Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

Efficacy and safety of telbivudine alone and combined with adefovir for the treatment of nucleos(t)ide-naive chronic hepatitis B in patients with high-level hepatitis B virus load / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To compare the efficacy of telbivudine monotherapy and telbivudine combination therapy with adefovir in patients with nucleos(t)ide-naive chronic hepatitis B, high-level hepatitis B virus (HBV) load and hepatitis B e antigen (HBeAg)-positivity, and to explore the relationship between treatment regimen adherence and treatment outcomes.</p><p><b>METODS</b>A retrospective study was performed with 123 HBeAg-positive, high-level viral load (HBV DNA≥10(7) copies/ml), nucleos(t)ide-naive chronic hepatitis B patients. Fifty-three of the patients received combination therapy with telbivudine and adefovir dipivoxil,while 70 patients received the telbivudine monotherapy. All patients were tested for rates of conversion to HBV DNA-negative status,alanine aminotransferase (ALT) normalization, HBeAg seroconversion, drug resistance, and side effects at treatment weeks 12, 24, and 48. Treatment regimen adherence was assessed through self-reporting, and interviews were used to explore the relationships to treatment outcomes. The chisquare test, t test and Fisher's exact test were used for statistical analyses.</p><p><b>RESULTS</b>The rates of HBV DNA negative conversion in the combination group at treatment weeks 12, 24 and 48 were 62.3% (33/53), 88.7% (47/53) and 94.3% (50/53) and were significantly different from those in the monotherapy group at weeks 12 and 24.The rates of ALT normalization were significantly different between the two groups at treatment week 12 (94.3% vs. 77.1%). The rate of HBeAg seroconversion in the combination group at treatment week 48 was 39.6%, and significantly different than that of the monotherapy group. The rates of drug-resistance in the combination and monotherapy groups at treatment week 48 were 3.8% and 11.4%, and the proportion of non-adherence to the treatment regimen was 53.3%, which significantly affected treatment outcome. No side effects occurred in either treatment group.</p><p><b>CONCLUSION</b>Telbivudine combination treatment with adefovir was more effective than telbivudine monotherapy and elicited a low drug resistance rate in nucleos(t)idenaive chronic hepatitis B patients with high-level HBV load and HBeAg-positivity. Adherence to the therapy regimen was a key factor influencing treatment outcomes.</p>

Construction of Tre enzyme eukaryotic expression vector and identification of its function in loxLTR sequence-specific recognition / 医学研究生学报

Objective Clearing HIV provirus is the key to cure AIDS .The study was to construct the Tre enzyme eukaryotic expression vector and identify its function in specific recognition of loxLTR sequence in HIV provirus . Methods Tre gene was in-serted into eukaryotic expression vector pcDNA 3.1 gene recombination manipulation by genetic recombination techniques including gene synthesis , PCR, restriction enzyme digestion and ligation .EGFPpA-LoxLTR sequence was inserted into pmCherry-N1 vector and was tested by restriction enzyme digestion , PCR and sequencing .Constructed vectors were electroporated into HeLa cells , then using fluorescence microscopy to observe fluorescence intensity changes . Results PCR, restriction enzyme digestion , electrophoresis and sequencing confirmed that Tre enzyme eukaryotic expression vector had been constructed successfully , and it could specifically recog-nize and cut loxLTR sequence after being transfected into Hela cells . Conclusion Constructed Tre enzyme eukaryotic expression vector can be expressed in Hela cells and specifically recognize loxLTR sequence , which has prepared the experimental ground for fur-ther studies of clearing HIV provirus .