinal flora, etc. In conclusion, TCM formulas appear to be promising for IBS treatment. This review provides a useful reference for the public in furthering a better understanding and acceptance of TCM formulas as IBS remedies.

Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells.

Anthraquinone compounds have been recognized to possess antiinflammatory, anti-fibrotic and anti-tumour properties and thus applied in human and veterinary therapeutics as active substances of medicinal products. Amongst the anthraquinones isolated from Rheum palmatum, also known as da-huang, rhein was detected as one of the highest metabolite contents in the bloodstream of mammals. The biological activities of rhein therefore deserve detailed investigation. In this study, we aimed to delineate the mechanism of inhibitory actions of rhein on fibrotic and tumorigenic processes by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction (PCR) and western blotting analyses in rat pancreatic stellate cells (LTC-14), human pancreatic ductal adenocarcinoma cells (PANC-1) and human colon carcinoma cells (SW480 and SW620). Our results demonstrated that the application of rhein notably suppressed the mRNA and protein levels of various fibrotic and tumorigenic mediators including alpha-smooth muscle actin, type I collagen, fibronectin, N-cadherin and matrix metalloproteinases in the testing mammalian cells. The mechanism of the suppressive actions of rhein was associated with the modulation of the sonic hedgehog and serine-threonine kinase signalling pathways. In conclusion, we suggest that rhein may serve as a therapeutic or an adjuvant agent in anti-fibrotic and anti-tumorigenic approaches.

Rhein, a natural anthraquinone derivative, attenuates the activation of pancreatic stellate cells and ameliorates pancreatic fibrosis in mice with experimental chronic pancreatitis.

Pancreatic fibrosis, a prominent histopathological feature of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma, is essentially a dynamic process that leads to irreversible scarring of parenchymal tissues of the pancreas. Though the exact mechanisms of its initiation and development are poorly understood, recent studies suggested that the activation of pancreatic stellate cells (PSCs) plays a critical role in eliciting such active course of fibrogenesis. Anthraquinone compounds possess anti-inflammatory bioactivities whereas its natural derivative rhein has been shown to effectively reduce tissue edema and free-radical production in rat models of inflammatory conditions. Apart from its anti-inflammatory properties, rhein actually exerts strong anti-fibrotic effects in our current in-vivo and in-vitro experiments. In the mouse model of cerulein-induced CP, prolonged administration of rhein at 50 mg/kg/day significantly decreased immunoreactivities of the principal fibrotic activators alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-ß) on pancreatic sections implicating the activation of PSCs, which is the central tread to fibrogenesis, was attenuated. Consequently, the overwhelmed deposition of extracellular matrix proteins fibronectin 1 (FN1) and type I collagen (COL I-α1) in exocrine parenchyma was found accordingly reduced. In addition, the expression levels of sonic hedgehog (SHH), which plays important roles in molecular modulation of various fibrotic processes, and its immediate effector GLI1 in pancreatic tissues were positively correlated to the degree of cerulein-induced fibrosis. Such up-regulation of SHH signaling was restrained in rhein-treated CP mice. In cultured PSCs, we demonstrated that the expression levels of TGF-ß-stimulated fibrogenic markers including α-SMA, FN1 and COL I-α1 as well as SHH were all notably suppressed by the application of rhein at 10 µM. The present study firstly reported that rhein attenuates PSC activation and suppresses SHH/GLI1 signaling in pancreatic fibrosis. With strong anti-fibrotic effects provided, rhein can be a potential remedy for fibrotic and/or PSC-related pathologies in the pancreas.

Inhibitory effect of the gallotannin corilagin on dextran sulfate sodium-induced murine ulcerative colitis.

The therapeutic effect of corilagin (1) was evaluated in an acute colitis model induced by dextran sulfate sodium (DSS) in mice, and the mechanism of action was investigated in this study. Animals were challenged with 2% DSS drinking water for 5 consecutive days and then intraperitoneally treated with 1 (7.5, 15, and 30 mg/kg) daily for 7 days. It was found that 1 significantly decreased the disease activity index, inhibited the shortening of colon length, reduced colon tissue damage, and suppressed myeloperoxidase activity. Moreover, 1 greatly suppressed the secretion of TNF-α, IL-6, and IL-1ß, inhibited the degradation of IκB α, and down-regulated expression of cleaved caspase-3 and cleaved caspase-9 in colon tissues of DSS-treated mice. These findings demonstrated that 1 exerts a protective effect on DSS-induced colitis, and its underlying mechanisms are associated with inhibition of the NF-κB pathway that mitigates colon inflammatory responses and apoptosis of intestinal epithelial cells.

The roles of the PDZ-containing proteins bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass.

PDZ domains are versatile protein interaction modules with the ability to dimerize and to recognize internal and carboxy-terminal peptide motifs. Their function in mediating the formation of multi-molecular signaling complexes is best understood at neuronal and epithelial membranes. In a screen for interactors that regulate transcription factor function in pancreatic beta cells, we isolated two PDZ-containing proteins Bridge-1 (PSMD9) and PDZD2, which contain one and six PDZ domains, respectively. Here, we review their functions in the regulation of pancreatic beta cells as a nuclear coactivator or extracellular signaling molecule. Bridge-1 interacts with both E12 and PDX-1 to stimulate insulin promoter activity. Recent gain-of-function analysis in both cell and transgenic models has revealed its functions to regulate both insulin gene expression and pancreatic beta-cell survival. Little is known about the intracellular function of PDZD2 that is predominantly localized to the endoplasmic reticulum of INS-1E cells. Interestingly, PDZD2 is proteolytically processed by caspase-3 to generate a carboxy-terminal secreted protein (sPDZD2) containing two PDZ domains. Expressed in fetal pancreatic progenitor and INS-1E cells, sPDZD2 when added as recombinant protein exerts concentration-dependent mitogenic effects on beta-like cells. We propose that the PDZ domain proteins Bridge-1 and PDZD2 likely transduce signals that regulate insulin production, proliferation, and survival of pancreatic beta cells.

Secreted PDZD2 exerts concentration-dependent effects on the proliferation of INS-1E cells.

PDZD2 (PDZ domain containing 2) is a multi-PDZ protein expressed in pancreas and many other tissues. PDZD2 shows extensive homology to pro-interleukin-16 (pro-IL-16) and is localized mainly to the endoplasmic reticulum. We have recently demonstrated that PDZD2, like pro-IL-16, is proteolytically cleaved at its C-terminus to generate a secreted protein, sPDZD2 (for secreted PDZD2). To understand the possible functional role of PDZD2 in pancreas, we investigated the cellular distribution of PDZD2 in adult pancreas using an antiserum that recognizes both the full-length and secreted forms of PDZD2. Immunohistochemical analysis revealed a strong expression of PDZD2 in pancreatic islet beta cells but not alpha cells. Consistent with the beta-cell-enriched expression of PDZD2, immunoblot analysis indicated expression of both full-length PDZD2 and sPDZD2 in the insulinoma cell line INS-1E. A recombinant sPDZD2 protein was synthesized for study of its functional effect on INS-1E cells. In culture media with limiting serum, co-incubation with sPDZD2 stimulated the proliferation of INS-1E cells. The mitogenic effect of sPDZD2 was concentration-dependent, and was associated with a slight inhibition of the insulin promoter activity at high sPDZD2 concentrations. As a potential mitogen of beta-like cells, sPDZD2 may be useful for the optimization of beta-cell growth and differentiation in vitro.

Saralasin, a nonspecific angiotensin II receptor antagonist, attenuates oxidative stress and tissue injury in cerulein-induced acute pancreatitis.

INTRODUCTION: Free radical-mediated pancreatic injury is believed to play a key role in the pathogenesis of acute pancreatitis. Most of these studies have focused on the effects of antioxidant enzymes and free radical scavengers on improving the pancreatic injury. Recent findings showed that cerulein-induced acute pancreatitis was associated with an upregulation of a local pancreatic renin-angiotensin system in the pancreas. In the current study we hypothesized that inhibition of this renin-angiotensin system by saralasin, a nonspecific antagonist for angiotensin II receptor, could attenuate the severity of cerulein-induced pancreatitis. METHODOLOGY: The effects of saralasin on oxidative stress and tissue injury in cerulein-induced pancreatitis were assessed by histopathologic analysis and on the basis of biochemical changes of plasma alpha-amylase level, pancreatic glutathione status, oxidative modification of protein, and lipid peroxidation. RESULTS: Data from the biochemical analysis showed that intravenous injections of saralasin at doses of 10 microg/kg to 50 microg/kg 30 minutes before the induction of acute pancreatitis significantly reduced pancreatic injury, as indicated by a decrease in plasma alpha-amylase activity in comparison with the cerulein-treated control. The effect of saralasin was further manifested by significant suppressions of glutathione depletion, oxidative modification of proteins, and lipid peroxidation in cerulein-treated rat pancreas. Histopathologic examination findings were in agreement with the biochemical data. CONCLUSIONS: These data suggest that prophylactic administration of saralasin can ameliorate the oxidative stress and tissue injury in cerulein-induced pancreatitis. Such a protective effect may provide new insight into the potential value of angiotensin II receptor antagonists in the clinical therapy for acute pancreatitis.