Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1.

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE2, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1.

Uncovering the Mechanisms and Molecular Targets of Weibing Formula 1 against Gastritis: Coupling Network Pharmacology with GEO Database.

Weibing Formula 1, a classic traditional formula, has been widely used clinically to treat gastritis in recent years. However, the potential pharmacological mechanism of Weibing Formula 1 is still unclear to date. A network pharmacology-based strategy was performed to uncover the underlying mechanisms of Weibing Formula 1 against gastritis. Furthermore, we structured the drug-active ingredients-genes-disease network and PPI network of shared targets, and function enrichment analysis of these targets was carried out. Ultimately, Gene Expression Omnibus (GEO) datasets and real-time quantitative PCR were used to verify the related genes. We found 251 potential targets corresponding to 135 bioactive components of Weibing Formula 1. Then, 327 gastritis-related targets were known gastritis-related targets. Among which, 60 common targets were shared between potential targets of Weibing Formula 1 and known gastritis-related targets. The results of pathway enrichment analysis displayed that 60 common targets mostly participated in various pathways related to Toll-like receptor signaling pathway, MAPK signaling pathway, cytokine-cytokine receptor interaction pathway, chemokine signaling pathway, and apoptosis. Based on the GSE60427 dataset, 15 common genes were shared between differentially expressed genes and 60 candidate targets. The verification results of the GSE5081 dataset showed that except for DUOX2 and VCAM1, the other 13 genes were significantly upregulated in gastritis, which was consistent with the results in the GSE60427 dataset. More importantly, real-time quantitative PCR results showed that the expressions of PTGS2, MMP9, CXCL2, and CXCL8 were significantly upregulated and NOS2, EGFR, and IL-10 were downregulated in gastritis patients, while the expressions of PTGS2, MMP9, CXCL2, and CXCL8 were significantly downregulated and NOS2, EGFR, and IL-10 were upregulated after the treatment of Weibing Formula 1. PTGS2, NOS2, EGFR, MMP9, CXCL2, CXCL8, and IL-10 may be the important direct targets of Weibing Formula 1 in gastritis treatment. Our study revealed the mechanism of Weibing Formula 1 in gastritis from an overall and systematic perspective, providing a theoretical basis for further knowing and application of this formula in the future.

Comparative serum microRNA array analysis of the spleen-stomach dampness-heat syndrome in different diseases: Chronic hepatitis B and chronic gastritis.

Spleen-stomach dampness-heat syndrome (SSDHS) is the common Traditional Chinese Medicine (TCM) syndrome observed in both chronic hepatitis B (CHB) and chronic gastritis (CG). The specialized TCM prescription for CHB and CG patients with SSDHS is same, but there is limited information about the biological characteristics of this TCM syndrome. This study aimed to identify the serum miRNAs profile for the SSDHS in two different diseases in order to evaluate the miRNA-mediated biological characteristics of this TCM syndrome. We performed comparative microarray analysis of serum miRNA expression profiles in 10 CHB patients with SSDHS (SSDHS-CHB), 10 CG patients with SSDHS (SSDHS-CG), and 10 healthy controls (HC). The selected miRNAs were further validated by qRT-PCR in 13 SSDHS-CHB patients, 13 SSDHS-CG patients, and 13 HC. Moreover, bioinformatics analysis (GO and KEGG pathway enrichment analyses) was applied to identify the involved target genes and pathways for these selected miRNAs. Nine significantly differentially expressed (SDE)-miRNAs in the SSDHS-CHB group and 24 SDE-miRNAs in the SSDHS-CG group were identified, compared with the HC group (fold change >2.0 and p < .05). Among these, upregulated hsa-miR-483-3p and downregulated hsa-miR-223-3p were identified as the common SDE-miRNAs for both SSDHS-CHB and SSDHS-CG groups. Bioinformatics analysis of the common SDE-miRNA's target genes showed their involvement in the regulation of inflammation, immune response, and tumorigenesis. SSDHS-specific hsa-miR-483-3p and hsa-miR-223-3p identified in this study indicated a relevance to the underlying biological basis of SSDHS, and may provide scientific basis for the application of same TCM prescription in CHB and CG.

Mechanism underlying Polygonum capitatum effect on Helicobacter pylori-associated gastritis based on network pharmacology.

Helicobacter pylori (H. pylori) infection is a common disease that can cause H. pylori-associated gastritis (HAG), peptic ulcers, and gastric cancer. As a traditional Chinese medicine, Polygonum capitatum (PC) manifests its unique advantages in the prevention and treatment of complex diseases and chronic diseases, due to its ability to clear heat, detoxify and relieve pain, promote blood circulation, and remove blood stasis. In order to explore the molecular mechanism of PC for HAG, the study collected the predicted targets of active compounds, conducted functional analysis by the STRING database, collected HAG differential expression genes, and conducted KEGG enrichment analysis on the intersection of predicted targets and differential expression genes of gastritis by Cluego. The results show that PC works mainly by affecting phosphorylation of IκBα, NF-κB p65, p38MAPK, and ERK1/2 and nuclear transposition of NF-κB p65 and p-p38MAPK, which has been proved by in vivo and in vitro experiments. These results suggest that PC may act on HAG with multiple targets and pathways, and play a key role in the process of HAG treatment.

Antiulcer Activity of Steamed Ginger Extract against Ethanol/HCl-Induced Gastric Mucosal Injury in Rats.

Ginger (Zingiber officianale), the most widely consumed species, is traditionally used as a folk medicine to treat some inflammatory diseases in China and Korea. However, the functional activity of steamed ginger extract on gastric ulcers has not been previously explored. The present study aimed to investigate antiulcer activity of steamed ginger extract (GGE03) against ethanol (EtOH)/HCl-induced gastric ulcers in a rat model. GGE03 (100 mg/kg) was orally administered for 14 days to rats before oral intubation of an EtOH/HCl mixture to induce gastric damage. Pretreatment with GGE03 markedly protected the formation of microscopic pathological damage in the gastric mucosa. Further, administration of GGE03 significantly increased mucosal total nitrate/nitrite production in gastric tissues, and elevated total GSH content, catalase activity and superoxide dismutase (SOD) expression as well as decreasing lipid peroxidation and myeloperoxidase (MPO) activity. Underlying protective mechanisms were examined by assessing inflammation-related genes, including nuclear factor-κB (NF-κB), prostaglandin E2 (PGE2), and pro-inflammatory cytokines levels. GGE03 administration significantly reduced the expression of NF-κB and pro-inflammatory cytokines. Our findings suggest that GGE03 possesses antiulcer activity by attenuating oxidative stress and inflammatory responses.

Network Pharmacology to Uncover the Biological Basis of Spleen Qi Deficiency Syndrome and Herbal Treatment.

Spleen qi deficiency (SQD) syndrome is one of the basic traditional Chinese medicine (TCM) syndromes related to various diseases including chronic inflammation and hypertension and guides the use of many herbal formulae. However, the biological basis of SQD syndrome has not been clearly elucidated due to the lack of appropriate methodologies. Here, we propose a network pharmacology strategy integrating computational, clinical, and experimental investigation to study the biological basis of SQD syndrome. From computational aspects, we used a powerful disease gene prediction algorithm to predict the SQD syndrome biomolecular network which is significantly enriched in biological functions including immune regulation, oxidative stress, and lipid metabolism. From clinical aspects, SQD syndrome is involved in both the local and holistic disorders, that is, the digestive diseases and the whole body's dysfunctions. We, respectively, investigate SQD syndrome-related digestive diseases including chronic gastritis and irritable bowel syndrome and the whole body's dysfunctions such as chronic fatigue syndrome and hypertension. We found innate immune and oxidative stress modules of SQD syndrome biomolecular network dysfunction in chronic gastritis patients and irritable bowel syndrome patients. Lymphocyte modules were downregulated in chronic fatigue syndrome patients and hypertension patients. From experimental aspects, network pharmacology analysis suggested that targets of Radix Astragali and other four herbs commonly used for SQD syndrome are significantly enriched in the SQD syndrome biomolecular network. Experiments further validated that Radix Astragali ingredients promoted immune modules such as macrophage proliferation and lymphocyte proliferation. These findings indicate that the biological basis of SQD syndrome is closely related to insufficient immune response including decreased macrophage activity and reduced lymphocyte proliferation. This study not only demonstrates the potential biological basis of SQD syndrome but also provides a novel strategy for exploring relevant molecular mechanisms of disease-syndrome-herb from the network pharmacology perspective.

Pharmacological Effects of Agastache rugosa against Gastritis Using a Network Pharmacology Approach.

Agastache rugosa is used as a Korean traditional medicine to treat gastric diseases. However, the active ingredients and pharmacological targets of A. rugosa are unknown. In this study, we aimed to reveal the pharmacological effects of A. rugosa on gastritis by combining a mice model and a network pharmacology method. The macrophage and gastritis-induced models were used to evaluate the pharmacological effects of A. rugosa. The results show that A. rugosa relieved mucosal damage induced by HCl/EtOH in vivo. Network analysis identified 99 components in A. rugosa; six components were selected through systematic screening, and five components were linked to 45 gastritis-related genes. The main components were acacetin and luteolin, and the identified core genes were AKT serine/threonine kinase 1 (AKT1), nuclear factor kappa B inhibitor alpha (NFKBIA), and mitogen-activated protein kinase-3 (MAPK3) etc. in this network. The network of components, target genes, protein-protein interactions, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was closely connected with chemokines and with phosphoinositide 3-kinase-Akt (PI3K/AKT), tumor-necrosis-factor alpha (TNFα), mitogen-activated protein kinase, nuclear factor kappa B, and Toll-like receptor (TLR) pathways. In conclusion, A. rugosa exerts gastro-protective effects through a multi-compound and multi-pathway regulatory network and holds potential for treating inflammatory gastric diseases.

Anti-inflammatory activities of Canarium subulatum Guillaumin methanol extract operate by targeting Src and Syk in the NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Canarium subulatum Guillaumin is an herbal medicinal plant native to Southeast Asia. Ethnopharmacological evidence suggests that plants of the genus Canarium cure a variety of inflammatory diseases. AIM OF THE STUDY: The pharmacological mechanisms of C. subulatum Guillaumin remain poorly understood. In this study, we investigate inflammatory mechanisms and target molecules using C. subulatum Guillaumin methanol extract (Cs-ME) in inflammatory reactions managed by macrophages. MATERIALS AND METHODS: To identify the anti-inflammatory activities of Cs-ME, lipopolysaccharide (LPS)-stimulated macrophages and a murine HCl/EtOH-induced gastritis model were chosen. The luciferase reporter gene assay, Western blot analysis, overexpression strategy, and the cellular thermal shift assay (CETSA) were employed to investigate the molecular mechanisms and target enzymes of Cs-ME. The active ingredients of this extract were also determined by HPLC. RESULTS: Released levels of nitric oxide (NO) and mRNA expression levels of iNOS and IL-6 were downregulated by Cs-ME without exhibiting cytotoxicity. This extract inhibited MyD88-induced promoter activity and the nuclear translocation of nuclear factor (NF)-κB. Moreover, we found that Cs-ME reduced the phosphorylation of NF-κB upstream signaling molecules including IκBα, IKKα/ß, Src, and Syk in LPS-stimulated macrophage-like RAW264.7 cells. The results of Western blot and CETSA confirmed that Src and Syk are anti-inflammatory targets of Cs-ME. In addition, orally injected Cs-ME alleviated HCl/EtOH-induced gastric ulcers in mice. HPLC analysis indicated that quercetin, luteolin, and kaempferol are major active components of this extract with anti-inflammatory activity. CONCLUSIONS: Cs-ME exhibits anti-inflammatory effects in vitro and in vivo by targeting Src and Syk in the NF-κB signaling pathway. Consequently, Cs-ME could be developed as an anti-inflammatory herbal medicine.

Network pharmacology-based strategy to investigate pharmacological mechanisms of Zuojinwan for treatment of gastritis.

BACKGROUND: Zuojinwan (ZJW), a classic herbal formula, has been extensively used to treat gastric symptoms in clinical practice in China for centuries. However, the pharmacological mechanisms of ZJW still remain vague to date. METHODS: In the present work, a network pharmacology-based strategy was proposed to elucidate its underlying multi-component, multi-target, and multi-pathway mode of action against gastritis. First we collected putative targets of ZJW based on TCMSP and STITCH databases, and a network containing the interactions between the putative targets of ZJW and known therapeutic targets of gastritis was built. Then four topological parameters, "degree", "betweenness", "closeness", and "coreness" were calculated to identify the major targets in the network. Furthermore, the major hubs were imported to the Metacore database to perform a pathway enrichment analysis. RESULTS: A total of 118 nodes including 59 putative targets of ZJW were picked out as major hubs in terms of their topological importance. The results of pathway enrichment analysis indicated that putative targets of ZJW mostly participated in various pathways associated with anti-inflammation response, growth and development promotion and G-protein-coupled receptor signaling. More importantly, five putative targets of ZJW (EGFR, IL-6, IL-1ß, TNF-α and MCP-1) and two known therapeutic targets of gastritis (CCKBR and IL-12ß) and a link target NF-κB were recognized as active factors involved in the main biological functions of treatment, implying the underlying mechanisms of ZJW acting on gastritis. CONCLUSION: ZJW could alleviate gastritis through the molecular mechanisms predicted by network pharmacology, and this research demonstrates that the network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine (TCM) from a holistic perspective.

Strawberry tannins inhibit IL-8 secretion in a cell model of gastric inflammation.

In the present study we chemically profiled tannin-enriched extracts from strawberries and tested their biological properties in a cell model of gastric inflammation. The chemical and biological features of strawberry tannins after in vitro simulated gastric digestion were investigated as well. The anti-inflammatory activities of pure strawberry tannins were assayed to get mechanistic insights. Tannin-enriched extracts from strawberries inhibit IL-8 secretion in TNFα-treated human gastric epithelial cells by dampening the NF-κB signaling. In vitro simulated gastric digestion slightly affected the chemical composition and the biological properties of strawberry tannins. By using pure compounds, we found that casuarictin may act as a pure NF-κB inhibitor while agrimoniin inhibits IL-8 secretion also acting on other biological targets; in our system procyanidin B1 prevents the TNFα-induced effects without interfering with the NF-κB pathway. We conclude that strawberry tannins, even after in vitro simulated gastric digestion, exert anti-inflammatory activities at nutritionally relevant concentrations.

PDK1 in NF-κB signaling is a target of Xanthium strumarium methanolic extract-mediated anti-inflammatory activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Xanthium strumarium L. (Asteraceae) has traditionally been used to treat bacterial infections, nasal sinusitis, urticaria, arthritis, chronic bronchitis and rhinitis, allergic rhinitis, edema, lumbago, and other ailments. However, the molecular mechanisms by which this plant exerts its anti-inflammatory effects are poorly characterized. Here we studied the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Xs-ME) and validated its pharmacological targets. MATERIALS AND METHODS: To evaluate the anti-inflammatory activity of Xs-ME, we employed lipopolysaccharide (LPS)-treated macrophages and an HCl/EtOH-induced mouse model of gastritis. We also used HPLC to identify the potentially active anti-inflammatory components of this extract. The molecular mechanisms of its anti-inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes. RESULTS: The production of nitric oxide (NO) and prostaglandin E2 (PGE2) were both suppressed by Xs-ME. Moreover, orally administered Xs-ME ameliorated HCl/EtOH-induced gastric lesions. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-κB. Signaling events upstream of NF-κB translocation, such as phosphorylation of AKT and the formation of PDK1-AKT signaling complexes, were also inhibited by Xs-ME. Moreover, Xs-ME suppressed the enzymatic activity of PDK1. Additionally, PDK1-induced luciferase activity and Akt phosphorylation were both inhibited by Xs-ME. We also identified the polyphenol resveratrol as a likely active anti-inflammatory component in Xs-ME that targets PDK1. CONCLUSION: Xs-ME exerts anti-inflammatory activity in vitro and in vivo by inhibiting PDK1 kinase activity and blocking signaling to its downstream transcription factor, NF-κB.

MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms.

Autoimmune gastritis is an organ-specific autoimmune disease of the stomach associated with pernicious anemia. The previous work from us and other groups identified MCPIP1 as an essential factor controlling inflammation and immune homeostasis. MCPIP1(-/-) developed severe anemia. However, the mechanisms underlying this phenotype remain unclear. In the present study, we found that MCPIP1 deficiency in mice resulted in severe anemia related to autoimmune mechanisms. Although MCPIP1 deficiency did not affect erythropoiesis per se, the erythropoiesis in MCPIP1(-/-) bone marrow erythroblasts was significantly attenuated due to iron and vitamin B12 (VB12) deficiency, which was mainly resulted from autoimmunity-associated gastritis and parietal cell loss. Consistently, exogenous supplement of iron and VB12 greatly improved the anemia phenotype of MCPIP1(-/-) mice. Finally, we have evidence suggesting that autoimmune hemolysis may also contribute to anemia phenotype of MCPIP1(-/-) mice. Taken together, our study suggests that MCPIP1 deficiency in mice leads to the development of autoimmune gastritis and pernicious anemia. Thus, MCPIP1(-/-) mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease.

Effect of moxibustion treatment on cell apoptosis and expressions of heat shock protein and second mitochondrial activator of caspase in acute gastric mucosal lesion of rats.

OBJECTIVE: To investigate the effect of moxibustion-acupoint treatment with acupoints of Zusanli (ST 36) and Zhongwan (RN 12) on cell apoptosis and the expressions of heat shock protein (HSP) 60, HSP70 and second mitochondrial activator of caspase (Smac) in rat models of acute gastric mucosal lesion (AGML), and explore the mechanisms underlying protection of gastric mucosal lesion. METHODS: Twenty-four Sprague Dawley rats were divided into 3 groups, blank controlled group (group A), controlled-point group (group B) and acupoint group (group C), 8 for each. After 8-day moxibustion treatment in group B and C, gastric lavage of anhydrous ethanol was used to created AGML in all three groups. The Guth method was employed to measure the ulcer index (UI) of gastric mucosal lesion and immunohistochemistry used to measure apoptosis with apoptosis index (AI) and examine the expressions of HSP60, HSP70 and Smac. RESULTS: Compared with group A, the expressions of UI, AI, Smac and HSP60 were markedly elevated in group B (P < 0.05 or P < 0.01). However the expression of HSP70 showed no obvious change (P > 0.05); the expressions of UI, HSP60 and HSP70 were markedly elevated in group C (P < 0.01) while those of AI and Smac became obviously suppressed (P < 0.01). Compared with group B, the expressions of UI, AI and Smac decreased significantly in group C (P < 0.01) while those of HSP60 and HSP70 increased markedly (P < 0.01), and the expressions of HSP60 and HSP70 were considerably up-regulated (P < 0.01). CONCLUSION: The moxibustion treatment could alleviate the gastric mucosal lesion caused by anhydrous ethanol, induce the over-expressions of HSP60 and HSP70, and down-regulate the expression of Smac, which could suppress cell apoptosis.

[Research on differentially expressed genes related to substance and energy metabolism between healthy volunteers and splenasthenic syndrome patients with chronic superficial gastritis].

OBJECTIVE: To analyze the metabolic states of the lipids, protein, carbohydrate, and nucleic acid for chronic superficial gastritis patients of splenasthenic syndrome (SS), and to explore the pathogenesis mechanism of SS based on substance and energy metabolisms. METHODS: During June 2004 to March 2005, recruited were four chronic superficial gastritis patients of SS who visited at the First Hospital of Guangzhou University of Chinese Medicine and Guangdong Provincial Hospital of Traditional Chinese Medicine. Four healthy volunteers were recruited from Guangzhou University of Chinese Medicine. Their gastric mucosa was extracted to perform experiments of DNA microarray. The dual-channel DNA microarray data were mined and bioinformatics analyzed by BRB ArrayTools and IPA software. RESULTS: Fifteen genes were involved in substance and energy metabolisms in 20 differentially expressed genes, accounting for 75%.Among these genes, one gene was up-regulated, 14 genes down-regulated, and 11 genes were enzyme gene. Differentially expressed genes related to lipid metabolism included ACAA2 and CYP20A1, manifested as fatty acid catabolism and cholesterol transformation. Genes related to protein metabolism included ALDH9A1, ASL, ASS1, PCY-OX1L, RPS28, UBE2D2, UBXN1, B3GNT1, GCNT1, and PPP1R3C, manifested as decreased amino acid metabolism that may affect the biologic processes such as autonomic nerve, urea cycle, etc., reduced protein synthesis, increased ubiquitination of fault fold proteins, and decreased post-translated modification of glycosylation and dephosphorylation. Genes related to carbohydrate metabolism included PPP1R3C, B3GNT1, and GCNT1, manifested as decreased glycogen and glycan syntheses. Genes related to nucleic acid metabolism included RMI1, SMARCD3, and PARP1, manifested as degraded DNA duplication and transcription, and increased DNA damage repair. CONCLUSIONS: The metabolisms of the lipids, protein, carbohydrate, and nucleic acid in chronic superficial gastritis patients of SS obviously decreased, manifested mainly as down-regulated enzyme gene expression. We inferred that these might be one of the vital pathogenesis mechanisms for nutrition dysmetabolism of SS.

Imbalanced network biomarkers for traditional Chinese medicine Syndrome in gastritis patients.

Cold Syndrome and Hot Syndrome are thousand-year-old key therapeutic concepts in traditional Chinese medicine (TCM), which depict the loss of body homeostasis. However, the scientific basis of TCM Syndrome remains unclear due to limitations of current reductionist approaches. Here, we established a network balance model to evaluate the imbalanced network underlying TCM Syndrome and find potential biomarkers. By implementing this approach and investigating a group of chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG) patients, we found that with leptin as a biomarker, Cold Syndrome patients experience low levels of energy metabolism, while the CCL2/MCP1 biomarker indicated that immune regulation is intensified in Hot Syndrome patients. Such a metabolism-immune imbalanced network is consistent during the course from CSG to CAG. This work provides a new way to understand TCM Syndrome scientifically, which in turn benefits the personalized medicine in terms of the ancient medicine and complex biological systems.

[Study on gene differential expressions of substance and energy metabolism in chronic superficial gastritis patients of Pi deficiency syndrome and of pi-wei hygropyrexia syndrome].

OBJECTIVE: To analyze the metabolic levels of energy and substance in chronic superficial gastritis (CSG) patients of Pi deficiency syndrome (PDS) and of Pi-Wei hygropyrexia syndrome (PWHS), including lipid, protein, nucleic acid, carbohydrate, trace element, and energy metabolism, and to study the pathogenesis mechanism of PDS from substance and energy metabolisms. METHODS: Recruited were 8 CSG patients who visited at First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine and Guangdong Provincial Hospital of Traditional Chinese Medicine from June 2004 to March 2005, including 4 patients of PDS and 4 of PWHS. Their gastric mucosae were used for experiments of DNA microarray. The dual-channel DNA microarray data were bioinformatically analyzed by BRB ArrayTools and IPA Software. RESULTS: Obtained were fifty-six differentially expressed genes involved in substance and energy metabolisms with the expression fold more than 2, including 11 genes up-regulated and 45 genes down-regulated. Of them, genes correlated to lipid metabolism included CRLS1, LRP11, FUT9, GPCPD1, PIGL, SULT1A4, B3GNT1, ST8SIA4, and ACADVL, mainly involved in the metabolic processes of fatty acid, cholesterol, phospholipids, and glycolipid. Genes correlated to protein metabolism included ASRGL1, AARSD1, EBNA1BP2, PUM2, MRPL52, C120RF65, PSMB8, PSME2, UBA7, RNF11, FBXO44, ZFYVE26, CHMP2A, SSR4, SNX4, RAB3B, RABL2A, GOLGA2, KDELR1, PHPT1, ACPP, PTPRF, CRKL, HDAC7, ADPRHL2, B3GNT1, ST8SIA4, DDOST, and FUT9, mainly involved in the biosynthesis processes of protein, ubiquitination, targeted transport and post-translation modification. Genes correlated to nucleic acid metabolism included DFFB, FLJ35220, TOP2A, SF3A3, CREB3, CRTC2, NR1D2, MED6, GTF2IRD1, C1ORF83, ZNF773, and ZMYND11, mainly involved in DNA replication and repair, transcription regulation. Genes correlated to carbohydrate metabolism included AGL, B3GNT1, FUT9, ST8SIA4, SULT1A4, DDOST, and PIGL, mainly involved in glucogen degradation and glycoconjugate biosynthesis. Genes correlated to trace element metabolism included COMMD1, SLC39A6, FTL, CHRFAM7A, SCGN, and S100A6, mainly involved in ion metabolisms of copper, zinc, ferri, and calcium. Genes correlated to energy metabolism included AK3 and COX7B, mainly involved in mitochondria structure and oxidative phosphorylation processes. CONCLUSION: The metabolic levels of energy and substance including lipid, protein, nucleic acid, carbohydrate, and trace element were obviously reduced in patients of PDS, which might be an important pathogenesis mechanism for its occurrence.

Multiple-antibiotic-resistant Helicobacter pylori infection eradicated with a tailor-made quadruple therapy.

In 2008, a 44-year-old woman with mild epigastralgia diagnosed as having Helicobacter pylori-positive chronic gastritis without peptic ulcer underwent eradication therapy with lansoprazole (LPZ), amoxicillin (AMPC) and clarithromycin (CAM) for 7 days, but it failed, so treatment with rabeprazole, AMPC, and metronidazole (MNZ) for another 7 days was given, but it also failed. She was then prescribed a modified, 14-day sequential therapy of LPZ and AMPC with an increased dose of CAM followed by MNZ supplement, but the infection was still not eradicated. The H. pylori was cultured and examined for antibiotic susceptibility with the agar dilution method and was found to be resistant to CAM, MNZ, and levofloxacin, and non-sensitive to AMPC, namely multiple-antibiotic-resistant, although sensitive to minocycline. The CYP2C19 genotype of the patient was an extensive metabolizer (G681A: G/A, G636A: G/G). In 2010, she gave informed consent for a 14-day, tailor-made, modified classical (or modified high-dose PPI + AMPC) quadruple therapy comprising 30 mg LPZ, 500 mg AMPC and 500 mg bismuth subnitrate, qid, and 100 mg minocycline, bid. Two months later, her urea breath test was negative. Histology and bacterial culture were still negative 1 year after the therapy. She did not have any adverse events during or after the novel therapy, nor did she feel any further epigastralgia.

Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice.

BACKGROUND & AIMS: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. METHODS: Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues. RESULTS: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers. CONCLUSIONS: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.

New phytopharmaceutical agent CJ-20001 modulates stress-induced inflammatory infiltration into gastric mucosa.

BACKGROUND/AIMS: CJ-20001 is a phytopharmaceutical agent and currently being investigated in a Phase II trial for the treatment of acute and chronic gastritis patients in Korea. In this study we addressed the protective effects of CJ-20001 against water immersion restraint stress (WIRS)-induced gastric injury in rats and studied the underlying mechanisms. METHODOLOGY: To evaluate the protective effect of CJ-20001 on stress-induced gastric lesions, rats were exposed to water immersion restraint stress. Inflammatory infiltration into gastric mucosa was examined by immunohistochemistry and in vitro invasion assay. Expression of proinflammatory cytokines was detected with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Pretreatment with CJ-20001 dose-dependently attenuated the WIRS-induced gastric lesions as demonstrated by gross pathology and histology. WIRS increased infiltration of mast cells and macrophages into the gastric mucosa and submucosal layer, whereas the inflammatory infiltration was markedly inhibited by CJ-20001 administration. An in vitro cell invasion assay showed that treatment with CJ-20001 decreased the migration of macrophages. CJ-20001 suppressed the expression of proinflammatory cytokines, IL-18, IP-10 and GRO/KC, in lipopolysaccharides (LPS)-treated macrophages. CONCLUSIONS: These data suggest that novel phytopharmaceutical agent CJ-20001 has the potent anti-inflammatory properties through inhibition of inflammatory infiltration in psycho-physiological stress-induced gastric injury.

[Effect of jianpi yiqi qingyou decoction on lymphocyte subsets and IL-2 mRNA in gastric tissue in rats with chronic superficial gastritis].

OBJECTIVE: To investigate the effect of Jianpi Yiqi Qingyou decoction on lymphocyte subsets and IL-2 mRNA in gastric tissue in rats with chronic superficial gastritis. METHOD: Wistar rats were randomly divided into 6 groups (11 for each): a blank control groups, the model of the control groups, the treatment groups (low-dose groups of traditional Chinese medicine, moderate-dose groups of traditional Chinese medicine, high-dose groups of traditional Chinese medicine) and lansoprazole groups. The models were made with the method in reference except a blank control groups. These rats are drinking freely with 0. 02% ammonia, continuous 90 days, and made preparations for experimental animal model of superficial gastritis. Making the model were detected by HE dying. The count of CD3+, CD4+ and CD8+ T cells were detected by immunohistochemistry. Using reverse transcriptase polymerase chain reaction (RT-PCR), the expression levels of IL-2 mRNA in gastric tissue were quantified. RESULT: Compared with that in model groups, the content of CD3+ T cells and CD4+ T cells in gastric tissue obviously increased in high dose of traditional Chinese medicine groups , the content of CD8+ T cells in gastric tissue obviously decreased in high dose of traditional Chinese medicine groups and the difference was significant (P < 0.01). The expression levels of IL-2 mRNA in gastric tissue obviously increased in moderate and high doses of traditional Chinese medicine groups, and the difference was significant compared with that in model group (P < 0.01). CONCLUSION: Jianpi Yiqi Qingyou decoction can obviously improve the content of CD3+ T cells and CD4+ T cells and the expression levels of IL-2 mRNA, decrease the content of CD8+ T cells in gastric tissue, improve immunity of rats. So the research results can provide some evidences for the treatment for chronic superficial gastritis.