Identification and validation of chemokine system-related genes in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with limited therapeutic options. Recent studies have demonstrated that chemokines play a vital role in IPF pathogenesis. In the present study, we explored whether the gene signature associated with chemokines could be used as a reliable biological marker for patients with IPF. Methods: Chemokine-related differentially expressed genes (CR-DEGs) in IPF and control lung tissue samples were identified using data from the Gene Expression Omnibus database. A chemokine-related signature of the diagnostic model was established using the LASSO-Cox regression. In addition, unsupervised cluster analysis was conducted using consensus-clustering algorithms. The CIBERSORT algorithm was used to calculate immune cell infiltration across patient subgroups. Finally, we established a mouse model of bleomycin-induced pulmonary fibrosis and a model of fibroblasts treated with TGFß1. Expression levels of chemokine-related signature genes were determined using real-time quantitative polymerase chain reaction (RT-qPCR). Results: We established a chemokine-related eleven-gene signature of a diagnostic model consisting of CXCL2, CCRL2, ARRB1, XCL1, GRK5, PPBP, CCL19, CCL13, CCL11, CXCL6, and CXCL13, which could easily distinguish between IPF patients and controls. Additionally, we identified two subtypes of IPF samples based on chemokine-related gene expression. Pulmonary function parameters and stromal scores were significantly higher in subtype 1 than in subtype 2. Several immune cell types, especially plasma cells and macrophages, differ significantly between the two subtypes. RT-qPCR results showed that the expression levels of Cxcl2 and Ccl2 increased considerably in bleomycin-induced mice. Meanwhile, Arrb1, Ccrl2, Grk5, and Ppbp expression was significantly reduced. Furthermore, multiple chemokine-related genes were altered in TGFß1 or TNFα-induced fibroblast cells. Conclusions: A novel chemokine-related eleven-signature of diagnostic model was developed. These genes are potential biomarkers of IPF and may play essential roles in its pathogenesis.

A nomogram for predicting risk of death during hospitalization in elderly patients with Alzheimer's disease at the time of admission.

Background and objectives: Elderly patients with Alzheimer's disease (AD) often have multiple underlying disorders that lead to frequent hospital admissions and are associated with adverse outcomes such as in-hospital mortality. The aim of our study was to develop a nomogram to be used at hospital admission for predicting the risk of death in patients with AD during hospitalization. Methods: We established a prediction model based on a dataset of 328 patients hospitalized with AD -who were admitted and discharged from January 2015 to December 2020. A multivariate logistic regression analysis method combined with a minimum absolute contraction and selection operator regression model was used to establish the prediction model. The identification, calibration, and clinical usefulness of the predictive model were evaluated using the C-index, calibration diagram, and decision curve analysis. Internal validation was evaluated using bootstrapping. Results: The independent risk factors included in our nomogram were diabetes, coronary heart disease (CHD), heart failure, hypotension, chronic obstructive pulmonary disease (COPD), cerebral infarction, chronic kidney disease (CKD), anemia, activities of daily living (ADL) and systolic blood pressure (SBP). The C-index and AUC of the model were both 0.954 (95% CI: 0.929-0.978), suggesting that the model had accurate discrimination ability and calibration. Internal validation achieved a good C-index of 0.940. Conclusion: The nomogram including the comorbidities (i.e., diabetes, CHD, heart failure, hypotension, COPD, cerebral infarction, anemia and CKD), ADL and SBP can be conveniently used to facilitate individualized identification of risk of death during hospitalization in patients with AD.

Association between helicobacter pylori infection and subclinical atherosclerosis: A systematic review and meta-analysis.

BACKGROUND: The relationship between Helicobacter pylori (H. pylori) infection and subclinical atherosclerosis has been confirmed, but these conclusions are still controversial. Therefore, we have performed a systematic review and meta-analysis to assess the association between H. pylori infection and subclinical atherosclerosis. METHODS: Databases including PubMed, Embase, Web of Science were searched for the articles on the association of carotid intima-media thickness or pulse wave velocity with H. pylori infection published up to January 1, 2020. Stata 12.0 was used to calculate standardized mean difference (SMD) and 95% confidence interval (95% CI); the I2 test was used to evaluate heterogeneity between studies and sensitivity analysis and subgroup analysis were used to explore the source of heterogeneity. Funnel plot, Begg test, and Egger test were used to estimate publication bias. RESULTS: Data were extracted from 18 studies involving 6776 subjects with H. pylori positive and 7794 with H. pylori negative. H. pylori positive subjects is significantly associated with increased subclinical atherosclerosis as determined by carotid intima-media thickness (SMD: 0.376 mm; 95% CI: 0.178, 0.574; P < .001, I2 = 90.6%), pulse wave velocity (SMD: 0.320 m/s; 95% CI: 0.242, 0.398; P < .001, I2 = 52.6%), compared with H. pylori negative. Similar results were observed when subgroups analysis were stratified according to age, male ratio, geographical location, H. pylori diagnosis, and study design. Sensitivity analyses showed that our results were robust. The Begg test or Egger test showed no significant publication bias (all P > .05). CONCLUSIONS: This meta-analysis confirmed a significant association between H. pylori and subclinical atherosclerosis, which will help H. pylori patients to establish effective strategies for the prevention and control of cardiovascular events.

Long-term subcutaneous injection of lipopolysaccharides and high-fat diet induced non-alcoholic fatty liver disease through IKKε/ NF-κB signaling.

Non-alcoholic fatty liver disease (NAFLD) was associated with increased level of lipopolysaccharides (LPS) which mechanism remained unclear on intervention between LPS and NAFLD. The aim was to explore the IKKε/NF-κB role and its intervention of LPS and high-fat diet (HFD) induced NAFLD. Male C57BL/6 mice were fed on high-fat diet (HFD) combined with or without simultaneously subcutaneous injection of LPS for 18 weeks. Body weight , blood biochemistry parameters, inflammatory mediator and liver lipid deposition were measured to evaluate LPS effect on NAFLD. Furthermore, IKKε selective inhibitor amlexanox (AM) was administrated by gavage to HFD + LPS induced mice. The indicators about metabolism and inflammation were examined and qRT-PCR, immunoblotting assay as well as immunohistochemistry were performed to assess IKKε/NF-κB activation and downstream gene expression. This study found that low-dose LPS + HFD aggravated more significant steatosis than simple HFD or high-dose LPS + HFD. Low-dose LPS exacerbated more prominent inflammation profile including increased IKKε and NF-κB expression in liver than HFD. Inhibiting IKKε/NF-κB signaling with amlexanox significantly prevented HFD + LPS induced metabolic disorders and hepatic steatosis. LPS-upregulated gene expression involved in glucolipid metabolism could be downregulated by amlexanox. Thus, the present study confirmed long-term combinational administration of subcutaneous low-dose LPS injection and HFD induced NAFLD model which had more significant phenotype in mice than simple HFD or high-dose LPS-induction. Targeting on IKKε/NF-κB signaling with its inhibitor amlexanox alleviated steatohepatitis, suggesting that IKKε/NF-κB signaling was responsible for effect of LPS and HFD on NAFLD.

Amlexanox reversed non-alcoholic fatty liver disease through IKKε inhibition of hepatic stellate cell.

AIMS: Amlexanox, an inhibitor of nuclear factor κB kinase epsilon (IKKε) and TANK-binding kinase 1(TBK1), was demonstrated to be effective in diabetes and obesity. The aim of this study was to explore the molecular mechanisms of its role in non-alcoholic fatty liver disease (NAFLD). MAIN METHODS: NAFLD mouse models were established by using eight-week-old male C57BL/6 mice fed with high-fat diet (HFD) or (and) lipopolysaccharide (LPS) for 18 weeks. From the beginning of HFD, HFD-induced mice were subjected to amlexanox or vehicle for 18 weeks. HFD + LPS-induced mice were treated with amlexanox or vehicle for the last 6 weeks. Blood biochemistry parameters were determined using automatic biochemistry analyzer. Histological changes of liver tissue were observed by hematoxylin-eosin (H&E) staining and Oil Red O staining. The expressions of IKKε and smooth muscle actin-α (α-SMA) were evaluated through immunohistochemistry. Serum inflammatory mediator was determined by enzyme linked immunosorbent assay (ELISA). Gene expressions involved in glucose and lipid metabolism, insulin signaling pathway were examined using quantitative RT-PCR or Western blotting. KEY FINDINGS: This study demonstrated that amlexanox reversed glucose and lipid metabolic disturbance and hepatic steatosis in NAFLD mice model. IKKε was specific expressed in hepatic stellate cells (HSCs) instead of hepatocytes. This study also found that amlexanox improved insulin signaling (Insulin-IRS-1-Akt) in hepatocytes through inhibiting inflammation (IKKε-NF-κB-TNF-α/IL-1α) in HSCs. SIGNIFICANCE: The present study confirmed that IKKε was specific expressed in HSCs. Inhibition of activated HSCs was responsible for effects of amlexanox on NAFLD, with improving insulin signal pathway in hepatocytes.

Non-invasive markers of cardiovascular risk in patients with subclinical hypothyroidism: A systematic review and meta-analysis of 27 case control studies.

It has been reported that subclinical hypothyroidism (SCH) is closely related to subclinical atherosclerosis. According to the impact of SCH on noninvasive markers of cardiovascular risk, we fulfilled a meta-analysis of included studies to provide an integrated overview. We searched electronic databases and included all relevant studies involving SCH and epicardial adipose tissue (EAT), carotid intima-media thickness (CIMT), pulse wave velocity (PWV), flow-mediated dilation (FMD) and glyceryl trinitrate-induced dilation (GNT- induced dilation). The result was calculated in a meta-analysis to assess the impact of SCH on these markers. A total of 27 studies were entered in the final analysis. Compared with euthyroid subjects, SCH patients exhibited a significantly increased CIMT (SMD: 0.369 mm; 95%CI: 0.038, 0.700; P = 0.029) and EAT (SMD: 1.167 mm; 95%CI: 0.869, 1.466; P = 0.000) and increased PWV (SMD: 3.574 m/s; 95%CI: 0.935, 6.213, P = 0.008). We also found significantly lower FMD (SMD: -1.525%, 95%CI: -2.156, -0.894, P = 0.000) and lower GNT-induced dilation (SMD: -0.384%, 95%CI: -0.625, -0.142, P = 0.002). Sensitivity analysis and subgroup analysis confirmed the above results. Our meta-analysis confirmed a significant association of SCH and cardiovascular risk with arterial wall thickening and stiffening and endothelial dysfunction. These findings will help to establish detailed cardiovascular prevention strategies for SCH patients.

Minimally invasive surgery versus open hepatectomy for hepatolithiasis: A systematic review and meta analysis.

OBJECTIVE: Hepatectomy for hepatolithiasis can be performed by following an open approach or a minimally invasive surgery (MIS) approach. MIS is associated with theoretical advantages, but there is no consensus regarding to the best treatment method for hepatolithiasis. The objective of this study was to evaluate the clinical outcomes of MIS hepatectomy compared with those of open hepatectomy in hepatolithiasis patients. METHODS: A systematic literature search was performed using PubMed, Embase and Cochrane Library databases. The data were analyzed with Stata version 12.0 software. Meta-regression analysis was used to explore the potential sources of heterogeneity. Egger's tests and Begg's funnel plots were employed to evaluate the publication biases. RESULTS: In total, 12 nonrandomized controlled trials were identified. Compared with open hepatectomy, the volume of intraoperative blood loss was significantly less in MIS hepatectomy (SMD = -0.226, P = 0.000). The intraoperative blood transfusion rate was also lower in MIS hepatectomy (RR = 0.569, P = 0.003). A shorter length of postoperative hospital stay was noted with MIS hepatectomy (SMD = -0.537, P = 0.000). MIS hepatectomy resulted in a lower rate of postoperative complications than open hepatectomy (RR = 0.595, P = 0.000). However, MIS hepatectomy resulted in a longer operation time (SMD = 0.473, P = 0.005). No significant differences were noted between MIS and open hepatectomy in the initial stone clearance rate (RR = 1.33, P = 0.218), the final stone clearance rate (RR = 1.040, P = 0.131), the stone recurrence rate (RR = 0.558, P = 0.072) or the cholangitis recurrence rate (RR = 0.610, P = 0.285). CONCLUSIONS: MIS hepatectomy is a safe approach for hepatolithiasis patients. MIS hepatectomy significantly reduces intraoperative blood loss, blood transfusion, postoperative hospital stay time and complications. The stone clearance and recurrence rates were similar for MIS hepatectomy and open hepatectomy. Additional well-designed randomized controlled trials and Western studies are needed to confirm these findings.

Effect of Probiotics on Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus: A Meta-Analysis of 12 Randomized Controlled Trials.

BACKGROUND It has been unclear whether supplemental probiotics therapy improves clinical outcomes in type 2 diabetic patients. This meta-analysis aimed to summarize the effect of probiotics on glucose and lipid metabolism and C-reactive protein (CRP) from 12 randomized controlled trials (RCTs). MATERIAL AND METHODS An up-to-date search was performed for all relevant RCTs up to April 2016 from PubMed, Embase, and Cochrane Library. Standardized mean difference (SMD) and weighted mean difference (WMD) were calculated for a fixed-effect and random-effect meta-analysis to assess the impact of supplemental probiotics on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile, and CRP level. RESULTS A total of 12 studies (684 patients) were entered into the final analysis. The effect of probiotics was significant on reducing HbA1c level (standardized mean difference [SMD], -0.38; confidence interval [CI], -0.62 to -0.14, P=0.002; I²=0%, P=0.72 for heterogeneity), fasting insulin level (SMD, -0.38; CI -0.59 to -0.18, P=0.0003; I²=0%, P=0.81 for heterogeneity), and HOMA-IR (SMD, -0.99; CI -1.52 to -0.47, P=0.0002; I²=86%, P<0.00001 for heterogeneity). Pooled results on effects of probiotics on FPG, CRP, or lipid profile were either non-significant or highly heterogeneous. CONCLUSIONS This meta-analysis demonstrated that probiotics supplementation was associated with significant improvement in HbA1c and fasting insulin in type 2 diabetes patients. More randomized placebo-controlled trials with large sample sizes are warranted to confirm our conclusions.