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BackgroundThe loss of tumor suppressor gene expression is involved in the carcinogenesis of gastric cancer (GC). Klotho is a recently identified tumor suppressor gene that epigenetically inactivated in gastric cancer. However, the signaling pathways involved in the suppressive role of klotho have rarely been reported in gastric cancer. In this study, we investigated the involvement of klotho in gastric cancer cell proliferation, apoptosis, and autophagy as well as the associated signaling.MethodsMethylation of klotho gene promoter in GC-7901, MNK-45 and AGS gastric cancer cells as well as GES-1 normal gastric epithelial cells was detected by bisulfate-based PCR. Restoration of klotho gene expression was established by applying a demethylating agent and delivering aklotho gene expression vector into GC-7901 cells. Cell viability was measured by CCK-8 assay. Cell apoptosis and cycling were analyzed by flow cytometry. Autophagy was measured by detecting LC3-I and LC3-II expression. Protein levels and phosphorylation were measured by Western blot assay.ResultsMethylation of klotho gene promoter and expression of the klotho gene were detected in GC cells. Restoration of klotho gene expression significantly inhibited cell proliferation, induced cell apoptosis, and increased LC3-I/LC3-II expression in GC cells. Restoration of klotho gene expression downregulated the phosphorylation levels of IGF-1 receptor, IRS-1, PI3K, Akt, and mTOR proteins. Both apoptosis and autophagy inhibitors blocked klotho-induced apoptosis and autophagy.ConclusionKlotho is a tumor suppressor in gastric cancer, which regulates IGF-1R phosphorylation and the subsequent activation of IRS-1/PI3K/Akt/mTOR signaling, tumor cell proliferation, apoptosis, and autophagy.

The klotho gene is a classical "aging suppressor" gene. Its roles in the pathology of chronic kidney diseases have been well documented. However, the role of Klotho in tumorigenesis, cancer progression, and prognosis is attracting more and more attention. Recent studies have shown that Klotho participates in the progression of several types of human cancers. Klotho functions as a tumor suppressor by inhibiting insulin/IGF1, p53/p21, and Wnt signaling. Silencing klotho gene expression is mainly mediated through promoter hypermethylation and histone deacetylation in cancer. Klotho has been proposed to take part in cell proliferation, survival, autophagy, and resistance to anti-cancer therapies.

Klotho is a tumor suppressor that, through the regulation of IGF-1R phosphorylation and subsequent activation of downstream Akt-p70S6K and ERK signaling, regulates HCC tumor cell proliferation, apoptosis, autophagy and invasion.

Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.

ObjectiveTo evaluate the trend of catastrophic health expenses (CHE) for inpatient care in relation to the commencement of the New Cooperative Medical Scheme (NCMS) in rural China from 2003 to 2013, and the roles of NCMS in protecting affected households from CHE.MethodsWe assessed the 10-year trend of the incidence and severity of CHE in rural households with hospitalised members using data from the Chinese National Health Services Survey. Generalised estimating equations were used to estimate the OR and 95% CI of the association between incidence rates of CHE (true0RCHE) and NCMS reimbursement.ResultsThe incidence and severity of CHE after NCMS reimbursement both decreased and their changes increased rapidly from 2003 to 2013. After adjustment of the covariates, true0RCHE before reimbursement was significantly higher than that after reimbursement, and the OR (95% CI) was 1.50 (1.24 to 1.81), 1.79 (1.69 to 1.90) and 2.94 (2.77 to 3.11) in 2003, 2008 and 2013, respectively.ConclusionThe incidence and severity of CHE both reduced after NCMS reimbursements in each year. Excluding some confounding factors, true0RCHE was significantly associated with NCMS reimbursement. NCMS partly protected the rural households with hospitalised members from CHE. However, the inequalities between different income groups still existed. true0RCHE in rural households with hospitalised members was still rather high in 2003, 2008 and 2013 even though they were covered by NCMS. This study will provide suggestions for further reforms in China and guidance for other low-income/middle-income countries.

BackgroundIn children with Henoch-Schonlein purpura (HSP), the severity of Henoch-Schonlein purpura nephritis (HSPN) is considered responsible for the prognosis of HSP. The pathological process from HSP to HSPN is not clear yet and current diagnostic tools have shortcomings in accurate diagnosis of HSPN. This study aims to assess clinical characteristics of HSP and HSPN, to identify metabolic perturbations involved in HSP progress, and to combine metabolic biomarkers and clinical features into a better prediction for HSPN.MethodsA total of 162 children were recruited, including 109 HSP patients and 53 healthy children (HC). The clinical characteristics were compared between HSPN and HSP without nephritis (HSPWN). The serum metabonomics analysis was performed to determine the metabolic differences in HSP and HC.ResultsAmong 109 HSP children, 57 progressed to HSPN. The increased D-dimer level was significantly associated with renal damage in HSP. The metabonomic profiles revealed alterations between various subgroups of HSP and HC, making it possible to investigate small-molecule metabolites related to the pathological process of HSP. In total, we identified 9 biomarkers for HSP vs. HC, 7 for HSPWN vs. HC, 9 for HSPN vs. HC, and 3 for HSPN vs. HSPWN.Conclusions(S)-3-hydroxyisobutyric acid, p-Cresol sulfate, and 3-carboxy-4-methyl-5-pentyl-2-furanpropanoic acid were found associated with the progress of HSP to HSPN. Moreover, resulting biomarkers, when combined with D-dimer, allowed improving the HSPN prediction with high sensitivity (94.7%) and specificity (80.8%). Together these findings highlighted the strength of the combination of metabonomics and clinical analysis in the research of HSP.

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