Sweet regulation - The emerging immunoregulatory roles of hexoses.

BACKGROUND: It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells. AIM OF REVIEW: Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field. KEY SCIENTIFIC CONCEPTS OF REVIEW: Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

Contribution of Rs780094 and Rs1260326 Polymorphisms in GCKR Gene to Non-alcoholic Fatty Liver Disease: A Meta-Analysis Involving 26,552 Participants.

BACKGROUND: Many published studies attempted to elucidate the implication of glucokinase regulator gene (GCKR) polymorphisms in the susceptibility to non-alcoholic fatty liver disease (NAFLD), but the results among them were still controversial. OBJECTIVE: This meta-analysis aims to precisely assess the relationship between the GCKR polymorphisms and the risk of NAFLD. METHODS: Systematic computerized searches in six databases were performed and updated on April 6, 2020. Meta-analyses were conducted by calling the R programs based on accumulated epidemiological data. Odds ratio (OR) and 95% confidential interval (CI) were calculated to summarize the effect estimates. RESULTS: In total, 25 studies including 6,598 cases and 19,954 controls were included. The pooled estimates indicated that the T allele carrier of the GCKR rs780094 polymorphism has predisposition to NAFLD (allele model: OR: 1.20, 95% CI: 1.11~1.29; homozygote model: OR: 1.38, 95% CI: 1.15~1.67; heterozygote model: OR: 1.25, 95% CI: 1.12~1.39; dominant model: OR: 1.29, 95% CI: 1.13~1.47; recessive model: OR: 1.18, 95% CI: 1.06~1.31), and the same as the rs1260326 polymorphism (allele model: OR: 1.32, 95% CI: 1.22~1.42; homozygote model: OR: 1.65, 95% CI: 1.40~1.94; heterozygote model: OR: 1.24, 95% CI: 1.07~1.43; dominant model: OR: 1.39, 95% CI: 1.21~1.59; recessive model: OR: 1.44, 95% CI: 1.28~1.62). Further stratified analyses according to age and ethnicity confirmed the statistical existence in most subgroups. CONCLUSION: This meta-analysis suggested that both of the GCKR rs780094 and rs1260326 polymorphisms are significantly associated with the increased risk of NAFLD.

Effect of the patatin-like phospholipase domain containing 3 gene (PNPLA3) I148M polymorphism on the risk and severity of nonalcoholic fatty liver disease and metabolic syndromes: A meta-analysis of paediatric and adolescent individuals.

BACKGROUND: The effect of the patatin-like phospholipase domain containing 3 gene (PNPLA3) I148M polymorphism on the risk and severity of paediatric and adolescent nonalcoholic fatty liver disease (NAFLD) remains inconclusive. OBJECTIVES: We aimed to estimate the effect of this polymorphism not only on early-onset NAFLD risk and severity but also on metabolic syndromes susceptibility. METHODS: A systematic literature search was performed to identify relevant datasets. The odds ratio of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals were calculated to assess the strength of the associations. RESULTS: Twenty-seven studies comprising 10 070 subjects were eligible. The summary effect showed that this polymorphism increased susceptibility to NAFLD development. Furthermore, it also indicated that nonalcoholic steatohepatitis (NASH) was more frequently observed in G allele carriers among paediatric and adolescent NAFLD patients. Moreover, the meta-analysis suggested that the variant was significantly associated with elevated liver damage indexes, including serum alanine transaminase, aspartate transaminase, gamma-glutamyltransferase concentrations, and liver fat content. However, the summary estimates for insulin resistance, lipid metabolism, and adiposity showed no significant associations. CONCLUSIONS: The PNPLA3 I148M polymorphism is associated with elevated early-onset NAFLD risk, severity, and liver damage but not with related metabolic syndromes.

The ADRB3 rs4994 polymorphism increases risk of childhood and adolescent overweight/obesity for East Asia's population: an evidence-based meta-analysis.

Whether the Adrenoceptor Beta 3 (ADRB3) gene rs4994 polymorphism could affect the individual risk of childhood and adolescent overweight/obesity remains controversial. This meta-analysis was performed to estimate the prevalence of this polymorphism in overweight/obesity, and test the potential association by summarizing existing evidence. Comprehensive literature search in PubMed, Web of Science, Cochrane Library, Wanfang, and CNKI databases was performed to identify eligible data sets. Finally, 16 studies involving 5,147 overweight/obese cases and 7,350 non-obese controls were included for further synthetic analyses. Odds ratio (OR) and its corresponding 95% confidence intervals (CIs) were statistically calculated. Totally, 69.9% of the included subjects came from East Asia. In the meta-analysis for overall population, statistically significant associations with increased risk of childhood and adolescent overweight/obesity were identified in allele model (OR 1.23, 95% CI 1.10-1.38), heterozygote model (OR 1.39, 95% CI 1.16-1.68), and dominant model (OR 1.31, 95% CI 1.12-1.54). Further stratified analysis according to geographical regions revealed that the statistical significance could only be detected in the East Asia subgroup in allele model, homozygote model, heterozygote model, and dominant model. In summary, our meta-analysis indicated that the ADRB3 rs4994 polymorphism could significantly increase the risk of childhood and adolescent overweight/obesity, especially for the East Asia's population.

The MMP-8 rs11225395 Promoter Polymorphism Increases Cancer Risk of Non-Asian Populations: Evidence from a Meta-Analysis.

This meta-analysis aimed to systematically review the evidence on cancer risk of the MMP-8 rs11225395 promoter polymorphism. Relevant studies published by 12 June 2019 were identified by systematically searching PubMed, Web of Science, Cochrane Library, CNKI and Wanfang databases. R programs and STATA software were used to calculate odds ratio (OR) and 95% confidence interval (CI). In total, 7375 cancer samples and 8117 controls were included by integrating 15 case-control data sets. Pooled estimates from the statistical analysis revealed no statistical significance for the association between this polymorphism and cancer risk. All pooled estimates resulting from subgroup analyses by cancer type and sample size were not materially altered and did not draw significantly different conclusions. The stratified analyses according to geographic region showed the statistical significance for increased cancer risk of the MMP-8 rs11225395 polymorphism in non-Asian populations under the allele model (OR = 1.11, 95% CI: 1.04-1.19), homozygote model (OR = 1.22, 95% CI: 1.05-1.41), heterozygote model (OR = 1.21, 95% CI: 1.07-1.36), and dominant model (OR = 1.21, 95% CI: 1.08-1.35). However, no statistical significance was detected in Asian populations. In conclusion, these findings suggested that the MMP-8 rs11225395 polymorphism is associated with elevated susceptibility to cancer in non-Asian populations.