Circumdatin G, a new alkaloid from the fungus Aspergillus ochraceus.

The crude extract of the broth of Aspergillus ochraceus was found to inhibit the final stage of polyprotein processing during hepatitis C virus replication. Bioassay-guided fractionation led to the isolation of the known compound mellein as the active component of the extract. Also isolated were circumdatin F and a new alkaloid, circumdatin G. The structure of circumdatin G was determined by spectroscopic analysis.

Cytonic acids A and B: novel tridepside inhibitors of hCMV protease from the endophytic fungus Cytonaema species.

Two novel human cytomegalovirus protease inhibitors, cytonic acids A (1) and B (2), have been isolated from the solid-state fermentation of the endophytic fungi Cytonaema sp. Their structures as p-tridepside isomers were elucidated by MS and NMR methods.

Three new pseudodistomins, piperidine alkaloids from the ascidian Pseudodistoma megalarva.

Bioassay-guided fractionation of the MeOH-CH2Cl2 extract of the Micronesian ascidian Pseudodistoma megalarva yielded three new piperidine alkaloids, pseudodistomins D-F (3-5) and the previously reported pseudodistomins B and C (1 and 2). The structure and stereochemistry of these compounds were established by interpretation of spectral data. Pseudodistomins B-F were found to be active in a cell-based assay for DNA damage induction, but the activity was due to an alternative mechanism.

Hepatitis C virus recurrence after liver transplantation: relationship to anti-HCV core IgM, genotype, and level of viremia.

OBJECTIVES: Factors that determine the severity of hepatitis C virus (HCV)-recurrent disease in patients undergoing orthotopic liver transplantation (OLT) for HCV cirrhosis have not been clearly identified. To address this issue, we evaluated the histological and virological outcome in 25 patients who underwent OLT for HCV cirrhosis. METHODS: HCV-RNA was detected by qualitative and quantitative polymerase chain reaction. The HCV genotype also was determined by polymerase chain reaction. Anti-HCV core IgM was tested by ELISA. Disease severity was expressed as a histological score. RESULTS: Sixteen patients had evidence of HCV-recurrent disease. HCV-RNA levels before transplantation (p = 0.029) and after transplantation (15 days, p = 0.004; 90 days, p = 0.040; 360 days, p = 0.010) were significantly higher among patients who subsequently developed recurrent hepatitis than among those who did not. The presence of anti-HCV core IgM before (p = 0.044) and after OLT (15 days, p = 0.017; 90 days, p = 0.037; and 360 days, p = 0.040) was significantly related to recurrence of hepatitis. The genotype was not related to the level of viremia, to the prevalence of recurrent hepatitis, to the presence of anti-HCV core IgM, or to disease severity. CONCLUSIONS: The recurrence of HCV hepatitis in patients undergoing OLT for HCV cirrhosis is related to higher levels of viremia and the presence of anti-HCV core IgM, but not to the HCV genotype. However, disease severity is not related to viremia levels, HCV genotype, or positivity of anti-HCV core IgM.

Viral replication in patients with concomitant hepatitis B and C virus infections.

The aim of this study was to assess the implications of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). The HBV and HCV status in 100 patients with chronic hepatitis was analysed. HBV DNA was studied using liquid hybridization and the polymerase chain reaction (PCR). HCV viremia was measured using qualitative and quantitative PCR. The HCV genotype was determined by PCR. Patients were divided into three groups according to their HCV-RNA and HBsAg status: group I consisted of 40 patients with chronic hepatitis caused by HBV; group II, 40 patients with chronic hepatitis caused by HCV; and group III, 20 patients infected with both viruses. The HBV-DNA level was higher in group I than in group III (66.4 vs. 11.5 pg/ml; p < 0.05). Quantification of HCV viremia revealed mean values of 36.9 copies x 10(5)/ml in group II and 5.5 copies/ml x 10(5) in group III (p < 0.05). The mean aminotransferase level and histological activity were higher in group III. HCV genotype lb was the predominant type. The data suggest that there is reciprocal inhibition of viral replication in patients with dual HBV and HCV infection. Liver disease appears to be more severe in patients with chronic hepatitis B and C.

[Recurrence of hepatitis caused by hepatitis c virus in patients receiving a liver transplant]. / Recidiva de la hepatitis por el virus de la hepatitis C en los pacientes receptores de trasplante hepático.

BACKGROUND: Liver disease due to hepatitis C virus (HCV) is an increasingly frequent indication for liver transplantation. We performed a clinical and virological study of 20 HCV-infected liver transplant recipients to correlate virological markers with histological recurrence of disease. PATIENTS AND METHODS: In ninety-four patients who were given transplants for end-stage cirrhosis, IgG and IgM antibodies to HCV and IgM to HCV tested by ELISA; all samples were further examined in a four-antigen recombinant immunoblot assay (2-RIBA). HCV viremia was measured by the conventional nested PCR, HCV genotype was determined by PCR amplification using type-specific primers. We have analyzed de novo infection by HCV, HCV recurrence and the influence of genotype in these recurrence. RESULTS: Nineteen of 20 antibody-positive patients (95%) had HCV RNA before transplantation. All 19 patients who were viremic before transplantation had persistent infection after LT. HCV genotype 1b was the predominant type before and after LT (75%). Ten of the 20 (50%) patients developed histological findings of chronic hepatitis (CH) in liver allografts. HCV recurrent liver disease after LT was not related with HCV genotype. Of 4 deaths after transplant in hepatitis C group, only one was related to recurrent disease. We have not found de novo hepatitis C. CONCLUSIONS: Our results indicate the general persistence of hepatitis C virus infection and the excellent short-term prognosis after liver transplantation. Chronic hepatitis by HCV in liver transplant was not related with HCV genotype.

Halistanol disulfate B, a novel sulfated sterol from the sponge Pachastrella sp.: inhibitor of endothelin converting enzyme.

As part of a search for novel inhibitors of endothelin converting enzyme (ECE), the MeOH extract of a South African sponge, Pachastrella sp., was shown to be active. Bioassay-guided fractionation of the extract yielded a novel sterol sulfate, halistanol disulfate B (1). The structure and stereochemistry of 1 was established mainly by interpretation of spectral data. Disulfate (1) was found to be active at a micromolar concentration in the ECE assay.

Plakortides, novel cyclic peroxides from the sponge Plakortis halichondrioides: activators of cardiac SR-CA(2+)-pumping ATPase.

As part of a search for novel activators of Ca2+ pumping activity of cardiac SR- (sarcoplasmic reticulum), the EtOAc extract of the Jamaican sponge Plakortis halichondrioides was shown to be active. Bioassay-guided fractionation of the extract followed by preparative TLC and HPLC yielded several known and novel compounds. Three of the novel cyclic peroxides, plakortides F, G, and H (3, 4, and 5) are the subject of this report. Their structures including relative stereochemistry were established by interpretation of spectral data. Micromolar concentrations of plakortides F-H (3-5) were found to significantly enhance Ca2+ uptake by SR.

[Hepatita B and C virus infections in patients with hepatocellular carcinoma]. / Infección por los virus de la hepatitis B y C en pacientes con carcinoma hepatocelular.

BACKGROUND: The prevalence of HBV and HCV infections in patients with hepatocellular carcinoma may be related to variations in the geographic area of study. For this reason, we have analized the relative prevalence of HBV and HCV infections in 94 patients with hepatocellular carcinoma from Cantabria (North of Spain). PATIENTS AND METHODS: We have studied 94 patients with hepatocellular carcinoma from January 1988 to December 1993. Commercially available radioimmunoassay or ELISA were used for detection of HBsAg, anti-HBs and anti-HBc. The HBV DNA was analized by PCR. The HCV infection was assayed by ELISA-2 and RT-PCR. RESULTS: The HBV infection was detected in 27 patients: 19 patients were HBsAg positive and 8 patients HBsAg negative, anti-HBc positive, DNA HBV positive by PCR. The HCV infection was found in 57 patients. Forty patients were infected with both viruses. Of the remain twenty-four, forty were alcoholics. We found in 61 patients more than one etiological factor. Hepatoma was the first manifestation of liver disease in 24 cases and these were more frequently in HCV than in those with HBV infection. Moreover, the first group were older and have lower alcohol intake. CONCLUSIONS: 1) In Cantabria, Spain, the majority of cases of hepatocellular carcinoma are related to HBV, HCV and alcohol. 2) Analysis of DNA HBV and RNA HCV by PCR allows the diagnosis of cryptic infections by both viruses, especially in the cases of HBV and HCV coinfection. 3) Hepatoma is the first manifestation of liver disease in a high percentage of cases.

Natural product drug discovery and development: new perspectives on international collaboration.

Until recently, the prevailing attitude in developed nations regarded the world's genetic resources, which are mainly concentrated in the developing world, as a common resource of humankind, to be exploited freely irrespective of national origin. With the devastation being wreaked in the tropical rainforests and the resurgence in interest in recent years in the discovery of novel drugs from natural sources, particularly plants and marine organisms, the international scientific community has realized that the conservation of these global genetic resources and the indigenous knowledge associated with their use are of primary importance if their potential is to be fully explored. With this realization has come a recognition that these goals must be achieved through collaboration with, and fair and equitable compensation of, the scientists and communities of the genetically rich source countries. The signing of the United Nations Convention on Biological Diversity by nearly all of the World's nations has emphasized the need for the implementation of such policies. In this review, the articles of the Convention of relevance to the activities and practices of the natural products scientific community are briefly discussed. This discussion is followed by a summary of policies for international collaboration and compensation being implemented by several developed country organizations, and the perspectives on the current developments given by representatives of some of the source countries located in the regions of greatest biodiversity.

Protein kinase C inhibitors: novel spirosesquiterpene aldehydes from a marine sponge Aka (= Siphonodictyon) coralliphagum.

Two novel spirosesquiterpene aldehydes, corallidictyals A [1] and B [2], were isolated as a mixture from the marine sponge Aka (= Siphonodictyon) coralliphagum, and their structures were determined by detailed spectroscopic methods. These compounds were identified in a screen for inhibitors of protein kinase C.

Marine natural products as a source of novel pharmacological agents.

Research into marine natural products is evolving from an empirical search for antimicrobial and cytotoxic compounds into a more mechanistic approach to the discovery of enzyme inhibitors and receptor antagonists with therapeutic potential. Several marine natural products have entered pharmaceutical development and others are making significant contributions to our understanding of cellular processes at the biochemical level.

15-Acetylthioxy-furodysinin lactone, isolated from a marine sponge Dysidea, sp. is a potent agonist to human leukotriene B4 receptor.

A sesquiterpene thioacetate, 15-acetylthioxy-furodysinin (SK&F 105900) has been isolated from the sponge Dysidea SP. This compound can bind specifically to the human peripheral blood polymorphonuclear leukocyte (PMN) and to the differentiated human monocytic leukemic U-937 cell membrane leukotriene B4 (LTB4) receptors with high-affinity. This compound can also promote a concentration-dependent chemotaxis in PMNs and an intracellular calcium mobilization in U-937 cells that can be blocked by the LTB4 receptor antagonist, LY-223982. Furthermore, the calcium mobilization induced by SK&F 105900 can specifically cross-desensitize with the LTB4-induced calcium mobilization. These observations indicate that SK&F 105900 is a novel and specific high-affinity agonist that can bind to the LTB4 receptors and activate the receptor-mediated signal transduction processes in human PMN and U-937 cells.

In vitro antiviral activity of dammar resin triterpenoids.

Nine triterpenes with antiviral activity against Herpes simplex virus types I and II in vitro were isolated from dammar resin. Each compound caused a significant reduction in viral cytopathic effect when Vero cells were exposed continuously to 1-10 micrograms/ml of compound for 48 h after viral challenge. The triterpenes were identified as dammaradienol [1], dammarenediol-II [2], hydroxydammarenone-I [3], ursonic acid [5], hydroxyhopanone [11], dammarenolic acid [15], shoreic acid [16], eichlerianic acid [17], and a novel compound, hydroxyoleanonic lactone [7], on the basis of their chromatographic, spectroscopic, and physical properties.

Role of secondary metabolites in feeding associations between a predatory nudibranch, two grazing nudibranchs, and a bryozoan.

The carnivorous nudibranch Roboastra tigris preys preferentially upon two nudibranchs,Tambja abdere and T. eliora, that in turn feed upon the bryozoan Sessibugula translucens. All four organisms contain tambjamines A-D (I-IV) that were shown to be fish feeding inhibitors. When attacked by Roboastra, T. abdere secretes a distasteful mucus containing a total of 3 mg of the tambjamines that sometimes causes the Roboastra to break off the attack. Under similar circumstances T. eliora attempts to swim away; it presumably contains insufficient of the tambjamines to deter Roboastra. Roboastra follows the slime trail of nudibranchs using contact chemoreception and reverses direction when the trail is broken. The slime trail ofT. abdere contains low concentrations of the tambjamines. In Y-maze experiments,T. eliora was attracted towards seawater containing S. translucens and seawater containing 10(-10) M tambjamines A and B (1∶1) but was repelled by seawater containing > 10(-8) M tambjamines A and B. At higher concentrations the mixture of tambjamines may be recognized as an alarm pheromone.