OBJECTIVETo investigate the effects of polyunsaturated fatty acids (PUFA) ω-3 and ω-6, and their middle metabolites PGE2 and PGE3 on angiogenesis formation of gastric cancer, and to explore associated mechanism.

METHODSThe effects of ω-3, ω-6, PGE2, PGE3 on the proliferation and migration of human umbilical vein endothelial cell (HUVEC) were measured by proliferation and migration assay respectively. The angiogenesis assay in vivo was used to measure the effects of ω-3, ω-6, PGE2 and PGE3 on neovascularization. In all the assays, groups without ω-3, ω-6, PGE2 and PGE3 were designed as the control.

RESULTSWith the increased concentration of ω-6 from 1 μmol/L to 10 μmol/L, the proliferation ability of HUVECs enhanced, and the number of migration cells also increased from 28.2±3.0 to 32.8±2.1, which was higher than control group (21.2±3.2) respectively (both P<0.05). With the increased concentration of ω-3 from 1 μmol/L to 10 μmol/L, the proliferation ability of HUVECs was inhibited, and the number of migration cells decreased from 15.8±2.0 to 11.0±2.1, which was lower than control group (22.1±3.0) respectively (both P<0.05). In the angiogenesis assay, compared with control group (standard number: 43 721±4 654), the angiogenesis ability of HUVECs was significantly enhanced by ω-6 in concentration-dependent manner (1 μmol/L group: 63 238±4 795, 10 μmol/L group: 78 166±6 123, all P<0.01). Meanwhile, with the increased concentration of ω-3 from 1 μmol/L to 10 μmol/L, the angiogenesis ability was significantly decreased from 30 129±3 102 to 20 012±1 541(all P<0.01). The proliferation and migration ability of HUVECs were significantly promoted by ω-6 metabolites PGE2 (P<0.05) in a concentration-dependent manner. In contrast, ω-3 metabolites PGE3 significantly inhibited the proliferation and migration ability of HUVECs in a concentration-dependent manner (all P<0.05). After rofecoxib (a COX-2 specific inhibitor) inhibited the expression of COX-2, the expression level of PGE2 was significantly decreased in a dose-dependent manner. In co-culture system, whose gastric cancer cells expressed positive COX-2, ω-6 could increase angiogenesis of gastric cancer cells(P<0.01), but ω-3 could inhibit such angiogenesis(P<0.01). In co-culture system, whose gastric cancer cells did not express COX-2, ω-3 could inhibit the angiogenesis of gastric cancer cells (P<0.05), but ω-6 had no effect on angiogenesis.

CONCLUSIONSThe PUFA ω-6 can enhance the angiogenesis via the promotion of proliferation and migration of HUVECs, and COX-2 and PGE2 may play an important role in this process, whereas, the ω-3 can inhibit the angiogenesis through its middle metabolites PGE3 to inhibit the proliferation and migration of HUVECs. Results of this experiment may provide a new approach to inhibit and prevent the spread of gastric cancer.

Alprostadil ; analogs & derivatives ; pharmacology ; Angiogenesis Inducing Agents ; metabolism ; pharmacology ; Angiogenesis Inhibitors ; pharmacology ; Cell Count ; methods ; Cell Line, Tumor ; drug effects ; physiology ; Cell Migration Assays ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Coculture Techniques ; Cyclooxygenase 2 ; pharmacology ; Dinoprostone ; metabolism ; pharmacology ; Fatty Acids, Omega-3 ; pharmacology ; Fatty Acids, Omega-6 ; metabolism ; pharmacology ; Fatty Acids, Unsaturated ; pharmacology ; Human Umbilical Vein Endothelial Cells ; drug effects ; physiology ; Humans ; Lactones ; pharmacology ; Neovascularization, Pathologic ; physiopathology ; Stomach Neoplasms ; physiopathology ; Sulfones ; pharmacology

With the deeper research of the proliferation, invasion and metastasis mechanisms of the gastric cancer, targeted therapy has become a hot spot in this field. The exploration of targeted agents for gastric cancer is mainly concentrated upon the drugs that target human epidermal growth factor receptor (HER) family, the vascular endothelial growth factor (VEGF), the phosphatidylinositol 3-kinase-protein kinase/mammalian target of rapamycin (PI3K/mTOR) and the NF-κB signaling pathways. The targeted drugs relevant to HER family include the Cetuximab, Nimotuzumab, Matuzumab, Panitumumab and Erlotinib which are aimed at HER-1, the Trastuzumab, Pertuzumab and T-DM1 (trastuzumab emtansine) which are aimed at HER-2, and the Lapatinib and Afatinib which are the multi-target agents of HER. The agents which target VEGF signaling pathway include the anti-VEGF monoclonal antibody (Bevacizumab), the anti-VEGFR drugs (Ramucirumab, Apatinib, Sorafenib, Sunitinib and cediranib), and the recombinant fusion protein (Aflibercept). The LY294002, BEZ235 and Everolimus which are aimed at PI3K/mTOR signaling pathway have shown great promise. Bortezomib has been researched more as a new agent which targets NF-κB signaling pathway. Currently, only Trastuzumab, Ramucirumab and Apatinib have been completed the stage 3 clinical trials and succeeded. In future, researches should focus on multi-target agents or applications in combination treatment. This review collects the recent researches and the clinical trials to summarize the current state and progress of research on gastric cancer targeted therapy.
Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; Humans ; Molecular Targeted Therapy ; NF-kappa B ; drug effects ; physiology ; Phosphatidylinositol 3-Kinases ; Stomach Neoplasms ; therapy ; Vascular Endothelial Growth Factor A

As a commensal or a pathogen, Helicobacter pylori can change the balance of a complex interaction that exists among gastric epithelial cells, microbes, and their environment. Therefore, unraveling this complex relationship of these mixtures can be expected to help prevent cancer as well as troublesome unmet medical needs of H. pylori infection. Though gastric carcinogenesis is a multi-step process, precancerous lesion can be reversible in the early phase of mucosal damage before reaching the stage of no return. However, biomarkers to predict rejuvenation of precancerous atrophic gastritis have not been identified yet and gastric cancer prevention is still regarded as an impregnable fortress. However, when we take the journey from H. pylori-associated gastritis to gastric cancer, it provides us with the clue for prevention since there are two main preventive strategies: eradication and anti-inflammation. The evidence supporting the former strategy is now ongoing in Japan through a nation-wide effort to eradicate H. pylori in patients with chronic gastritis, but suboptimal apprehension to increasing H. pylori resistance to antibiotics and patient non-compliance still exists. The latter strategy has been continued in the author's research center under siTRP (short-term intervention to revert premalignant lesion) strategy. By focusing on the role of inflammation in the development of H. pylori-associated gastric carcinogenesis, this review is intended to explain the connection between inflammation and gastric cancer. Strategies on H. pylori eradication, removal of inflammation, and reverting preneoplastic lesion will also be introduced. In the end, we expect to be able to prevent gastric cancer by take a detour from the unpleasant journey, i.e. from H. pylori-associated gastritis to gastric cancer.
Animals ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Biomarkers/metabolism ; Disease Models, Animal ; Gastritis/*etiology ; Helicobacter Infections/*complications/drug therapy ; Helicobacter pylori/drug effects/metabolism/physiology ; Humans ; Stomach Neoplasms/etiology/*prevention & control ; Virulence Factors/metabolism

BACKGROUND/AIMS: Postprandial symptoms of fullness and abdominal discomfort are common after fatty meals. Gastric lipases hydrolyze 10% to 20% of dietary triglycerides during the stomach trituration period of digestion. The aim of this study was to evaluate the effects of acid-resistant lipase on upper gastrointestinal symptoms, including fullness and bloating, as well as on gastric myoelectrical activity after healthy subjects ingested a high-fat, liquid meal. METHODS: This study utilized a double-blind, placebo-controlled, crossover design with 16 healthy volunteers who ingested either a capsule containing 280 mg of acid-resistant lipase or a placebo immediately before a fatty meal (355 calories, 55% fat). Participants rated their stomach fullness, bloating, and nausea before and at timed intervals for 60 minutes after the meal. Electrogastrograms were obtained to assess the gastric myoelectrical activity. RESULTS: Stomach fullness, bloating, and nausea increased significantly 10 minutes after ingestion of the fatty meal (p<0.01), whereas normal gastric myoelectrical activity decreased and tachygastria increased (p<0.05). With lipase, reports of stomach fullness were significantly lower compared with placebo (p<0.05), but no effect on gastric myoelectrical activity or other upper gastrointestinal symptoms was observed. CONCLUSIONS: The high-fat meal induced transient fullness, bloating, nausea, and tachygastria in healthy individuals, consistent with post-prandial distress syndrome. Acid-resistant lipase supplementation significantly decreased stomach fullness.
Abdominal Pain/etiology/psychology ; Adult ; Cross-Over Studies ; Diet, High-Fat/*adverse effects/psychology ; *Dietary Supplements ; Double-Blind Method ; Dyspepsia/etiology/*prevention & control/psychology ; Female ; Gastrointestinal Motility/drug effects/physiology ; Healthy Volunteers ; Humans ; Lipase/*administration & dosage ; Male ; Meals ; Middle Aged ; Myoelectric Complex, Migrating ; Nausea/etiology/psychology ; Postprandial Period ; Stomach/*drug effects/physiology ; Young Adult

PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1alpha. Recent reports suggested that HIF-1alpha also mediated the induction of class III beta-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1alpha and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro. MATERIALS AND METHODS: The protein expression levels of HIF-1alpha and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel. RESULTS: Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1alpha and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1alpha and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1alpha and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. CONCLUSION: We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.
Angiogenesis Inhibitors/pharmacology ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; *Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockdown Techniques ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Paclitaxel/*pharmacology ; Pregnancy Proteins/pharmacology ; Stomach Neoplasms/drug therapy/genetics ; Tubulin/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors/*physiology ; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors/*physiology

OBJECTIVETo study the effects of lysyl oxidase (LOX) on the migration and adhesion of the human gastric cancer cell line HGC-27 cells in vitro.

METHODSThe human gastric cancer cell line HGC-27 cells were cultured in vitro, and treated with different concentration of β-aminopropionitrile (BAPN). The ability of migration was assessed by wound-healing assay. The ability of adhesion was detected by homogenous and heterogeneous adhesion experiments.

RESULTSCompared that with 0 mmol/L BAPN, the ability of migration of the cells after treatment with 0.2 mmol/L BAPN was descended at 8, 24, 32 and 48 h; the number of cells with homogeneous adhesion was increased from (6.97 ± 0.07) × 10(3)/ml to (7.78 ± 0.11) × 10(3)/ml; and the number of cells with heterogeneous adhesion was decreased from (8.98 ± 0.15) × 10(3)/ml to (8.35 ± 0.10) × 10(3)/ml, both < 0.05. Compared with that of cells treated with 0 mmol/L and 0.2 mmol/L BAPN, the migration ability of cells after treatment with 0.3 mmol/L BAPN was descended at 8, 24, 32 and 48 h; the number of cells with homogeneous adhesion was raised to (8.02 ± 0.11) × 10(3)/ml and the number of cells with heterogeneous adhesion was down to (7.93 ± 0.07) × 10(3)/ml (P < 0.05).

CONCLUSIONLOX may promote the metastasis of cancer cells by enhancing invasion, increasing heterogeneous adhesion and decreasing homogeneous adhesion.

Aminopropionitrile ; administration & dosage ; pharmacology ; Cell Adhesion ; drug effects ; Cell Line, Tumor ; Cell Movement ; drug effects ; Dose-Response Relationship, Drug ; Humans ; Neoplasm Invasiveness ; Protein-Lysine 6-Oxidase ; antagonists & inhibitors ; metabolism ; physiology ; Stomach Neoplasms ; enzymology ; pathology

This study is to observe the difference in pharmacological characteristics between circular smooth muscles of rat isolated gastric body and gastric fundus, and to investigate the effects of nucleoside and nucleotide on circular smooth muscle of the rat gastric body and the involved receptors. Circular muscle strips of the rat gastric body and gastric fundus were prepared, and contractile responses to agonists were investigated with a technique of drug-receptor interaction in functional system. There was no significant difference between the circular muscle strips of the gastric body and gastric fundus in the responses to KCl, and no difference in EC50 values of contractile responses for 5-HT and His between the two kinds of preparations (P > 0.05). However, Emax values of contractile responses to 5-HT and His [(0.81 +/- 0.26) and (0.88 +/- 0.27) g] in gastric body were significantly smaller than those in gastric fundus [(2.67 +/- 0.61) and (1.90 +/- 0.68) g, P < 0.01], and EC50 value of CCh produced contractile response [(0.45 +/- 0.15) micromol x L(-1)] in gastric body was significantly higher than that in gastric fundus [(0.20 +/- 0.09) micromol x L(-1), P < 0.01]. In precontracted circular muscle strips of the gastric body, ATP (0.1-3000 micromol x L(-1)) produced only a contractile response concentration-dependently, but the same concentration of ATP induced a biphasic response (relaxation followed by a contraction) in precontracted circular muscle strips of the gastric fundus. ATP, UTP, ADP, 2-MeSATP and alpha,beta-MeATP produced contractile responses concentration-dependently in circular muscle strips of the rat gastric body. The EC50 value for 2-MeSATP [(7.2 +/- 5.2) nmol x L(-1)] was about 500 times lower than that for Ach [(3.47 +/- 1.20) micromol x L(-1)]. The rank order of potency for the contraction was 2-MeSATP>ADP>ATP=UTP>alpha,beta-MeATP>adenosine. The contractile responses to ATP and UTP were not significantly affected by phentolamine, propranolol, atropine or tetrodotoxin. In conclusion, there is a significant difference in pharmacological characteristics between the circular smooth muscles of the rat gastric body and gastric fundus and nucleotides might be important mediators responsible for the contraction via a specific P2Y receptor in circular smooth muscle of the rat gastric body.
Adenosine ; pharmacology ; Adenosine Diphosphate ; pharmacology ; Adenosine Triphosphate ; analogs & derivatives ; pharmacology ; Animals ; Gastric Fundus ; drug effects ; physiology ; Male ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; physiology ; Purinergic P2 Receptor Agonists ; Rats ; Rats, Wistar ; Receptors, Purinergic P2 ; drug effects ; Stomach ; drug effects ; physiology ; Thionucleotides ; pharmacology ; Uridine Triphosphate ; pharmacology

OBJECTIVEImproving the traditional fermentation technology by some unidentified strains into the modern pure inoculation fermentation technology. For selecting better fermentation strains, the quality of various Shenqu fermentated with different pure inoculation be compared.

METHODIsolating the strains from self-fermented Shenqu, then with other 2 certain strains, to conduct the pure inoculation fermentation. Then compare the quality of them according to the difference in the chemical composition, activity of enzyme and the impact to the digestive function in mice of the finished Shenqu.

RESULTSFour strains were isolated. One of them, a mucor genus of mold is better than others.

CONCLUSIONModern pure inoculation fermentation can ensure the quality and the medication safety of Shenqu. New fermentation technology is feasible.

Animals ; Bacillus subtilis ; growth & development ; metabolism ; Drugs, Chinese Herbal ; metabolism ; pharmacology ; Female ; Fermentation ; physiology ; Food Microbiology ; Male ; Mice ; Random Allocation ; Stomach ; drug effects ; metabolism

OBJECTIVETo investigate the effect and mechanism of ghrelin and its synthetic peptide GHRP-6 on gastric motor in mice.

METHODSIn vivo, the dose-dependent effects of ghrelin (20,50,100,200 mug/kg) and GHRP-6 (20,50,100,200 mug/kg) on gastric emptying were measured by intragastric application of phenol red test which was adapted for use in mice. The effects of atropine, NG-nitro-L-arginine methyl ester (L-NAME), and D-Lys(3)-GHRP-6 (GHS-R antagonist) on the gastric motor induced by ghrelin and GHRP-6 (100 mug/kg) were also investigated. In vitro, the effects of ghrelin (0.01,0.1,1.0,10.0 mumol/L) and GHRP-6 (0.01,0.1,1.0,10.0 mumol/L) on spontaneous contraction of mice fundic muscle strips were studied as well.

RESULTSBoth ghrelin (50,100,200 mug/kg) and GHRP-6 (50,100,200 mug/kg) significantly accelerated gastric emptying (P<0.05), but they failed to accelerate gastric emptying in the presence of atropine, L-NAME and D-Lys(3)-GHRP-6 (P<0.05). Ghrelin (0.1, 1.0, 10.0 mumol/L) and GHRP-6 (0.1, 1.0, 10.0 mumol/L) induced significant contraction of fundic muscle strips in concentration-dependent manner (P<0.05), which could be blocked by tetrodotoxin.

CONCLUSIONGhrelin and its synthetic peptide GHRP-6 accelerate gastric emptying perhaps by activating GHS-R of cholinergic excitatory pathways and nitrergic nervous pathways in the enteric nervous system.

Animals ; Female ; Gastric Emptying ; drug effects ; Ghrelin ; pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Oligopeptides ; pharmacology ; Stomach ; drug effects ; physiology

OBJECTIVETo evaluate the relationship between mammalian target of rapamycin (mTOR) signaling pathway and histone acetylation in cell survival, cell cycle, gene expression and protein level on human gastric cancer cells.

METHODSHuman gastric cancer cell lines, MKN45 and SGC7901 were treated with trichostatin A, rapamycin and/or LY294002, a PI3K inhibitor. Cell viability was analyzed by methylthiazolyl tetrazolium. Cell cycle distribution was evaluated by flow cytometry. The transcription level of p21(WAF1) gene was detected by using real-time polymerase chain reaction. Proteins were detected by Western blotting.

RESULTSCell viability remarkably reduced after treatment by more than two drugs (P< 0.01). Through flow cytometry assessment, MKN45 cells were arrested in G2 phase (P< 0.05), while SGC7901 cells were in G2 or G1 phase (P< 0.05) whether treated with single or more than two drugs. The expression of p21(WAF1) mRNA was remarkably increased in the gastric cancer cells treated with conjoined drugs (P< 0.01). Phosphorylation of Akt, p70S6K and 4E-BP1 was significantly reduced in cells treated with conjoined drugs (P< 0.01). And histone acetylation of H4/H3 was also increased in cells treated with conjoined drugs (P< 0.01).

CONCLUSIONmTOR singnaling pathway has an important relationship with histone acetylation in gastric cancer cell lines. There is a co-effect of mTOR inhibitor and histone deacetylase inhibitor on gastric cancer cells.

Acetylation ; drug effects ; Adaptor Proteins, Signal Transducing ; metabolism ; Blotting, Western ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Chromones ; pharmacology ; Cyclin-Dependent Kinase Inhibitor p21 ; genetics ; Flow Cytometry ; Histones ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Morpholines ; pharmacology ; Phosphoproteins ; metabolism ; Phosphorylation ; drug effects ; Polymerase Chain Reaction ; Protein Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Ribosomal Protein S6 Kinases, 70-kDa ; metabolism ; Signal Transduction ; drug effects ; physiology ; Sirolimus ; pharmacology ; Stomach Neoplasms ; metabolism ; pathology ; physiopathology ; TOR Serine-Threonine Kinases