Hepatic Vps33b deficiency aggravates cholic acid-induced cholestatic liver injury in male mice.

Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11, Ugt1a1, Ntcp, Oatp1b1, Bsep, and Mrp2. Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

Targeted bile acids and gut microbiome profiles reveal the hepato-protective effect of WZ tablet (Schisandra sphenanthera extract) against LCA-induced cholestasis.

Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) can significantly protect against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration. However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCA-induced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.

[Shufeng Huoxue Formula suppresses proliferation and regulates melanin metabolism in murine B16 melanoma cells in vitro through autophagy pathway].

OBJECTIVE: To investigate the role of autophagy in the regulatory effect of Shufeng Huoxue Fumula (SFHXF) on the proliferation and melanin metabolism in cultured murine B16 melanoma cells. METHODS: B16 cells were treated with solutions containing 0.12, 0.25, 0.49, 0.98, or 1.96 mg/mL SFHXF preparations, rapamycin (an autophagy inducer), or rapamycin+SFHXF. The changes in the proliferation of B16 cells were assessed using MTT assay, and tyrosinase activity and melanin content in the cells were determined. The expressions of autophagy-related proteins P62, p-mTOR, LC3B, and beclin 1 in the cells were detected using Western blotting. RESULT: Compared with the blank control cells, treatments with SFHXF both in the presence and in the absence of rapamycin concentration-dependently inhibited the cell proliferation (P<0.05) and obviously increased tyrosinase activity and melanogenesis in B16 cells (P<0.05); 0.98 mg/mL SFHLF, rapamycin+0.98 mg/mL SFHXF, and 50 nmol/L rapamycin all significantly up-regulated the expressions of LC3B-II and beclin 1 and down-regulated the expressions of P62 and p-mTOR in the cells. CONCLUSION: SFHXF can regulate melanin metabolism and enhance tyrosinase activity and melanogenesis through the autophagy pathway to inhibit the proliferation of B16 cells in vitro.

The impact of metabolic syndrome and hypertension on medical costs of patients with acute myocardial infarction at hospital.

OBJECTIVE: This study aimed to find out the impact of metabolic syndrome (MS) and hypertension on medical costs of patients with acute myocardial infarction (AMI) at hospital. METHODS: Patients with AMI at Qilu Hospital of Shandong University during January 2011 to May 2013 were separated into four groups according to whether with MS or history of hypertension. Comparison of medical costs, complication rate and cost-effectiveness ratio were analyzed. RESULTS: We found that total costs, each day costs, medical treatment costs, chemical examination costs and drug costs were significantly different in four groups. In variance analysis, MS led to high medical costs without significance. Hypertension was a significant factor influencing medical costs and lead to low medical costs. In multiple linear regression, we found that body mass index (BMI) and percutaneous coronary intervention (PCI) were important predictors of total costs and each day costs. With higher BMI and utilization rate of PCI, medical costs were increased. Trend of total costs in four groups is similar to that of the rate of PCI utilization. CONCLUSIONS: Metabolic syndrome has no impact on medical costs because of discordance in MS components. Hypertension will lead to lower PCI utilization rate, which results in less medical costs and bad hospital outcomes.

A medical costs study of older patients with acute myocardial infarction and metabolic syndrome in hospital.

BACKGROUND: Older patients with acute myocardial infarction (AMI) usually have a poor prognosis, but whether this poor prognosis leads to high hospital costs remains unclear. This study investigated the clinical outcomes of and costs incurred by older patients with AMI and metabolic syndrome (MS) in hospital. METHODS AND RESULTS: Patients with AMI seen at Qilu Hospital of Shandong University between January 2011 and May 2013 were separated into four groups: young non-MS patients (n=282), older non-MS patients (n=324), young MS patients (n=217), and older MS patients (n=174). We found that advanced age was significantly associated with worse clinical outcomes, and that the clinical outcomes in patients with AMI and MS are also worsened. At the same cost (RMB¥10,000), older patients with and without MS had a markedly increased number of cardiovascular incidences compared with younger patients without MS. In a comparison of the incremental cost-effectiveness ratio (ICER) of percutaneous coronary intervention, older patients without MS had a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with young patients without MS, but a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with older MS patients. CONCLUSION: Older AMI patients have poor clinical outcomes and their treatment is not cost-effective; however, the results are worse in patients with AMI and MS. Percutaneous coronary intervention is a cost-effective therapy in older patients with AMI, but its cost-effectiveness decreases in patients with AMI and MS.

Impact of type 2 diabetes mellitus on hospitalization costs in older patients with acute myocardial infarction.

BACKGROUND: The purpose of this study was to evaluate the impact of type 2 diabetes mellitus on hospitalization costs in older patients with acute myocardial infarction (MI). METHODS: Retrospective analysis of data from the case retrieval system of Qilu Hospital of Shandong University located in Jinan city of Shandong Province was done for patients with acute MI from January 1, 2011 to December 31, 2012. RESULTS: Stenting was an important factor affecting older patients' total hospitalization costs (ß=0.685, P=0.000) and treatment costs during the follow-up period (duration of hospital stay only, ß=0.508, P=0.000). Stenting was also a protective factor in the prevention of acute heart failure (HF) in older patients with acute MI during the follow-up period (odds ratio 0.189, 95% confidence interval 0.059-0.602, P=0.005). Implementation of percutaneous coronary intervention reduced the incidence of acute HF in older inpatients with acute MI (27.8% versus 4.3%, P=0.001) and without diabetes (18.2% versus 3.8%, P=0.001). Moreover, among the elderly, the incremental cost-effectiveness ratio estimate for implementing percutaneous coronary intervention in diabetic patients was higher than in nondiabetic patients. CONCLUSION: Stenting was a protective factor for preventing acute HF in the elderly during the follow-up period. From the perspective of reducing the incidence of acute HF in inpatients, implementation of percutaneous coronary intervention after an acute MI is more cost-effective in older patients with diabetes mellitus than in those without it.

Visceral adiposity index score indicated the severity of coronary heart disease in Chinese adults.

BACKGROUND: Visceral adiposity contributes to cardiometabolic risk, and visceral adiposity index (VAI) had significant correlation with visceral adiposity. We aimed to explore whether VAI was associated with cardiac structure and function and assess the impact of the cut-off points of VAI defining visceral adipose dysfunction (VAD) on the severity of coronary heart disease (CHD). METHODS: A total of 95 patients with CHD were divided into Control (nondiabetic CHD patients) and DM group (diabetic CHD patients). Then the two groups were respectively divided into VAD absent and VAD groups. Clinical, echocardiographic and coronary artery angiographic indexes were acquired to examine in relation to VAI. RESULTS: A significant increasing trend among the four groups of patients (Control + VAD absent, Control +VAD, DM + VAD absent and DM +VAD groups) were observed for waist circumference (WC), body mass index (BMI), systolic blood pressure (SBP), glucose, VAI and Gensini score (P<0.05 for all). The following variables were associated with VAI: total cholesterol, nonesterified fatty acid, Waist-Hip ratio and SBP. VAI was independently associated with Gensini score. CONCLUSIONS: The extent of CHD was more severe in diabetes, and VAI as a simple indicator of visceral adipose mass was strongly associated with the severity of CHD. The cut-off points of VAI used for defining VAD were more useful in diabetic CHD patients in identifying the severity of CHD.

ß1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to ß-blocker therapy and prognosis.

AIMS: The risk stratification of patients for heart failure (HF) remains a challenge, as well as the anticipation of the response to ß-blocker therapy. Since the pivotal role of ß1 adrenergic receptor (ß1-AR) in HF, many publications have studied the associations between the ß1-AR polymorphisms (Ser49Gly and Arg389Gly) and HF, with inconsistent results. Thus, we performed a meta-analysis of studies to evaluate the impact of ß1-AR polymorphisms on susceptibility to HF, the response to ß-blocker therapy and the prognosis of HF. METHODS AND RESULTS: Electronic databases were systematically searched before August 2011. We extracted data sets and performed meta-analysis with standardized methods. A total of 27 studies met our inclusion criteria. It was found that in East Asians, the Gly389 allele and Gly389 homozygotes significantly increased the HF risk, while the Gly389 allele and Gly389 homozygotes trended to decrease the risk of HF in whites. With the similar reduction of heart rate, overall, the Arg389 homozygotes showed a better response to ß-blocker therapy. Furthermore, the Arg389 homozygotes were significantly associated with better LVEF improvement in East Asians and a mixed population. And in white people, the Arg389 homozygotes made a greater LVESd/v improvement and trended to be associated with better LVEDd/v improvement. However, the prognosis of Arg389 homozygotes HF patients was similar to those with Gly389 carriers. The Ser49Gly polymorphism did not impact the risk or prognosis of HF. CONCLUSION: Based on our meta-analysis, the Gly389 allele and Gly389 homozygotes were risk factors in East Asians while trending to protect whites against HF. Furthermore, Arg389 homozygote is significantly associated with a favorable response to ß-blocker treatment in HF patients. However, neither of the two polymorphisms is an independent predictor of the prognosis of HF.