ABSTRACT
Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5-7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3-6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia (p = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020-1.087; p = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.
ABSTRACT
In chronic pancreatitis, PSCs are activated by proinflammatory cytokines to induce pancreatic fibrogenesis. HDAC inhibition protected against the pancreatic fibrosis and the apoptosis of PSCs through induced apoptosis and depressed inflammation. In our study, we found that miR-15 and miR-16 decreased significantly in chronic pancreatitis and HDAC inhibition could recover the levels of these two miRNAs. HDAC regulated the transcription of miR-15 and miR-16, which then modulate the apoptosis and fibrosis of PSCs. And we proved that Bcl-2 and Smad5 were the target genes of miR-15 and miR-16, which illustrated how HDAC inhibition alleviated the apoptosis and fibrogenesis of PSCs in chronic pancreatitis. These results suggested that HDAC inhibition protects against CP by promoting apoptosis and TGF-ß/Smads signaling pathways, and indicated that HDAC inhibition is a potential therapy to alleviate CP patients in clinic, and these need to be explored further.
Subject(s)
Apoptosis/genetics , Histone Deacetylase Inhibitors/pharmacology , MicroRNAs/genetics , MicroRNAs/metabolism , Pancreas/pathology , Pancreatic Stellate Cells/pathology , Pancreatitis, Chronic/drug therapy , Pancreatitis, Chronic/genetics , Pancreatitis, Chronic/pathology , Up-Regulation/drug effects , Cells, Cultured , Fibrosis , Gene Expression/drug effects , Histone Deacetylase Inhibitors/therapeutic use , Humans , Pancreas/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
Activation of YAP/TEAD signaling is very common in the progression of HCC (Hepatocellular carcinoma). Nuclear pore complex (NPC) regulates the shuttling of proteins between cytoplasm and nucleus. Nuclear accumulation of YAP protein has been observed in the majority of HCC tissues. However, whether NPC could regulate the YAP/TEAD signaling remains unknown. In this study, it was found NUP37, the component of NPC, significantly up-regulated in HCC clinical samples and mouse model. Over-expression of NUP37 promoted the growth, migration and invasion of HCC cells, while knocking down the expression of NUP37 inhibited the growth, migration, invasion and metastasis of HCC cells and improved the survival of the mouse model. NUP37 interacted with YAP and activated YAP/TEAD signaling by enhancing the interaction between YAP and TEAD. Taken together, these data demonstrated the oncogenic roles of NUP37 in the progression of HCC and suggested that NUP37 might be a promising therapeutic target.
