Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis.

AIMS: Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. MAIN METHODS: Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. KEY FINDINGS: During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis. SIGNIFICANCE: IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.

Circulating Biomarkers for Predicting Infliximab Response in Rheumatoid Arthritis: A Systematic Bioinformatics Analysis.

BACKGROUND Infliximab shows good efficacy in treating refractory rheumatoid arthritis (RA). However, many patients responded poorly and related studies were inconsistent in predictive biomarkers. This study aimed to identify circulating biomarkers for predicting infliximab response in RA. MATERIAL AND METHODS Public databases of Gene Expression Omnibus (GEO) and ArrayExpress were searched for related microarray datasets, focused on the response to infliximab in RA. All peripheral blood samples were collected before infliximab treatment and gene expression profiles were measured using microarray. Differential genes associated with infliximab efficacy were analyzed. The genes recognized by half of the datasets were regarded as candidate biomarkers and validated by prospective datasets. RESULTS Eight microarray datasets were identified with 374 blood samples of RA patients, among which 191 (51.1%) were diagnosed as non-responders in the subsequent infliximab treatment. Five genes (FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1) were associated with the efficacy and recognized by half of the datasets. The 5-gene model showed a good predictive power in random- and prospective-designed studies, with AUC (area under receiver operating characteristic [ROC] curve)=0.963 and 1.000, and it was also applicable at the early phase of treatment (at week 2) for predicting the response at week 14 (AUC=1.000). In the placebo group, the model failed to predict the response (AUC=0.697), indicating the model's specificity in infliximab treatment. CONCLUSIONS The model of FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1 in peripheral blood is useful for efficiently predicting the response to infliximab treatment in rheumatoid arthritis.

Elevated circulating Neuregulin4 level in patients with diabetes.

BACKGROUND: Neuregulin4 (Nrg4) is a novel adipokine expressed in adipose tissues, enriched in brown adipose tissue, and able to improve whole-body metabolism in rodent, thus having the potential to treat obesity-associated disorders such as diabetes. However, the association between serum Nrg4 levels and diabetes risk in human remains unclear. This study was designed to examine circulating Nrg4 levels in subjects with different glucose tolerance status. METHODS: Age-, sex-, and body mass index-matched subjects (n = 310: 83 normal glucose tolerance [NGT], 129 prediabetes, and 96 diabetes) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (Reaction study) were included. Serum Nrg4 was measured via enzyme-linked immunosorbent assay. Basic anthropometric parameters, fasting plasma glucose and 2-hours postload plasma glucose, hemoglobin A1c , and serum lipid profile were also measured. RESULTS: The serum Nrg4 levels were higher in patients with diabetes than those with NGT and prediabetes (diabetes: 396.8[65.9, 709.4], NGT: 80.1[0, 554.1], prediabetes: 168.0[32.9, 463.9] pg/mL [median (interquartile range), both P < 0.05]). The Nrg4 concentration was correlated with fasting plasma glucose. When the top versus bottom quartiles of serum Nrg4 concentrations were compared with adjustment for age and sex, an odds ratio of 3.005 was observed in diabetes prevalence, which persisted after adjusting other potential confounding variables. Other nonglucose parameters as body mass index; waist, hip, and neck circumferences; alanine aminotransferase; triglyceride; high-density lipoprotein; uric acid; and estimated glomerular filtration rate were also correlated with serum Nrg4 (P < 0.05). CONCLUSIONS: The circulating Nrg4 level is elevated in the prediabetic and diabetic patients compared to control and is an independent risk factor associated with diabetes.

Antioxidant and anti-inflammatory activities of the phenolic extracts of Sapium sebiferum (L.) Roxb. leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Sapium sebiferum have long been used in Traditional Chinese Medicine (TCM) for the treatment of eczema, shingles, edema, swelling, ascites, scabs, and snakebites, among other maladies. AIM OF THIS STUDY: The present study aimed to investigate the antioxidant and anti-inflammatory effects of the phenolic extracts of Sapium sebiferum leaves using in vitro and in vivo models. MATERIALS AND METHODS: The in vitro antioxidant activities of the extracts were measured using common chemical methods (total phenolic content; total flavonoid content; scavenging of DPPH·, ABTS+·, superoxide, and nitrite radicals; reducing power; ß-carotene bleaching; and FTC assays). The in vivo topical anti-inflammatory activities were tested using the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dermatitis animal model. The SOD and CAT activities and the GSH content of ear tissue were also determined using test kits. RESULTS: The extracts of Sapium sebiferum leaves exhibited strong in vitro antioxidant activities. They also showed significant (P<0.001) and dose-dependent anti-inflammatory activities in an acute dermatitis model at the doses of 0.03 mg/ear, 0.1mg/ear, and 0.3mg/ear. The application of Sapium sebiferum leaf extracts increased the SOD and CAT activities and the GSH content relative to those of the TPA treatment group. The anti-inflammatory effect of the Sapium sebiferum leaf extract was positively correlated with its antioxidant activity. CONCLUSION: These results demonstrate that Sapium sebiferum leaf extract is an effective anti-inflammatory agent in the TPA-induced dermatitis model, and its anti-inflammatory effect is related, at least in part, to its antioxidant activity.

[Correlation between polymorphism of sex hormone binding globulin and occurrence of hepatocellular carcinoma].

OBJECTIVE: This study aims to investigate the correlation between polymorphism of sex hormone-binding globulin (SHBG) Asp327Asn (rs6259) locus and occurrence of hepatocellular carcinoma (HCC). METHODS: 621 cases with HCC and 621 cancer-free controls from two hospitals of Guangxi were recruited from January, 2007 to June, 2010. Single nucleotide polymorphisms (SNP) of SHBG Asp327Asn were detected by ABI7500 Fast Real-Time fluorescence quantitative PCR. Multivariate unconditional logistic regression was applied to analyze risk of HCC among different genotypes carriers and their interaction with the exposure factors. The Kaplan-Meier survival analysis was used to detect the relationship between onset age of HCC and genotypes. RESULTS: The frequencies of Asp/Asp, Asp/Asn and Asn/Asn genotype in case group were 86.31% (536/621), 12.40% (77/621) and 1.29% (8/621), respectively; while those in control group were 81.00% (503/621), 17.39% (108/621) and 1.61% (10/621), respectively. Significant difference in the genotype frequencies distribution was found between case and control groups (χ2=6.465, P<0.05). Compared with those harboring Asp/Asp genotype, multivariate logistic regression analysis revealed that the HCC risk of Asn/Asn+Asp/Asn genotype carriers was significantly decreased (adjusted OR=0.63, 95%CI: 0.40-0.98). Interaction analysis showed that there was interaction between the polymorphisms and two exposure factors, drinking (adjusted OR=3.45, 95%CI: 1.74-6.83) and HBV infection (adjusted OR=40.77, 95%CI: 21.60-76.97). Among those male patients with history of drinking, survival analysis indicated that the mean age of onset of individuals harboring Asp/Asp genotypes ((47.99±0.75) years-old) was 6 years earlier than those with Asn/Asn or Asp/Asn genotypes ((53.68±2.07) years-old) (χ2=6.91, P<0.01). CONCLUSION: Polymorphism of SHBG (Asp327Asn) may be associated with both the risk of HCC occurrence and onset age of HCC.

[Allergens and their relationships to childhood bronchial asthma in the Jiading District of Shanghai].

OBJECTIVE: To study allergens and their relationship to the occurrence of childhood bronchial asthma in the Jiading District of Shanghai. METHODS: Three hundred and eighty-two 4 to 12-year-old children with asthma in the remission stage from Nanxiang Hospital in the Jiading District of Shanghai were used as a case group (asthma group), and 402 children from two primary schools and two kindergartens in Jiading were enrolled by cluster sampling and served as control group. Parents of the children completed a questionnaire on living conditions and allergy-related disease history. Skin prick test (SPT) for 18 common allergens was carried out in both groups. In order to examine the effect of environment and living conditions on SPT results, children in the control group were further divided into two sub-groups according to birth place: migrant (219 cases) and resident (183 cases). RESULTS: SPT results revealed that the main allergens identified in the Jiading region were dermatophagoides farinae, house dust mites, shrimps, cockroaches, and dog hair. The SPT positive rate was 67.9% in the asthma group, and this was significantly higher than in the control group (31.8%) (P<0.01). The environment and living conditions in the migrant group were significantly different from the resident group (P<0.01), whereas the SPT positive rate for this group was significantly lower than in the resident group (P<0.01). CONCLUSIONS: Allergens in the Jiading region mainly originate from dermatophagoides farinae, household dust mites, shrimps, cockroaches and dog hair. Children with asthma are more susceptible to allergens. Environment and living conditions may be relevant, to a certain extent, to an SPT positive rate.