Previous studies have suggested that hepatitis B virus (HBV) variants may account for the presence of HBV DNA in hepatitis B surface antigen (HBsAg)-negative patients (occult HBV infection). However, it is not known how widespread these variants are and how they influence the course of liver disease. To determine the prevalence of variants within the major hydrophilic region (MHR) of HBsAg, we investigated 2,565 subjects, including subjects with chronic hepatitis, cryptogenic cirrhosis, hemodialysis patients, and blood donors. Chronic hepatitis B virus (HBV) infection is a global public health problem that affects over 300 million individuals, or 5% of the world's population.

This study aims to systematically determine the activities and expressions of cytochrome P450s (CYP) in hepatocellular carcinoma (HCC) patients to support their optimal use in personalized treatment of HCC. Activities of seven major drug-metabolizing CYP enzymes (CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4) were determined in tumors and pericarcinomatous tissues harvested from 26 patients with hepatitis B virus-positive HCC using probe substrates. Protein and mRNA levels of these CYPs were also measured using isotope label-free LC/MS-MS method and realtime PCR, respectively. Maximal metabolic velocity (V max ) of CYP probe substrates was decreased by 2.5-to 30-fold in tumor microsomes, accompanied by a corresponding decrease in their protein and mRNA expression levels. However, K m values and turnover numbers of substrates in tumor microsomes were not changed. High correlations between activities and CYP protein levels were also observed, but the correlation between activities and mRNA levels was often poor. There was a major decrease in the degree of correlation in CYP expression in tumor tissues, suggesting that CYP expression levels are greatly disrupted by the tumorigenic process. Our unprecedented systemic study of the effects of HCC on CYPs demonstrated that activities of CYPs were seriously impaired and their expression patterns were severely altered by HCC. We proposed that determination of the CYP protein expression profile by LC/MS-MS in each patient is a promising approach that can be clinically used for individualized treatment of HCC.

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. The accumulation of Aβ in the brain is thought to play a causative role in the development of cognitive dysfunction in Alzheimer's disease. The p75 neurotrophin receptor is of great importance to protect against the Aβ burden and its expression is regulated by histone acetylation. This study investigated whether the phytochemical sulforaphane, a pan-histone deacetylase inhibitor, up-regulates the p75 neurotrophin receptor expression via affecting histone acetylation in protection against Alzheimer's disease. We found that sulforaphane ameliorated behavioral cognitive impairments and attenuated brain Aβ burden in Alzheimer's disease model mice. Additionally, sulforaphane reduced the expression of histone deacetylase1, 2, and 3, up-regulated p75 neurotrophin receptor, and increased levels of acetylated histone 3 lysine 9 and acetylated histone 4 lysine 12 in the cerebral cortex of Alzheimer's disease model mice as well as in Aβ-exposed SH-SY5Y cells. Furthermore, silencing of histone deacetylase1 and 3, but not histone deacetylase2, gene expression with small interfering RNA caused up-regulation of p75 neurotrophin receptor in SH-SY5Y cells. In conclusion, this study demonstrates that sulforaphane can ameliorate neurobehavioral deficits and reduce the Aβ burden in Alzheimer's disease model mice, and the mechanism underlying these effects may be associated with up-regulation of p75 neurotrophin receptor mediated, apparently at least in part, via reducing the expression of histone deacetylase1 and 3.

The use of an isotope label-free absolute quantification method for the simultaneous determination of 9 CYPs and 5 UGTs in human liver microsomes reveals that expression levels of CYPs and UGTs in human liver are severely impact by HCC, which could impact drug metabolism, disposition and pharmacotherapy.

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BackgroundSorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC), is metabolized by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients.MethodsSorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs) and adjacent normal hepatic microsomes (NHLMs) of HCC patients (n = 18). Commercial hepatic microsomes (CHLMs) were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting.ResultsThe mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax) of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold) than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients’ samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs.ConclusionsSorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

The mortality of acute-on-chronic liver failure (ACLF) patients complicated with invasive pulmonary aspergillosis (IPA) was extremely high. We aimed to explore prognostic value of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) lung score and to establish an optimal voriconazole regimen for ACLF patients complicated with IPA. We retrospectively screened hospitalized ACLF patients in our hospital from July 2011 to April 2016, from which 20 probable IPA cases were diagnosed. Along with onsets of IPA, deteriorated diseases severity, especially lung conditions were found in those 20 ACLF patients. It was found that IPA patients with CLIF-SOFA lung score <2 had better 28-day survival than those with lung score >1 (11/13 vs 0/7, p < 0.001). Based on plasma voriconazole concentration measurement, an optimal voriconazole regimen (loading doses: 0.2 g twice daily; maintenance doses, 0.1 g once daily) was established, which resulted in rational trough plasma drug concentrations (1–5 μg/mL), good clinical outcomes (90-day survival rate of 6/8) and no observed adverse events. In conclusion, CLIF-SOFA lung score >1 was able to identify ACLF patients complicated with IPA encountering much higher 28-day mortality. An optimal voriconazole regimen was safe and effective in our ACLF patients complicated with IPA.

The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions in vitro. Then, a bioresponsive polyethylene glycol (PEG)/DNA hybrid hydrogel was developed to support a controllable release of SCAP-Exo for diabetic bone defects. This system could be triggered by the elevated pathological cue (MMP-9) in response to the dynamic diabetic microenvironment. It was further confirmed that the administration of the injectable SCAP-Exo-loaded PEG/DNA hybrid hydrogel into the mandibular bone defect of diabetic rats demonstrated a great therapeutic effect on promoting vascularized bone regeneration. In addition, the miRNA sequencing suggested that the mechanism of dual-functional SCAP-Exo might be related to highly expressed miRNA-126-5p and miRNA-150-5p. Consequently, our study provides valuable insights into the design of promising bioresponsive exosome-delivery systems to improve bone regeneration in diabetic patients.