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Squalene monooxygenase (SQLE) is the rate-limiting enzyme of cholesterol biosynthesis. It plays a crucial role in regulating cholesterol homeostasis. Increasing evidence shows that SQLE is closely related to the occurrence, development, metastasis, and poor prognosis of various cancers. SQLE can not only promote the proliferation of cancer cells and epithelial-mesenchymal transformation but also play an important role in maintaining the stemness of cancer stem cells and regulating cholesterol homeostasis. SQLE may be a potential molecular target for cancer therapy. In this review, the role of SQLE in regulating cholesterol homeostasis in vivo; its function in the occurrence, development, and metastasis of various cancers; and its molecular mechanism were summarized. Screening new SQLE inhibitors may provide new ideas for targeted cancer therapy.
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Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both and . The study was performed using male C57BL/6 mice fed with methionine- choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of and , reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A . These effects were confirmed by the experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the -oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.
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Objective To explore the level of interleukin 35-producing B cells (i35-Breg) as well as its effect factors,interleukin-35 (IL-35),in peripheral blood of patients with chronic hepatitis B (CHB),and their relationship with hepatitis B virus (HBV) DNA and liver inflammatory degree.Methods A total of 35 treatment-naive CHB patients,17 interferon (IFN)-treated HBeAg-positive CHB patients and 15 healthy controls (HC) were enrolled.The levels of i35-Breg and IL-35 in peripheral blood were tested by flow cytometry and enzyme-linked immunosorption assay (ELISA).Kruskal-Wallis test,Wilcox rank sum test and two variables correlation analysis were used for statistical analysis.Results The percentage of i35-Breg cells as well as IL-35 level in peripheral blood of naive CHB patients were 3.05％ (0.89％,4.97％) and 2.81 μg/L (0.30 μg/L,12.33 μg/L),respectively,which were both significantly higher than those in HC group,which were 0.17％ (0.13％,0.45％) and 0.17 μg/L(0,1.93 μg/L),respectively.The difference were statistical significant (Z=-3.309 and-2.419,respectively,P=0.001 and 0.016,respectively).The peripheral level of i35-Breg was negatively correlated with the viral load in treatment-naive CHB patients (r=-0.529,P=0.008),while there was no correlation between the peripheral level of IL-35 and the viral load in treatment-naive CHB patients (r=0.11,P=0.54).The levels of i35-Breg and IL-35 in HBeAg positive CHB patients were 3.16％ (1.34％,5.62％) and 4.58μg/L (0.79μg/L,22.37 μg/L),respectively,which were both higher than those in HC group.The difference was statistically significant (F=3.39 and 3.37,respectively,both P＜0.01).Compared to HC group,the IL-35 levels in peripheral blood of CHB patients with ALT and AST levels less than 300 U/L were 3.03 μg/L (0.74 μg/L,22.37 μg/L) and 3.25 μg/L (0.83 μg/L,22.35 μg/L),respectively,with statistically significant difference (F=2.868 and 3.114,respectively,both P＜0.01).Compared to HC group,the peripheral level of i35-Breg in treatment-naive CHB patients with ALT levels less than 300 U/L was 3.14％ (1.03％,4.65％),with statistically significant difference (F=3.219,P=0.004).The IL-35 level showed a decreased trend in CHB who received IFN therapy,but there was no statistically significant difference (x2 =1.45,P =0.48).Furthermore,the baseline IL-35 level in patients who developed sustained viral response (SVR) was 0 (0,13.33 g/L),which was lower than that in patients who developed partial or primary no response 0.61 μg/L (0,24.72 μg/L).However,there was no statistical difference (F=0.75,P =0.68).Conclusions i35-Breg as well as its effect factor,IL-35,are involved in the progression of chronic HBV infection.The percentage of i35-Breg cells as well as IL-35 level in peripheral blood of treatment-naive CHB patients are increased.The peripheral level of i35-Breg is negatively correlated with the viral load,while there is no correlation between the peripheral level of IL-35 and the viral load.The percentage of i35-Breg cells as well as IL-35 level in CHB patients with low inflammatory degree are increased.
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Objective To investigate the efficacy and safety of different optimal therapy strategies for hepatits B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients with suboptimal response to peginterferon-α-2a (peg-IFN-α-2a) at 24 weeks.Methods This open-label,single-center and prospective clinical observational study was conducted in Department of Infectious Diseases at Shanghai Changhai Hospital between January 2009 and December 2011.The cases of HBeAg-positive CHB with suboptimal response to peg-IFN-α-2a at week 24 were enrolled.Based on virological markers and patient preference,patients were treated with either peg-IFN-α-2a add-on adefovir dipivoxil (ADV) or switch-to telbivudine (LdT).Hepatitis B virus (HBV) virological and serological data were collected at week 12,24 and 48 after the initiation of optimal therapy.Adverse reactions were also monitored.Therapeutic efficacy was compared between two groups of patients before and after treatment by x2 test.Kruskall Wallis test and Mann-Whitney test were used for analysis of continuous variables.Results Among 193 HBeAg positive CHB patients treated with interferon,67 had suboptimal response and were enrolled.Forty five cases received peg IFN-α-2a add-on ADV treatment and 22 cases received switch-to LdT treatment.After 48 weeks of optimized therapy,the total tBeAg seroconversion rate was 25.3 ％.The rates of HBeAg loss,HBV DNA negative and alanine aminotransferase normalization were 26.8％,73.1％ and 83.5％,respectively.The peg-IFN-α-2a switch-to LdT strategy had better HBV DNA inhibition efficiency compared with the peg-IFN-α-2a add-on ADV strategy at week 12,24 and 48 (P=0.00,0.00 and 0.01,respectively).However,there was no significant difference of HBV DNA negative rate between two groups at week 48 (x2 =0.01,P=0.89).The obviously intolerable adverse reaction was not reported in two optimized strategy groups.Conclusions The 48-week optimized treatment for HBeAg positive CHB with suboptimal response to peg-IFN-α-2a at week 24 could achieve a higher HBeAg seroconversion rate.The switch-to LdT strategy may have better HBV DNA inhibition efficiency.Both strategies show satisfactory safety and tolerance.
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ObjectiveTo investigate the effects of the imbalance between regulatory T cells (Treg) and T helper 17 cells (Th17) in patients with chronic hepatitis B virus (HBV) infection.MethodsThe serum concentration of Treg/Th17 differentiation-related cytokines in 34 patients with chronic hepatitis B (CHB),20 patients with HBV related acute on chronic liver failure (ACHBLF),and 20 healthy controls (NC) were measured by enzyme-linked immunosorbent assay (ELISA) and proportion of peripheral Th17 and Treg cells were analyzed by flow cytometry.Numeration data was analyzed by Fisher's exact propability method and measurement data was tested by one-factor analysis of variance or Turkey multiple comparison.Results The levels of Th17 differentiation-related cytokines,II-1β (3.97±2.85) pg/mL,IL-6 (12.75±-8.87) pg/mL,and IL-21 (360.0±335.7) pg/ mL in patients with ACHBLF were significantly increased than those in NC,which were (1.87 ±0.94) pg/mL(q=4.559,P＜0.01),(5.28±0.72) pg/mL(q=7.309,P＜0.01) and (46.68±20.17) pg/mL(q=6.946,P＜0.01 ),respectively.The proportion of Th17 increased markedly in patients with ACHBLF than that in NC(q=3.972,P＜0.05).However,compared to NC and patients with ACHBLF,the Treg differentiation-related cytokine,TGF-β,in patients with CHB,increased significantly (q=4.536 and 5.323,respectively; both P＜0.01).And the population of Treg also increased markedly in CHB patients.The level of IL-17A which was the characteristic effector cytokine of Th17 was the highest in patients with ACHBLF.The peripheral Th17 cell proportion was positively correlated with the level of serum total bilirubin in patients with ACHBLF (γ=0.74,P＜0.01).Conclusions Th17 and Treg imbalance including cytokine profiles and cell numbers exists in patients with chronic HBV infection.The Th17 are active in patients with ACHBLF and Treg are active in patients with CHB.
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Objective To explore a simple and effective operative procedure for treatment of pa-tellar fractures.Methods The clinical data of 108 patients (including 76 males and 32 females) with patellar fractures were analyzed.The age of the patients ranged from 18 years to 82 years.There were 67 patellar fractures on the right extremities and 41 on the left.Fracture types included transfractures in 43 patients, comminuted fractures in 54, torn fractures in eight and longitudinal fractures in three.Period from injury to operation ranged from 3 hours to 10 days.During operation, the broken patella was exposed for reduction and temporary pliers fixation;then, a five-pointed star woven with two absorbable sutures was placed on the broken patella, two semi-circular sutures around the patellar edge were made with su-tures which were through five points of the five-pointed star.When two sutures were pulled and knotted,the five-pointed star was also stretched to fix the patellar fractures firmly.Models of transverse patellar fractures were made in 20 knee joints of catties, which were divided into two groups randomly.Patellar fractures in Group A were fixed with five-pointed star lattice sutures and those in Group B with AO inten-sion bands.Loading test was performed on quadriceps femoris with materials test system for measuring the width of each fractured patella after the test.Results All patients were followed up for 6-60 months (mean 20 months) , which showed that all patellar fractures were healed.According to Bostman scoring system, the efficacy was excellent in 76 patients and good in 32.The experiment showed no statistical difference in the fracture disjunction distance between two methods (P > 0.05).Conclusion For treatment of patellar fractures, five-pointed star lattice sutures have the advantages of simple operation,reliable fixation, early postoperative exercise, fast recovery, satisfactory outcome and free need of reoper-ation for removing internal fixation.
