Age is a predicting factor for the association between CagA positive Helicobacter pylori (Hp) infection and serum pepsinogen I:II ratio in a high gastric cancer risk region in China

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Regulation of lipogenesis by toll like receptor pathway: effect on stearyl-CoA Desaturase-1

Conference Theme: A Decade of Positive AgingInflammation is commonly observed in many chronic diseases including metabolic disorders, cardiovascular diseases, cancer and autoimmune diseases which are often associated with aging. Senior patients are often taking multiple drugs to controlling these diseases, and population ageing drastically increases the medical most of these diseases. To reduce such medical burden and improve patient compliance, one of the concepts to develop drugs with multi-target. As inflammation is one of the common pathophysiological factors of these diseases, anti-inflammatory drugs seem to be the drug of choice. Unfortunately, although genetic modified animal model and association studies in human demonstrates positive results, the clinical evidence showing beneficial effect of anti-inflammatory drugs in these chronic diseases is controversial. Many of the positive animal studies have focused the role of toll-like receptor (TLR), a classic pathway of innate immunity, in these diseases. In spite of its immune-originality, many cell types other than immune cells express TLR. Evidence of these positive animal studies only demonstrated the TLR effect mediated by the immune cells, and the function in non-immune cells has largely been ignored. Whether this missing area explains the limited effect of anti-inflammatory drug in these diseases shown in clinical study is noteworthy to be explored. In this project, we used a different angle to study the role of TLR pathway in metabolic diseases. Despite that many studies showed the harmful effect elicited by activation of TLR, our data demonstrated that when we genetic deleted one of the downstream cytosolic branches of TLR pathway, TRIF in mice, they displayed a worsened metabolic phenotype under a high fat diet. Hepatic steatosis and elevated fasting blood glucose were present in these TRIF knockout mice. The increased hepatic accumulation of lipid was due to the abnormal upregulation of lipogenesis pathway in hepatocytes. We further showed that activation of TRIF pathway can inhibit the critical lipogenic protein, stearyl-CoA desaturase -1 (SCD-1) in hepatocytes. It appeared that SCD-1 was a direct target of the downstream transcription factor, interferon regulatory factor-3 (IRF3) which is activated through TRIF pathway. These results highly suggested an unconventional effect of TLR pathway in non-immune cells. This study gave us a new understanding of the role and function of TLR/TRIF pathway in non-immune cells during metabolism, thus a different angle to design a more effective therapeutic strategy in treating multiple chronic diseases including metabolic diseases and their fatal complications

Regulation of adipogenesis by toll-like receptor 5 pathway

Toll-like receptor 5 (TLR5) recognizes the bacterial product, flagellin. Its activation leads to cytokine production that is important for host defense against invading pathogens. In spite of the pro-inflammatory nature of TLR5, deficiency of TLR5 exacerbated metabolic dysfunction in diet-induced obese mouse model (Gewirtz et al. Science, 328: 228-231, 2010). In this study, we found that TLR5 was expressed in both preadipocytes and adipocytes, and tried to characterize the functions of TLR5 in these metabolic cells Six week old wild type (WT) and TLR5-knockout (T5KO) mice were fed a high fat diet for five weeks, andthey both showed a similar body weight gain and daily food intake, but NMR spectroscopy revealed a decreased whole-body fat mass in T5KO mice. Particularly, gonadal adipose tissues in T5KO mice were significantly smaller compared with those in WT, whereas the adipose inflammatory status was unaltered. The in vitro experiments showed that TLR5-deficient stromal vascular cells isolated from visceral fat depots had reduced adipogenic capacity. In addition, elevated triglyceride accumulation was observed in livers from T5KO mice. iIt is possible that TLR5 pathway participates in adipogenesis to mediate adipose tissue expansion and prevents ectopic storage of lipids in liver after high fat diet feeding. It is noteworthy to further explore the possible direct functions of TLR5 in metabolic cells

Metabolic function of toll like receptor mediated by TRIF

Conference Theme: Nutritional Immunology: Role in Health and Diseas

TRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells. The aggravated steatosis in Trif-/- mice was due to the increased hepatocyte transcription of the gene encoding stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), the rate-limiting enzyme for lipogenesis. Activation of the TRIF pathway by polyinosinic:polycytidylic acid [poly(I:C)] suppressed the increase in SCD1 abundance induced by palmitic acid or an HFD and subsequently prevented lipid accumulation in hepatocytes. Interferon regulatory factor 3 (IRF3), a transcriptional regulator downstream of TRIF, acted as a transcriptional suppressor by directly binding to the Scd1 promoter. These results suggest an unconventional metabolic function for TLR/TRIF signaling that should be taken into consideration when seeking to pharmacologically inhibit this pathway

Upper gastrointestinal evaluation of Chinese patients with non-cardiac chest pain

Aims: To test the usefulness of upper gastrointestinal investigations and quality of life assessment in Chinese patients with non-cardiac chest pain. Methods: Seventy-eight consecutive patients with noncardiac chest pain underwent upper endoscopy. Eight patients had upper gastrointestinal pathology (10%). The remaining 70 patients received acid perfusion test, oesophageal manometry and 24-h ambulatory oesophageal pH (n = 65)/manometry (n = 61), and the results were compared with those of healthy controls (n = 20). Symptoms and quality of life (SF-36) were assessed by standard validated questionnaire. Results: Significant acid reflux symptoms were present in five (5/70. 7%) patients. Abnormal 24-h oesophageal pH, indicating gastro-oesophageal reflux, was found in 19 (19/65, 29%) patients. The percentage of simultaneous contractions was higher and the percentage peristalsis was lower in patients with non-cardiac chest pain when compared with normal subjects by 24-h ambulatory manometry. Patients with non-cardiac chest pain had a lower SF-36 score when compared to controls. Conclusions: Typical acid reflux symptoms are uncommon in Chinese patients with non-cardiac chest pain, but abnormal 24-h pH results, indicating gastro-oesophageal reflux, were found in 29% of patients. Ineffective contractions were more frequently found in patients with non-cardiac chest pain by 24-h ambulatory manometry, which may have a bearing on the impaired quality of life in such patients. Upper gastrointestinal investigations are useful for the evaluation of Chinese patients with non-cardiac chest pain.link_to_subscribed_fulltex

Helicobacter pylori Eradication to Prevent Gastric Cancer in a High-Risk Region of China: A Randomized Controlled Trial

Context: Although chronic Helicobacter pylori infection is associated with gastric cancer, the effect of H pylori treatment on prevention of gastric cancer development in chronic carriers is unknown. Objective: To determine whether treatment of H pylori infection reduces the incidence of gastric cancer. Design, Setting, and Participants: Prospective, randomized, placebo-controlled, population-based primary prevention study of 1630 healthy carriers of H pylori infection from Fujian Province, China, recruited in July 1994 and followed up until January 2002. A total of 988 participants did not have precancerous lesions (gastric atrophy, intestinal metaplasia, or gastric dysplasia) on study entry. Intervention: Patients were randomly assigned to receive H pylori eradication treatment: a 2-week course of omeprazole, 20 mg, a combination product of amoxicillin and clavulanate potassium, 750 mg, and metronidazole, 400 mg, all twice daily (n = 817); or placebo (n = 813). Main Outcome Measures: The primary outcome measure was incidence of gastric cancer during follow-up, compared between H pylori eradication and placebo groups. The secondary outcome measure was incidence of gastric cancer in patients with or without precancerous lesions, compared between the 2 groups. Results: Among the 18 new cases of gastric cancers that developed, no overall reduction was observed in participants who received H pylori eradication treatment (n = 7) compared with those who did not (n = 11) (P = .33). In a subgroup of patients with no precancerous lesions on presentation, no patient developed gastric cancer during a follow-up of 7.5 years after H pylori eradication treatment compared with those who received placebo (0 vs 6; P = .02). Smoking (hazard ratio [HR], 6.2; 95% confidence interval [CI], 2.3-16.5; P<.001) and older age (HR, 1. 10; 95% CI, 1.05-1.15; P<.001) were independent risk factors for the development of gastric cancer in this cohort. Conclusions: We found that the incidence of gastric cancer development at the population level was similar between participants receiving H pylori eradication treatment and those receiving placebo during a period of 7.5 years in a high-risk region of China. In the subgroup of H pylori carriers without precancerous lesions, eradication of H pylori significantly decreased the development of gastric cancer. Further studies to investigate the role of H pylori eradication in participants with precancerous lesions are warranted.link_to_subscribed_fulltex