Jiawei Taohe Chengqi Decoction attenuates hepatic fibrosis by preventing activation of HSCs through regulating Src/ERK/Smad3 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei Taohe Chengqi Decoction (JTCD) is a Traditional Chinese Medicine (TCM) formula modified from Taohe Chengqi Decoction in the classic ancient literature of TCM "Treatise on Febrile Diseases". Clinical and pharmacological studies have shown that JTCD has a therapeutic effect on hepatic encephalopathy, non-alcoholic fatty liver, cirrhotic ascites, and can alleviate acute liver injury in rats. Our previous studies confirmed that JTCD could alleviate hepatic fibrosis and activation of hepatic stellate cells (HSCs). However, its mechanism remains unclear. AIM OF THE STUDY: This study aimed to elucidate the mechanism of Src Signal on hepatic fibrosis and HSCs activation, and whether JTCD inhibited hepatic fibrosis and HSCs activation through affecting Src Signal. MATERIALS AND METHODS: In vivo, sixty specific pathogen free male C57/BL6 mice were divided into following six groups: Control group, Model group, SARA group, JTCD low dose group, JTCD medium dose group and JTCD high dose group. Then we established a carbon tetrachloride (CCL4)-induced hepatic fibrosis mice model, each JTCD group was given the corresponding dose of JTCD by gavage, the SARA group was given Saracatinib and the control group was given saline, once a day for 4 consecutive weeks. UPLC-Q-TOF-MS analyzed chemical components of JTCD. Pathological examination including Hematoxylin and Eosin (H&E), Masson and Sirius red staining was used to observe the characteristic of hepatic fibrosis. Automatic biochemical analyzer detected the levels of alanine aminotransfease (ALT), and aspartate transaminase (AST) in serum. Western-blot and immunohistochemical staining (IHC) detected protein expression. In vitro, we used shRNA to knock down the expression of Src in immortalized human hepatic stellate cell line (LX-2), then intervened with ERK1/2 agonists/inhibitors and JTCD-containing serum after transforming growth factor ß1 (TGF-ß1) treatment. Immunofluorescence and western-blot detected protein expression. The migratory characteristic of HSCs was assessed by wound-healing assay. RESULTS: We identified 135 chemical components in the water extract of JTCD, and the water extract of JTCD contains a variety of anti-hepatic fibrosis components. Compared to the model group, hepatic fibrosis performance was significantly improved, the serum levels of ALT and AST were significantly decreased in JTCD groups and SARA group, IHC staining and western blot results indicated that JTCD decreased the expressions of α-smooth muscle actin (α-SMA), phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3. In vitro, JTCD-containing serum could significantly decrease the protein expressions of α-SMA, phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3 according to the results of western-blot and immunofluorescence, in addition, JTCD-containing serum inhibited the mobility and activation of LX-2. What's more, after intervening with Src-shRNA, ERK1/2 agonists/inhibitors and JTCD-containing serum, the western-blot results showed that Src/ERK/Smad3 signal has an important role in hepatic fibrosis and HSCs, and JTCD attenuates hepatic fibrosis by preventing activation of HSCs through regulating Src/ERK/Smad3 signal pathway. CONCLUSIONS: The results showed that Src kinase promoted hepatic fibrosis and HSCs activation through the ERK/Smad3 signal pathway. More importantly, the mechanism by which JTCD attenuated hepatic fibrosis and HSCs activation was by inhibiting the Src/ERK/Smad3 signal pathway.

The prognostic value of MELD-XI in elderly patients with ST-segment elevation myocardial infarction: an observational study.

BACKGROUND: The model for end-stage liver disease excluding international normalized ratio (MELD-XI) is a simple score for risk assessment. However, the prognostic role of MELD-XI and its additional value to current risk assessment in elderly patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is uncertain. METHODS: In all, 1029 elderly patients with STEMI undergoing PCI were consecutively included and classified into three groups according to the TIMI risk score: low-risk (≤ 3, n = 251); moderate-risk (4-6, n = 509); and high-risk (≥ 7, n = 269) groups. Multivariate analysis was performed to identify risk factors for adverse events. RESULTS: The overall in-hospital mortality was 5.3% and was significantly higher in the high-risk group (1.2% vs. 3.3% vs. 13.0%, p < 0.001). The optimal cut-off of the TIMI risk score and MELD-XI for in-hospital death was 7 and 13, respectively. MELD-XI was associated with in-hospital (adjusted odds ratio = 1.09, 95% CI = 1.04-1.14, p = 0.001) and one-year (adjusted hazard ratio = 1.05, 95% CI = 1.01-1.08, p = 0.005) mortality independently of the TIMI risk score. Combining TIMI risk score and MELD-XI exhibited better predictive power for in-hospital death than TIMI risk score (area under the curve [AUC] = 0.810 vs. 0.753, p = 0.008) or MELD-XI alone (AUC = 0.810 vs. 0.750, p = 0.018). Patients with TIMI risk score ≥ 7 and MELD-XI ≥ 13 had the worst prognosis. CONCLUSION: MELD-XI could be considered as a risk-stratified tool for elderly patients with STEMI undergoing PCI. It had an additive prognostic value to TIMI risk score.

20(S)-Protopanaxdiol Suppresses the Abnormal Granule-Monocyte Differentiation of Hematopoietic Stem Cells in 4T1 Breast Cancer-Bearing Mouse.

Panax notoginseng (PN) has been used as a qi- and blood-activating (Huoxue) drug for thousands of years in China. It has also been widely used as an anticancer drug at present. As a Huoxue drug, the effect of PN on hematopoietic differentiation in tumor-bearing body has been paid more and more attention. Our research found that panax notoginseng saponins (PNS), especially panaxadiol saponins (PDS) and its aglucon 20(S)-Protopanaxdiol (PPD), could improve the immunosuppressive state by regulating the abnormal hematopoietic differentiation in a tumor-bearing body by multiple ways. An interesting phenomenon is that PDS reduced the neutrophil-lymphocyte ratio (NLR) via its inhibition effect on the granule-monocyte differentiation of spleen cells, which is associated with a decrease in the secretion of tumor MPO, G-CSF, PU.1, and C/EBPα. Otherwise, PDS increased the proportion of both hematopoietic stem cells and erythroid progenitor cells in the bone marrow, but inhibited spleen erythroid differentiation via inhibiting secretion of tumor EPO, GATA-1, and GATA-2. This study suggests that PNS regulated the tumor-induced abnormal granule-monocyte differentiation of hematopoietic stem cells, affecting the distribution and function of haemocytes in tumor-bearing mice.

Identification and functional study of immortalized mouse thymic epithelial cells.

As the key cells in a three-dimensional scaffold within the thymus, Thymic epithelial cells (TECs) play critical roles in the homing, migration and differentiation of T cell precursors through adhesive interactions and the release of various cytokines. In this study, primary cultures of mouse TECs were isolated and identified with TEC-specific antibodies CK5 and CK8. These TECs were immortalized by retroviral transduction of simian virus (SV) 40 large T antigen. We then compared the functions of TECs and immortalized TECs (iTECs). Cell morphology and the proliferative capacity of TECs and iTECs were observed by inverted microscope photography and crystal violet assay after passage. A soft agar assay was then performed to observe their clone formation ability. The expression levels of epithelial cell related factors, such as IL-7, Lptin, Pax-9, Sema3A and et al., were detected by IF and qPCR. TECs were co-cultured with human acute monocytic leukemia cells (THP-1), and the effect of TECs on promoting THP-1 proliferation was observed with flow cytometry and CFSE labeling. Senescence-associated ß-galactosidase assay was measured to detect the anti-aging capabilities of the cells. Cell cycle distribution was analyzed by propidium iodide (PI) staining, and paclitaxel (PTX)-induced apoptosis was detected by Annexin V-PI staining to evaluate the anti-apoptotic ability of the cells. Throughout, we found that the immortalized TECs still retain the characteristics of primary TECs, such as the morphology, function and epithelial characteristics; however, iTECs have stronger capabilities in proliferation and anti-aging. Our research suggests that the iTECs were successfully immortalized by SV40 large T antigen, and that the biological characteristics and functions of iTECs were similar to the original TECs. This immortalized cell can be used as an efficient cell model in functional research of the thymus substituting primary TECs with iTECs.

Differences In Gastrointestinal Safety Profiles Among Novel Oral Anticoagulants: Evidence From A Network Meta-Analysis.

BACKGROUND: There is no consensus at present regarding the differences in the risk of GI bleeding across various NOAC regimens. Therefore, we performed a network meta-analysis to compare the risk of gastrointestinal bleeding after different NOAC regimens. METHODS: PubMed, Cochrane, Web of Science, Clinicaltrial.gov and Clinicaltrialresults.org were searched for randomized controlled trials (RCTs) assessing gastrointestinal bleeding of all NOAC regimens from inception to January 2018. The primary endpoint was major gastrointestinal (MGI) bleeding. The meta-regression was performed to access the association between the MGI bleeding events and mortality. The network meta-analysis was carried out with the Bayesian random-effect model. RESULTS: A total of 25 RCTs, including 139,392 patients, were identified. Meta-regression analysis showed that MGI bleeding was correlated with fatal bleeding events (odds ratios [OR], 1.76; 95% confidence interval [CI], 1.13-2.77], P=0.015). The network meta-analysis results showed that compared to the conventional regimens, rivaroxaban was associated with increased risk of MGI bleeding (OR, 1.37; 95% credible interval [CrI], 1.00-1.85), but not the apixaban (OR, 0.77; 95% CrI, 0.53-1.07]), edoxaban (OR, 0.86; 95%CrI, 0.52-1.18) and dabigatran etexilate (OR, 1.22; 95% CrI, 0.82-1.69). Compared to rivaroxaban, apixaban (OR, 0.56; 95% CrI, 0.35-0.88) and edoxaban (OR, 0.62; 95% CrI, 0.35-0.96) showed a significantly lower risk of MGI bleeding. Apixaban had the highest probability of being the safest option with regard to the risk of MGI bleeding (89.1%), followed by edoxaban (77.4%), conventional therapy (51.4%), dabigatran etexilate (23.8%) and rivaroxaban (8.3%). CONCLUSION: The risk of GI bleeding significantly varies among different NOAC regimens, and evidence shows that apixaban and edoxaban had the most favorable MGI bleeding safety profile, while rivaroxaban and dabigatran etexilate were the least safe.

Optimal timing of complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease: a pairwise and network meta-analysis.

INTRODUCTION: The optimal revascularization strategy for patients with ST-segment elevation myocardial infarction and multivessel disease is unclear. In this study, we performed a meta-analysis to determine the optimal revascularization strategy for treating these patients. METHODS: Searches of PubMed, the Cochrane Library, clinicaltrial.gov, and the reference lists of relevant papers were performed covering the period between the year 2000 and March 20, 2017. A pairwise analysis and a Bayesian network meta-analysis were performed to compare the effectiveness of early complete revascularization (CR) during the index hospitalization, delayed CR, and culprit only revascularization (COR). The primary endpoint was the incidence of major adverse cardiac events (MACE), which were defined as the composite of recurrent myocardial infarction (MI), repeat revascularization, and all-cause mortality. The secondary endpoints were the rates of all-cause mortality, recurrent MI, and repeat revascularization. This study is registered at PROSPERO under registration number CRD42017059980. RESULTS: Eleven randomized controlled trials including a total of 3,170 patients were identified. A pairwise meta-analysis showed that compared with COR, early CR was associated with significantly decreased risks of MACE (relative risk [RR] 0.47, 95% CI 0.39-0.56), MI (RR 0.55, 95% CI 0.37-0.83), and repeat revascularization (RR 0.35, 95% CI 0.27-0.46) but not of all-cause mortality (RR 0.78, 95% CI 0.52-1.16). These results were confirmed by trial sequential analysis. The network meta-analysis showed that early CR had the highest probability of being the first treatment option during MACE (89.2%), MI (83.3%), and repeat revascularization (80.4%). CONCLUSION: Early CR during the index hospitalization was markedly superior to COR with respect to reducing the risk of MACE, as CR significantly decreased the risks of MI and repeat revascularization compared with COR. However, further study is warranted to determine whether CR during the index hospitalization can improve survival in patients with concurrent ST-segment elevation myocardial infarction and multivessel disease. The optimal timing of CR remains inconclusive considering the small number of studies and patients included in the analysis comparing early and delayed CR.

Effect of Dipeptidyl Peptidase-4 Inhibitors on Heart Failure: A Network Meta-Analysis.

BACKGROUND: Previous meta-analyses evaluating the effectiveness of individual dipeptidyl peptidase-4 (DPP-4) inhibitors on the risk of heart failure (HF) were limited because of the small number of trials with direct comparisons between two treatments. METHODS: A Bayesian network meta-analysis was performed to investigate the relationship between DPP-4 inhibitors and the risk of HF in patients with type-2 diabetes mellitus. The primary outcome was the occurrence of HF or hospital admission for HF. RESULTS: Fifty randomized controlled trials were identified. Relative to placebo, no increased risk of HF events was seen for vildagliptin (risk ratio [RR] 0.71; 95% confidence interval [CI] 0.25-1.68), sitagliptin (RR 0.86; CI 0.43-1.57), or saxagliptin (RR 0.84; 95% CI 0.33-1.61), but alogliptin was associated with a higher risk of HF (RR 2.13; 95% CI 1.06-6.26). Vildagliptin and sitagliptin were associated with a significantly decreased risk of HF compared with alogliptin. Vildagliptin had the highest probability to be the safest option with regard to the risk of HF (49.18%), followed by saxagliptin (26.56%), sitagliptin (20.76%), linagliptin (0.25%), and alogliptin (0.12%). A statistically significant inconsistency was noted in some comparisons. CONCLUSIONS: The risk of HF needs to be taken into account when prescribing DPP-4 inhibitors. Evidence suggests that vildagliptin may be the least harmful agent with regard to the risk of HF. However, a statistically significant inconsistency was identified in the Bayesian network meta-analysis. Therefore, further studies are warranted to evaluate the cardiovascular safety of DPP-4 inhibitors.