Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A growing number of chronic liver disease patients, especially those with metabolic syndrome-associated nonalcoholic fatty liver disease or hepatitis C virus-associated dysmetabolic syndrome, will take statins to prevent cardiovascular disease. As a result, clinicians will weigh complex issues raised by the interaction of statins with liver metabolism in these disorders. In this article, we critically review data concerning statins and liver pathophysiology with an emphasis on nonalcoholic fatty liver disease and hepatitis C virus, while also touching on other chronic liver diseases. Basic research interests include statins' mechanism of action and their effects on cholesterol-related cell signaling pathways and angiogenesis. From the clinical standpoint, many chronic liver diseases increase cardiovascular risk and would undeniably benefit from sustained statin use. The false alarms and security accompanying aminotransferase monitoring, however, are disturbing in light of the scarcity of data on statins' long-term effects on liver histology. Although some actions of statins might eventually prove to be particularly useful in nonalcoholic steatohepatitis, hepatitis C virus, or hepatocellular carcinoma, others may prove harmful. The lack of definitive data makes a fully informed decision impossible. Research using histological endpoints is urgently needed to determine the indications and contraindications of this extraordinary class of agents in patients with chronic liver disease.
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PMID:Statins in liver disease: a molehill, an iceberg, or neither? 1866 46

Although continuous improvements have been made in fighting rejection with immunosuppressive drugs in transplant recipients, this success story has been tempered by an associated high incidence of cancer. The latest projections are that cancer might exceed cardiovascular disease as the leading cause of death among transplant recipients. Indeed, immunosuppression reduces our natural ability to destroy cancer cells and to inhibit viral infections potentially linked to cancer development. Therefore, a strategy to counter the problem of cancer in transplantation is needed. Recently, mammalian target of rapamycin (mTOR) inhibitors have demonstrated potential as both immunosuppressive and anticancer agents. Although mTOR inhibitors prevent organ transplant rejection, this class of drugs has potential anticancer properties that may be useful in the "balance of effects" toward cancer-free survival in transplant recipients. Mechanisms of mTOR inhibitors' anticancer effects are multiple, affecting processes including angiogenesis, cell proliferation, cell survival, and molecular oncogenic signaling. Importantly, experimental work supports the view that tumor inhibition can be accomplished with mTOR inhibitors while protecting allografts against rejection. Most recently, prospective randomized clinical studies have been initiated to test the concept that mTOR inhibitors reduce cancer while simultaneously inhibiting allograft rejection. One such study, the SiLVER trial, examines hepatocellular carcinoma recurrence in mTOR inhibitor-treated liver transplant patients. More robust evidence as to whether cancer risk can be reduced in transplant recipients with mTOR inhibitors may come from such clinical trials.
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PMID:The impact of mTOR inhibitors on the development of malignancy. 1910 Sep 4

Lecithin is an essential biological component and widely used as a nutritional supplement for protecting cells from oxidation, increase fat burning and preventing cardiovascular disease. Lecithin contains fatty acids identified as the peroxisome proliferator-activated receptor (PPAR) agonists. However, the role of lecithin in adipogenesis and lipogenesis remains elusive. 3T3-L1 cells and mouse primary preadipocytes were used to characterize the properties of lecithin related to adipogenesis and lipogenesis. We found that lecithin promoted adipocyte differentiation and differentiation-specific gene expression, and increased triglycerides and free fatty acid levels in the adipocytes. These effects are independent of the clonal expansion of 3T3-L1 cells and the upstream PPARgamma regulator, CCAAT-enhancer-binding protein beta. Furthermore, lecithin induced lipid accumulation in human hepatoma HepG2 cells. Our data suggest that lecithin is involved in adipogenesis, lipogenesis and hepatic lipid accumulation and it is implicated in obesity and hepatic steatosis.
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PMID:Lecithin promotes adipocyte differentiation and hepatic lipid accumulation. 1928 19

Tribbles homolog 3 (TRB3) is a pseudokinase that has been implicated in the control of stress response, cell viability and metabolic processes, and has been linked to medical conditions, including insulin resistance, cardiovascular disease and diabetes. Therefore, the understanding of mechanisms that regulate TRB3 expression is of considerable importance. We have previously described the existence of several human (h) TRB3 mRNA isoforms that differ in their 5'-untranslated region (5'-UTR). In this study, we use a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) system to characterize the expression levels of hTRB3 mRNA isoforms in HepG2 hepatoma cells cultured in regular medium or exposed to arsenite, and investigate the effect of hTRB3 5'-UTR variants on the efficiency of mRNA translation. The data indicate that of the hTRB3 mRNA splice variants, 1A is predominant (>80% of molecules) in both the stressed and unstressed states, and that the remainder consists mainly of 1B4, with the variants 1B1, 1B2 and 1B3 together forming less than 1% of the population in either condition. In addition to the substantial transcriptional upregulation of all hTRB3 mRNA splice variants, the exposure of cells to arsenite results in a marked increase in the proportion of splice variant 1A molecules containing a truncated 5'-UTR. The shortened 1A 5'-UTR proved to be translationally more efficient than the untruncated 1A 5'-UTR, due to the lack of an inhibitory upstream open reading frame (uORF). Thus, increased transcription as well as altered usage of 5'-UTR variants contributes to the upregulation of hTRB3 protein synthesis in stressful conditions.
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PMID:Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5'-UTR. 1950 41

Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibited increases in the transforming growth factor-beta1 (TGF-beta1) mRNA and alpha-smooth muscle actin (alpha-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of alpha-SMA and TGF-beta1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of alpha-SMA and TGF-beta1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-beta1 expression via Nrf2/ARE activation.
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PMID:Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. 1964 58

Elevated circulating levels of acute phase proteins (APP) are associated with inflammation and inflammatory disorders such as cardiovascular disease. APP are mainly synthesised by hepatocytes and their transcription is induced by pro-inflammatory cytokines such as interleukin-1 (IL-1). The molecular mechanisms underlying the IL-1-induced expression of key transcription factors implicated in the regulation of APP are poorly understood. We have investigated this aspect using the CCAAT/enhancer binding protein-delta (C/EBPdelta) as a model gene. IL-1 induced the expression of C/EBPdelta mRNA and protein in the human hepatoma Hep3B cell line, a widely employed model system for studies on cytokine signalling in relation to the expression of APP. The IL-1-mediated induction of C/EBPdelta expression was attenuated in the presence of pharmacological inhibitors against c-Jun N-terminal kinase (JNK) (curcumin and SP600125), casein kinase 2 (CK2) (apigenin) and nuclear factor-kappaB (NF-kappaB) (NF-kappaB activation inhibitor). RNA interference assays showed significant attenuation of the IL-1-induced expression of C/EBPdelta following knockdown of the p50 and p65 subunits of NF-kappaB. IL-1 induced NF-kappaB DNA binding and activation by this transcription factor and this was attenuated by curcumin and apigenin. Taken together, these results suggest a potentially crucial role for NF-kappaB in the IL-1-induced expression of C/EBPdelta, and thereby downstream APP genes regulated by this transcription factor.
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PMID:Requirement for nuclear factor kappa B signalling in the interleukin-1-induced expression of the CCAAT/enhancer binding protein-delta gene in hepatocytes. 1980 21

Since android overweight/obesity and insulin resistance are independent risk factors for cardiovascular disease, we investigated their impact on basal and postprandial scavenger receptor BI (SR-BI) and ATP binding cassette transporter A1 (ABCA1)-mediated serum cholesterol efflux. Twelve android overweight to obese and 9 normal weight controls women underwent body composition analysis by dual energy X-ray absorptiometry, a euglycemic hyperinsulinemic clamp, and an oral fat load with blood sampling at initial time (T0), 4h (T4) and 10h (T10) after the fat load. Serum lipids and HDL-parameters, capacities of serum to promote cholesterol efflux from SR-BI expressing Fu5AH hepatoma cells or from ABCA1-expressing J774 macrophages and to abilities of serum to induce a net removal of cholesterol from macrophage foam cells were measured at T0, T4 and T10. Sera from overweight/obese exhibited moderately decreased SR-BI-mediated cholesterol efflux capacities, in accordance with reduced HDL concentrations, but importantly increased ABCA1-mediated cholesterol efflux and increased cholesterol extraction capacities over the postprandial period, partly related to higher prebeta-HDL concentrations. In multiple regression analyses, android obesity-related parameters and HDL-PL or prebeta-HDL levels remained the only independent correlates for SR-BI or ABCA1-dependent fractional cholesterol efflux while only prebeta-HDL levels remained correlated to cholesterol extraction capacities. Our results suggest that android overweight/obesity may not result in an impaired cholesterol efflux capacity.
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PMID:Impact of android overweight or obesity and insulin resistance on basal and postprandial SR-BI and ABCA1-mediated serum cholesterol efflux capacities. 1983 7

Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ~5 fold and glucose 6-phosphate dehydrogenase activities were decreased by ~25% compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased significantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to function in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.
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PMID:Dehydroepiandrosterone supplement increases malate dehydrogenase activity and decreases NADPH-dependent antioxidant enzyme activity in rat hepatocellular carcinogenesis. 2012 70

A significant increase of potent immunosuppressive agents over the last two decades has contributed to improved patient and graft survival after liver transplantation (LT). Numerous ongoing studies aim to determine the most effective immunosuppressive protocols while minimizing drug-related side effects. These protocols often combine several drugs with different mechanisms of action and toxicities allowing dosage adjustment. There is also a trend towards tailored immunosuppressive regimens according to the etiology of liver disease and comorbidities such as renal dysfunction and cardiovascular disease. The introduction of antibody induction therapies and antimetabolites resulted in an increasing number of studies with steroid minimization and calcineurin inhibitor (CNI) reduction protocols. Combined mycophenolate mofetil and minimal dose CNI therapy has shown to be safe and to improve kidney function and cardiovascular risk profile in the majority of studies. Sirolimus (SRL) and everolimus constitute a new class of compounds designated as the mammalian target of rapamycin (mTOR) inhibitors, which exhibit immunosuppressive and antiproliferative effects. There are conflicting results with respect to renal improvement upon switch to mTOR inhibitor therapy with concomitant reduction/elimination of CNI. Further trials will determine whether earlier conversion to mTOR inhibitors enable prevention of CNI-related renal dysfunction. Future results from randomized controlled studies will also show whether SRL can improve recurrence-free survival in patients transplanted for hepatocellular carcinoma.
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PMID:Current immunosuppressive approaches in liver transplantation. 2019 32

Elevated plasma levels of C-reactive protein (CRP), the prototype acute-phase protein (APP), are predictive for future cardiovascular events. Controversial evidence suggests that CRP may play a causal role in cardiovascular disease. CRP synthesis inhibition is a potential approach for reducing cardiovascular mortality. We show here that endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain and digitoxin, inhibit IL-1beta- and IL-6-induced APP expression in human hepatoma cells and primary human hepatocytes (PHH) at nanomolar concentrations. Inhibition is demonstrated on transcriptional and on protein level. The molecular target of cardiac glycosides, i.e. the alpha1 subunit of the Na(+)/K(+)-ATPase, is strongly expressed in human hepatocytes. Inhibition of APP synthesis correlates with the potency of cardiac glycosides at the Na(+)/K(+)-ATPase. The trigger for APP expression inhibition is an increase in intracellular calcium since the calcium ionophore calcimycin is also active. Qualified specificity of oubain for hepatocellular APP synthesis inhibition is demonstrated by lack of effectivity on IL-1beta-induced IL-6 release from primary human coronary artery smooth muscle cells. The inhibitory activity of cardiac glycosides on CRP expression may have important implications for the treatment of cardiovascular disease. Cardiac glycosides may be used for CRP synthesis inhibition in the future.
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PMID:Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. 2020 26


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