Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular epidemiological studies of populations at high risk for liver cancer have shown that hepatitis B virus (HBV) and aflatoxin B1 exposures are two major risk factors for this disease. Oltipraz is currently being considered for clinical trial to protect against aflatoxin B1-induced hepatocarcinogenesis based on its proven protective effect in many different animal models. In addition, oltipraz inhibits human immunodeficiency virus (HIV) replication. The inactivation of reverse transcriptase of HIV appears to be the antiviral mechanism. It has been demonstrated that a number of compounds that inhibit HIV replication also inhibit HBV replication in vitro. Therefore, we tested the possibility of oltipraz blocking HBV replication in 2.2.15 cells (clonal cells derived from HepG2 cells that were transfected with a plasmid containing HBV DNA) in vitro. Results of the experiments indicate that oltipraz has a dose-dependent inhibitory effect on HBV replication and specifically blocks HBV transcription in 2.2.15 cells. In addition, oltipraz induces endogenous wild-type p53 protein in a dose- and time-course-dependent manner. Taken together, we speculate that the effects of oltipraz against replication of HBV and specific blocking of HBV transcription may be through the induction of p53-mediated pathway in 2.2.15 cells. In addition to its known chemopreventive action on aflatoxin B1 hepatocarcinogenesis, oltipraz was shown here to inhibit HBV replication. These dual effects put oltipraz as the excellent candidate for the chemopreventive agent of human hepatocellular carcinoma.
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PMID:Oltipraz, a novel inhibitor of hepatitis B virus transcription through elevation of p53 protein. 988 68

We observed six cases of haemophiliacs with HIV-induced immunodeficiency who died from fatal liver failure despite the absence of evident cirrhosis. They all had the infection with hepatitis viruses (two patients with hepatitis B and D viruses and four patients with hepatitis C virus) and their CD4 counts were severely decreased. They were much younger than cirrhotic haemophiliacs without HIV. Their serum levels of hyaluronic acid and type IV collagen were lower than those in haemophiliacs with cirrhosis, and were normal. No patients had experienced symptoms or concomitant diseases characteristic of cirrhosis, such as ascites, jaundice, oesophageal/gastric varices or hepatocellular carcinoma, except for one case who had a history of mild ascites. The characteristics of this liver failure were different from liver failure resulting from cirrhosis caused by chronic hepatitis, which suggests liver failure that is specific to patients with immunodeficiency. This kind of liver failure can be a factor threatening survival in patients with HIV infection and with hepatitis virus co-infection in an immunodeficient state.
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PMID:Fatal liver failure in haemophiliacs with HIV-induced immunodeficiency: observation of six patients. 1021 59

The telomere hypothesis postulates stabilization of telomere length and telomerase activation as key events in cellular immortalization and carcinogeneses. Accordingly, telomerase has been suggested as a novel and highly selective target for design of antitumor drugs. Screening of a chemical library including 16 000 synthetic compounds yielded six that strongly inhibited telomerase activity in extracts of cultured human cells, including four isothiazolone derivatives and two unrelated compounds. The most potent inhibitor was 2-[3-(trifluoromethyl)phenyl]isothiazolin-3-one (TMPI), a concentration of 1.0 microM inhibited telomerase activity by 50% according to a telomere repeat amplification protocol (TRAP) assay. Analysis using partially purified telomerase from AH7974 rat hepatoma cells demonstrated noncompetitive inhibition with the telomere-repeat primer and mixed inhibition with the dNTPs; the inhibition constant was 2.5 microM. TMPI did not inhibit eukaryotic DNA polymerase alpha, beta, or human immunodeficiency virus reverse transcriptase (HIV RT). Thus, inhibition by TMPI was highly selective for telomerase. Inhibition by TMPI was quenched by 1 mM of dithiothreitol or glutathione, suggesting that TMPI inhibits telomerase by acting at a cysteine residue. TMPI inhibition of this enzyme may find application as an antineoplastic agent.
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PMID:Isothiazolone derivatives selectively inhibit telomerase from human and rat cancer cells in vitro. 1047 2

Hepatitis C virus infection, which is far more prevalent than human immunodeficiency virus (HIV)-1, can lead to cirrhosis, hepatocellular carcinoma, hepatic failure, and death. Like HIV-1, hepatitis C is transmitted parenterally, sexually, and from mother to infant. The American Academy of Pediatrics and the Centers for Disease Control and Prevention (CDC) recently recommended that all children born to women who are infected with hepatitis C virus or have risk factors for infection be screened for hepatitis C. Most infected women are asymptomatic and unaware of their infection, so routine prenatal testing is needed to fully meet that goal. We do not believe that current data justify universal testing, but we believe it is time for all obstetricians to test selectively based on risk factors.
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PMID:Hepatitis C: screening in pregnancy. 1057 99

It is now widely accepted that 85% or more of individuals with acute hepatitis C virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However, there has been much controversy about the inevitability of developing cirrhosis and HCC and the time frames in which they are likely to occur. Natural history studies have provided varying estimates of the risk of progression in chronic hepatitis C. Part of this variation may be a result of viral-specific, host, and/or environmental factors, but much of it undoubtedly is a result of the difficulties of doing natural history studies in this disease: acute onset is rarely identified, chronic infection is often asymptomatic, and the duration of disease is prolonged. Three types of studies--prospective, retrospective, and retrospective-prospective (nonconcurrent prospective)--have attempted to determine the clinical outcomes of chronic HCV infection and have provided widely varying estimates. The combined population data indicate that the disease progresses slowly over approximately 30 years, on average. Approximately 20% of infected individuals will progress to fibrosis and cirrhosis. Of these, approximately 20% will progress to HCC. The likelihood of progression appears to be independent of genotype or viral load but increases with alcohol intake, male sex, age over 40 years at infection, and coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). Results of ongoing nonconcurrent studies are needed to determine disease progression in the third, fourth, and fifth decades of infection and to better define the factors that affect progression.
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PMID:Natural history of hepatitis C. 1065 49

Numerous studies have reported effects of antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus nucleoside analogs, zidovudine (3'-azido-3'-deoxythymidine) (AZT), 2',3'-dideoxycytidine (ddC), 2', 3'-dideoxyinosine (ddI), 2',3'-didehydro-2',3'-deoxythymidine (d4T), and beta-L-2',3'-dideoxy-3'-thiacytidine (3TC), as well as the metabolite of AZT, 3'-amino-3'-deoxythymidine (AMT), on mitochondrial function in a human hepatoma cell line, this issue has been reexamined. Evidence for a number of mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in lactic acid levels. Only in mitochondria isolated from AZT (50 microM)-treated cells was significant inhibition of cytochrome c oxidase and citrate synthase found. Our investigations also demonstrated that AZT, d4T, and 3TC did not affect the synthesis of the 11 polypeptides encoded by mitochondrial DNA, while ddC caused 70% reduction of total polypeptide content and ddI reduced by 43% the total content of 8 polypeptides (including NADH dehydrogenase subunits 1, 2, 4, and 5, cytochrome c oxidase subunits I to III, and cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent mitochondrial dysfunction is more prevalent with AZT treatment.
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PMID:Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells. 1068 9

Hepatitis B and C are, and will remain for some time, major health problems in Egypt and the entire continent of Africa. Both infections can lead to an acute or silent course of liver disease, progressing from liver impairment to cirrhosis and decompensated liver failure or hepatocellular carcinoma (HCC) in a 20-30 year period. In addition, hepatitis B and C infection rates differ in different settings, and prognosis may be worse in conjunction with schistosomiasis in Egypt, malaria in Sudan and human immunodeficiency virus (HIV) in other African populations. Unlike hepatitis B virus (HBV), for which the prospects for controlling the spread of infection by vaccination are promising, prospects for development of an effective vaccine against hepatitis C virus (HCV) are limited. As well as screening of blood for transfusion and using sterile needles for injection, preventive measures should be undertaken to reduce the risk of contact (often described as community-acquired infection). Until more is known about the unidentified routes of transmission in tropical and subtropical settings it will be difficult to be specific about the kind of measures which may be effective. Success may largely depend on changing habits within the population. Prevention should be the main goal of current efforts until low-cost, effective therapies become available.
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PMID:Prevalence of hepatitis B and C in Egypt and Africa. 1072 51

Chronic infection with hepatitis B virus (HBV) in humans is strongly linked to the development of hepatocellular carcinoma (HCC). Activation of growth-regulatory genes may play a crucial role in carcinogenesis. Proto-oncogene expression has been shown to be higher in HCC tissue with integrated HBV DNA than in the normal liver. Earlier, we showed that the 3' end of the HBV major surface gene (S) (426-855 nucleotides of the S region) is a transactivator of the X promoter-enhancer regulatory element in co-transfection experiments. This region expresses a truncated carboxy terminal S protein extending from amino acid residues 102 to 226. In this study, the truncated S protein (trc-S) was examined for its enhancing activity on several viral and cellular regulatory elements. The results indicate that trc-S activates rous sarcoma virus long terminal repeat (LTR), human T-lymphotropic virus 2 LTR, human immunodeficiency virus 1 LTR, and the c-jun and c-fos promoters. Electrophoretic mobility shift assays carried out to investigate its DNA-binding properties established that trc-S binds to HBV X promoter and oligonucleotides representing binding sites for the AP1 and TFIID transcription factors. The specificity of this interaction was confirmed by using competition experiments and supershift assays. These experiments suggest that trc-S is a transactivator of several cellular and viral promoters and that this activity is mediated by direct interaction with DNA.
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PMID:Hepatitis B virus surface (S) transactivator with DNA-binding properties. 1074 25

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.
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PMID:Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. 1077 Sep 16

Hepatitis C (HCV) infection occurs in as many as 33% of the patients with human immunodeficiency virus (HIV) infection. In view of their improved survival, liver disease will become more clinically significant in patients coinfected with HIV/HCV. Several studies in patients with hemophilia have shown that coinfected patients develop earlier and more severe liver disease, including hepatocellular carcinoma. In nonhemophilic cohorts, lower CD4 counts are associated with an increased prevalence of cirrhosis. However, HCV infection does not seem to alter the natural history of HIV infection in most cases. Human immunodeficiency virus coinfection in pregnant women increases the risk of perinatal HCV transmission 2-fold, with more than 25% of occurrences involving transmission of both viruses: cesarean delivery significantly decreases this risk. The expanded use of highly active antiretroviral therapy may lead to further improvement in morbidity and mortality from HIV infection. Thus, the management of coexistent HCV liver disease will need to be formulated. We suggest that alcohol be disallowed. Interferon and ribavirin in combination are likely to become the therapy of choice, particularly in coinfected patients with higher CD4 counts, lower HCV viremia, and non-1 genotype. During treatment, complete blood cell counts need to be closely monitored. Future controlled trials will determine the efficacy and safety of long-acting interferon preparations. Administration of highly active antiretroviral therapy, with the intent to prevent decreases in CD4 counts, seems crucial in stemming liver disease progression. However, some drugs have clear-cut hepatotoxic potential and patients with known liver disease should be closely monitored. Arch Intern Med. 2000;160:3365-3373.
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PMID:Hepatitis C in patients with human immunodeficiency virus infection: diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues. 1111 28


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