LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Associations between metabolic score for visceral fat and the risk of cardiovascular disease and all-cause mortality among populations with different glucose tolerance statuses.

AIMS: To investigate the associations between metabolic score for visceral fat (METS-VF) and clinical outcomes among populations with different glucose tolerance statuses. METHODS: We analysed 6827 participants aged ≥ 40 years with different glucose tolerance statuses from a cohort study. The associations between METS-VF and cardiovascular disease (CVD) events and all-cause mortality were assessed using Cox regression, restricted cubic spline and receiver operating characteristic curves. RESULTS: During a follow-up of 5.00 years, there were 338 CVD events and 307 subjects experienced all-cause death. The METS-VF quartile (Quartile 4 versus 1) was significantly related to CVD events [adjusted HRs and 95% CIs: 5.75 (2.67-12.42), 2.80 (1.76-4.48), and 3.31 (1.28-8.54) for subjects with normal glucose tolerance, prediabetes and diabetes, respectively] and all-cause mortality [adjusted HRs and 95% CIs: 2.80 (1.43-5.49), 4.15 (2.45-7.01), and 4.03 (1.72-9.42), respectively]. Restricted cubic spline suggested a dose-response association of METS-VF with the risk of CVD events and all-cause mortality. The area under curve for CVD events and all-cause mortality was higher for METS-VF than for the other obesity and IR indexes in subjects with different glucose tolerance statuses. CONCLUSIONS: The METS-VF was associated with an increased risk of CVD events and all-cause mortality and could be used as a predictive index of the risk of CVD events and all-cause mortality among populations with different glucose tolerance statuses.

Dose-response association between sedentary time and incident of diabetes in Chinese middle-aged and older adults: The 4C study.

AIMS: To investigate the dose-response relationship of total sedentary time with incident diabetes in Chinese middle-aged and older adults. METHODS: The present study followed 100,525 participants aged ≥ 40 years old from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was a prospective study conducted in 25 communities across mainland China. Associations between sedentary time and incident diabetes were assessed with Cox regression and restricted cubic splines. RESULTS: During a median follow-up of 3.8 years, 7,529 participants developed diabetes. After adjustment for multiple variables, high levels of sedentary time (≥ 30 h/week) was associated with increased risk for developing diabetes (hazards ratio, 1.08; 95 % confidence intervals 1.02, 1.14) compared with low levels of sedentary time (<20 h/week). Restricted cubic spline analyses revealed an inverted U-shaped relation between sedentary time with diabetes. Subgroup analyses found that the observed association remained significant in subgroup of individuals with body mass index (BMI) ≥ 25 kg/cm2 or diastolic blood pressure (DBP) ≥ 90 mm Hg. However, the significant association was diminished in participants with sufficient physical activity (PA) (P = 0.22). CONCLUSIONS: The multicenter, population-based, prospective study suggested an inverted U-shaped relation between sedentary time with diabetes. PA alleviated the deleterious effects associated with sedentary time.

TP53 /KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma.

Background: Due to high invasiveness and heterogeneity, the morbidity and mortality of intrahepatic cholangiocarcinoma (ICC) remain unsatisfied. Recently, the exploration of genomic variants has decoded the underlying mechanisms of initiation and progression for multiple tumors, while has not been fully investigated in ICC. Methods: We comprehensively analyzed 899 clinical and somatic mutation data of ICC patients from three large-scale cohorts. Based on the mutation landscape, we identified the common high-frequency mutation genes (FMGs). Subsequently, the clinical features, prognosis, tumor mutation burden (TMB), and pharmacological landscape from patients with different mutation carriers were further analyzed. Results: We found TP53 and KRAS were the common FMGs in the three cohorts. Kaplan-Meier survival curves and univariate and multivariate analysis displayed that TP53 and KRAS mutations were associated with poor prognosis. Considering the co-mutation phenomenon of TP53 and KRAS, we stratified patients into "Double-WT," "Single-Hit," and "Double-Hit" phenotypes by mutation status. Patients with the three phenotypes showed significant differences in the mutation landscape. Additionally, compared with "Double-WT" and "Single-Hit" phenotypes, patients with "Double-Hit" presented a dismal prognosis and significantly high TMB. Through chemotherapy sensitivity analysis, we identified a total of 30 sensitive drugs for ICC patients, of which 22 were drugs sensitive to "Double-WT," 7 were drugs sensitive to "Double-Hit," and only one was a drug sensitive to "Single-Hit." Conclusion: Our study defined a novel mutation classification based on the common FMGs, which may contribute to the individualized treatment and management of ICC patients.

Disrupted homeostasis of synovial hyaluronic acid and its associations with synovial mast cell proteases of rheumatoid arthritis patients and collagen-induced arthritis rats.

Hyaluronic acid (HA) is the main component of the extracellular matrix (ECM) of joints, and it is important for a lubricating joint during body movement. Degradation is the main metabolic process of HA in vivo. Hyaluronidases (HAase) were known for HA degradation. The inflammation-induced HA rapid-metabolism can reduce HA viscosity and concentration in joints. Mast cells (MC) containing their specific proteases were found in synovium tissue. It is unclear if MC-proteases could be involved in HA degradation pathways. This study aims to explore the correlations between HA concentration vs mast cell proteases, or matrix metalloproteinase-2/9 (MMP-2/9) and to investigate the association of MC-specific proteases with disrupted synovial HA homeostasis in rheumatoid arthritis (RA) or collagen-induced arthritis rats. The synovial fluid samples from no-RA and RA patients were collected; the collagen-induced arthritis (CIA) rat model was established; HA concentration and the activities of MC-protease and MMP-2/9 in the samples were detected, and the correlations were analyzed. In vitro interaction experiment was carried out by mixing MC-proteases with HA to observe the degradation speed. The HA concentrations in synovial fluids were decreased in RA patients and CIA rats compared with those in no-RA subjects or normal rats respectively. The activities of mast cell proteases in synovial fluids were increased and positively correlated with MMP-9, but negatively correlated with HA concentrations. In vitro study, the addition of MC-chymase and tryptase promoted the speed in HA degradation. MC-proteases may influence HA degradation pathway.

Association of circulating galectin-3 with gestational diabetes mellitus, progesterone, and insulin resistance.

BACKGROUND/OBJECTIVE: Because galectin-3 has been proposed to regulate obesity and insulin resistance in mice, we hypothesized that circulating galectin-3 levels are associated with presence of gestational diabetes mellitus (GDM), progesterone, and insulin resistance. METHODS: Circulating galectin-3 levels were measured using an enzyme-linked immunosorbent assay (ELISA) in women with GDM (n = 137) and their controls (n = 81). Associations of galectin-3 and progesterone with GDM and insulin resistance were evaluated using regression models. RESULTS: Circulating galectin-3 levels were increased in the individuals with GDM (P < .001) and associated significantly with progesterone (r = 0.42, P < .001), gestational age at sampling (r = 0.23, P < .001), current body mass index (BMI; r = 0.17, P = .02), estrogen (r = 0.15, P < .03), fasting glucose (r = 0.41, P < .001), fasting insulin (r = 0.39, P < .001), and homeostasis model assessment of insulin resistance (HOMA-IR; r = 0.44, P < .001). After adjustment for potential confounders, including current BMI, subjects in the highest tertile of galectin-3 levels were more likely to have GDM (odds ratio 4.71, 95% confidence interval 2.01-11.06) as compared with the lowest tertile. The association between circulating galectin-3 levels and GDM remained significant after adjusting for progesterone, but significantly attenuated after adjustment with HOMA-IR. Furthermore, the multiple linear regression analyses after adjustment for confounders showed an independent association between galectin-3 levels and HOMA-IR (ß = .41, P < .001), suggesting that association of circulating gelactin-3 levels with GDM might be mediated via insulin resistance. Progesterone demonstrated the expected associations with galectin-3, GDM, and HOMA-IR. CONCLUSIONS: Circulating galectin-3 levels are associated with GDM possibly through increased insulin resistance. The association of galectin-3 with progesterone highlights a potential role of progesterone in its interaction with galectin-3.

Plasma Metabolomics Analysis Identifies Abnormal Energy, Lipid, and Amino Acid Metabolism in Abdominal Aortic Aneurysms.

BACKGROUND Abdominal aortic aneurysm (AAA) is a complicated aortic dilatation disease. Metabolomics is an emerging system biology method. This aim of this study was to identify abnormal metabolites and metabolic pathways associated with AAA and to discover potential biomarkers that could affect the size of AAAs. MATERIAL AND METHODS An untargeted metabolomic method was used to analyze the plasma metabolic profiles of 39 patients with AAAs and 30 controls. Multivariate analysis methods were used to perform differential metabolite screening and metabolic pathway analysis. Cluster analysis and univariate analysis were performed to identify potential metabolites that could affect the size of an AAA. RESULTS Forty-five different metabolites were identified with an orthogonal projection to latent squares-discriminant analysis model and the differences between them in the patients with AAAs and the control group were compared. A variable importance in the projection score >1 and P<0.05 were considered statistically significant. In patients with AAAs, the pathways involving metabolism of alanine, aspartate, glutamate, D-glutamine, D-glutamic acid, arginine, and proline; tricarboxylic acid cycling; and biosynthesis of arginine are abnormal. The progression of an AAA may be related to 13 metabolites: citric acid, 2-oxoglutarate, succinic acid, coenzyme Q1, pyruvic acid, sphingosine-1-phosphate, platelet-activating factor, LysoPC (16: 00), lysophosphatidylcholine (18: 2(9Z,12Z)/0: 0), arginine, D-aspartic acid, and L- and D-glutamine. CONCLUSIONS An untargeted metabolomic analysis using ultraperformance liquid chromatography-tandem mass spectrometry identified metabolites that indicate disordered metabolism of energy, lipids, and amino acids in AAAs.

Triiodothyronine Promotes Cell Proliferation of Breast Cancer via Modulating miR-204/Amphiregulin.

Breast cancer (BC) severely threatens women's life, and Triiodothyronine (T3) shows a positive role on BC cell proliferation, while the potential mechanism underlying it is still unclear. T3 was used to stimulate BC cell lines MCF-7 and T47-D. Real-time PCR was performed to determine the expression of miRNAs, while western blot was used to measure protein expression of Amphiregulin (AREG), AKT and p-AKT. The interaction between miR-204 and AREG was determined using luciferase reporter assay. MTT was performed to detect cell viability. The expression of miR-204 was decreased, while AREG and p-AKT was increased in T3 stimulated BC cell lines. T3 stimulation promoted cell viability. miR-204 targets AREG to regulate its expression. T3 promoted expression of AREG and p-AKT, while miR-204 overexpression reversed the effect of T3, however, pcDNA-AREG transfection abolished the effect of miR-204 mimic. T3 promoted cell viability of BC cells via modulating the AKT signaling pathway. The detailed mechanism was that the down-regulated miR-204 that induced by T3 stimulation promoted the expression of AREG, the up-regulated AREG activated AKT signaling pathway, while the activated AKT signaling promoted cell proliferation.

The regulatory role of Dipeptidyl peptidase I on the activation of immune granulocytes.

Dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease, required for activation of serine proteases of granulocytes including mast cells (MCs), neutrophils (NPs) and others, which were found in synovial tissue of patients with rheumatoid arthritis (RA). But, the role of DPPI associated with those cells in RA development is unclear. In this study, the collagen-induced-arthritis (CIA) rat-model was employed to investigate the expression and activity levels of DPPI and its association with RA progress. Primary granulocytes were freshly extracted from bone-marrows of normal or CIA rats, human mast cell line LAD-2 and primary neutrophils, human-recombinant-DPPI, DPPI-inhibitor Gly-Phe-CHN2 , LTB4, anti-IgE antibody, calcium ionophore were used to study the regulatory role of DPPI in cell activations. The increased DPPI activities in synovial fluids, serum, and bone-marrow homogenates of CIA rats associated with RA severities progress were observed after injections. MMP2/9 expressions in SFs and bone-marrow were in different patterns. Regular-Blood-Tests have shown the high leveled DPPI activities associated with granulocytes differentiations in-vivo in blood of CIA rats. In-vitro cell models, DPPI up-regulated the proliferation of primary bone-marrow granulocytes of normal rats, but inhibited that of CIA rats. DPPI up-regulated and Gly-Phe-CHN2 down-regulated MCs intracellular DPPI and chymase activities. Gly-Phe-CHN2 also inhibited the LTB4 -activated-NPs and NP-elastase activities. Following stimulation of calcium ionophore, the net-releases of DPPI and ß-hexosaminidase from MCs were increased over a time-course, while Gly-Phe-CHN2 down-regulated MCs and NPs activation. Our findings demonstrate the role of DPPI in regulating MCs and NPs activation, and modulating proteolysis in the process of RA.