Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eight liver biopsy specimens from five patients with PAS-negative intracisternal hyalin were investigated by immunofluorescence for: (1) immunoglobulins (Ig) G, A, M, D, E; (2) light chains (kappa and lambda); (3) complement components C1q, C4, C3c, C5, C9; (4) C1-inactivator; (5) C3-activator; (6) alpha 1-antitrypsin; (7) alpha 1-antichymotrypsin; (8) plasminogen; (9) fibrinogen; (10) fibrinogen breakdown products D and E; (11) fibronectin; (12) prealbumin; (13) albumin; (14) betalipoprotein; (15) apolipoprotein; (16) alpha 1- and alpha 2-glycoprotein; (17) cholinesterase; (18) ceruloplasmin; (19) haemopexin; (20) myoglobin; (21) placenta lactogen; (22) transferrin; (23) actin; (24) myosin; (25) cathepsin D; and (26) hepatitis B surface and core antigens (HBsAg and HBcAg). The globules reacted significantly with antisera against C3c (three patients), C4 (three patients), C3-activator (one patient) and fibrinogen (two patients). The cause of the protein accumulation is not clear. Serial studies indicate the possibility of a disturbance of protein secretion and an as yet unidentified immune complex disorder.
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PMID:Immunohistological investigations of PAS-negative globular intracisternal hyalin in human liver biopsy specimens. 285 88

An inverse correlation between hepatitis B virus (HBV) and steady-state levels of apolipoprotein AI and CIII mRNAs was observed in two hepatoma cell lines. Analysis of a third line containing an inducible viral genome implicated viral pregenomic RNA in apolipoprotein mRNA reduction. We conclude that HBV alters infected cells despite the absence of overt cytopathogenicity.
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PMID:Hepatitis B virus-mediated changes of apolipoprotein mRNA abundance in cultured hepatoma cells. 1269 52

Liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. This has been attributed to the high incidence of hepatitis B infection. Hepatitis B proteins, such as the hepatitis B X protein (HBx) that is large hepatitis B surface protein could regulate transcription of many candidate genes for liver carcinogenesis. It has known that patients who suffered from acute hepatitis B could have lipid disorders such as decreased plasma level of high-density lipoproteins (HDL). Furthermore, aberrations of lipid metabolism are often seen in the chronic hepatitis B infection. Plasma lipid profiles could be changed under HCC. In majority of the reports in HCC, plasma levels of triglycerides (TG), cholesterol, free fatty acids (FFA), HDL, low-density lipoproteins (LDL), lipoprotein (a) (Lp(a)), apolipoprotein AI (apoAI) and apoB were slight to significantly decreased, however, in some cases plasma levels of TG and Lp(a) might be increased. It has been suggested that analysis of plasma levels of lipids, lipoproteins and apolipoproteins in the patients suffered from HCC reflects on the hepatic cellular impairment status. Studies revealed that alterations seen in the plasma levels of lipids, lipoproteins and apolipoproteins reflecting patients' pathologic conditions. Decreased serum levels of cholesterol and apoAI may indicate a poor prognosis. Human leukaemic cells and certain tumor tissues have a higher receptor-mediated uptake of HDL and LDL than the corresponding normal cells or tissues. LDL and HDL have therefore been proposed as a carrier for the water-insoluble anti-cancer agents.
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PMID:Influence of liver cancer on lipid and lipoprotein metabolism. 1651 89

The major pandemics caused by chronic viral infections is produced by HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV), with estimates of 38, 70, and 250 million people worldwide, respectively (Fig. 1). During the last couple of years, the advent of direct oral antivirals has allowed pursuing global HCV eradication. In an unprecedented manner, these drugs cure more than 95% of hepatitis C patients when given for only 2-3 months. The enthusiasm on HCV has renewed the interest for curative strategies for both HIV and HBV. However, important biological differences between all three viruses may preclude envisioning a similar rapid success for either HIV or HBV than for HCV infection. As shown in figure 1, once infection of targeted cells has occurred, the viral genetic material only replicates in the cytosol for HCV whereas it enters the nucleus and integrates into the chromosomes as provirus for HIV or is converted in a circular covalently closed form (cccDNA) for HBV (Fig. 1). Blocking viral nucleic acid replication for a minimum lag of time allows definitive clearance of HCV infection, with degradation of residual cytoplasmic HCV-RNA strands. In contrast, blocking viral replication has only a transient effect on HIV or HBV, as mRNA expression resumes following treatment discontinuation, given the stability of the HIV provirus or the HBV cccDNA, respectively. The European Liver meeting took held in Paris on April 2018. A relatively large number of presentations addressed distinct new hepatitis B therapeutic strategies. Table 1 summarizes some of the molecules that have been investigated so far with more promising results, grouping them into distinct drug classes (Soriano et al. Exp Op Inv Drugs 2017;26:843-51), based on their distinct mechanism of action and targeted steps in the HBV life cycle (Fig. 2). Considering the pros and cons of novel HBV therapeutic candidates, it has become apparent new HBV gene therapies among the most attractive. Several advances have contributed to position gene therapy in front within the experimental HBV armamentarium. First, progresses in delivery systems, including the use of polymers and nanoformulations have allowed developing easier forms of administration that now are becoming subcutaneous and monthly. Second, the synthetic production of oligonucleotide formulations has reduced costs. Third, the specificity against HBV is higher than for other experimental agents, as immune modulators that enhance innate immunity, such as TLR agonists (i.e., GS-9620) or checkpoint inhibitors (i.e., nivolumab). Fourth, significant declines in serum hepatitis B surface antigen (HBsAg) are demonstrated during gene therapy, which have never been seen using the most potent polymerase inhibitors (i.e., tenofovir or entecavir). Finally, unanticipated significant reductions in cccDNA are seen with HBV gene therapy, most likely as prove of an indirect benefit of waning the immunosuppressive effect of large over amounts of HBsAg released by infected hepatocytes that contributes to T-cell exhaustion. In a pioneering study, Roche was the first to publish the potent effect of an oral small molecule that blocked HBV gene expression (Mueller et al. J Hepatol 2018;68:412-20). The drug belonged to the dihydroquinolizinone class, and directly or indirectly modified viral RNAs, promoting their degradation. This posttranscriptional silencing was accompanied by rapid drops in HBV-DNA and more importantly in serum HBsAg in the humanized mice. However, Roche decided to discontinue any further clinical development of the drug. Nowadays, two major groups of agents are being developed as HBV gene therapies. At this time, interference RNA (iRNA) molecules and nucleic acid polymers (NAPs) are the most promising. Overall, iRNA is double-stranded RNA molecules, 20 nucleotides long. One strand matches a segment of specific HBV mRNA and induces its degradation. Several iRNA molecules have entered into Phase II clinical trials (Flisiak et al. Exp Op Biol Ther, in press), including ARB-1467 and AB-729 (Arbutus), ARO-HBV (Arrowhead), ALN-HBV (Alnylam), and IONIS-HBVRx (Ionis). In most cases, they are tested as part of combination therapy with nucleos(t)ide analogs and/or peginterferon. NAPs are phosphorothioate 40 length oligonucleotides that no map any HBV sequence. However, they interact with a liver host target protein (apolipoprotein-like) and result in specific inhibition of HBV mRNAs. This is followed by rapid suppression of HBsAg release (Roehl et al. Mol Ther Nuc Acids 2017;8:1-12). In a pilot study with intravenous REP-2139, investigators from Replicor demonstrated strong reductions in HBV-DNA along with significant drops in HBsAg and seroconversion in some patients. More interestingly was the recognition of significant reductions in hepatic cccDNA, most likely a result of an indirect effect following the removal of large amounts of HBsAg from the bloodstream that contributes to impaired T-cell responses in chronic hepatitis B patients (Bazinet et al. EASL, Paris 2018; abstract FRI-343). An improved NAP, named REP-2165 and subcutaneous administration are currently being tested.
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PMID:Hepatitis B Gene Therapy Coming to Age. 2993 6