Biomedical subjects

J B Hudson

Publications and source records attributed to J B Hudson.

At least 19 recordsLinked to original sources

PubMed1999

Bromohypericins are potent photoactive antiviral agents.

Several hypericin derivatives, previously shown to have interesting light-mediated biological activities, were evaluated for antiviral activities against herpes simplex virus and influenza virus. Three brominated hypericins, the dibromo- and tetrabromo-derivatives and the natural compound gymnochrome B were all very active against both viruses, particularly herpes simplex virus, although light was required in all cases for maximum activity. The dibromohypericin was the most potent, under standard assay conditions, gymnochrome B was approximately as active as hypericin itself and tetrabromohypericin significantly less so. Surprisingly, hexamethylhypericin, which is known to have potent anti-protein kinase (PK) C activity, as well as anticell proliferation properties, showed no antiviral activity at all. The compounds were also evaluated in different serum concentrations. All the active compounds were inhibited by increasing concentrations of serum, but to different degrees, such that their relative antiviral potencies changed to some extent. Thus, in summary, there was no correlation between antiviral and anti-PK or anticellular activities, and consequently it is not possible at present to define those structural features of hypericin-type molecules that are required for their various biological activities.

Animals↗

PubMed1998

Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm.

Dorsal mesoderm induction in arthropods and ventral mesoderm induction in vertebrates are closely related processes that involve signals of the BMP family. In Drosophila, induction of visceral mesoderm, dorsal muscles, and the heart by Dpp is, at least in part, effected through the transcriptional activation and function of the homeobox gene tinman in dorsal mesodermal cells during early embryogenesis. Here we present a functional dissection of a tinman enhancer that mediates the Dpp response. We provide evidence that mesoderm-specific induction of tinman requires the binding of both activators and repressors. Screens for binding factors yielded Tinman itself and the Smad4 homolog Medea. We show that the binding and synergistic activities of Smad and Tinman proteins are critical for mesodermal tinman induction, whereas repressor binding sites prevent induction in the dorsal ectoderm and amnioserosa. Thus, integration of positive and negative regulators on enhancers of target genes appears to be an important mechanism in tissue-specific induction by TGF-beta molecules.

Amino Acid Sequence↗

PubMed1998

The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4.

The Transforming Growth Factor-beta superfamily member decapentaplegic (dpp) acts as an extracellular morphogen to pattern the embryonic ectoderm of the Drosophila embryo. To identify components of the dpp signaling pathway, we screened for mutations that act as dominant maternal enhancers of a weak allele of the dpp target gene zerknŁllt. In this screen, we recovered new alleles of the Mothers against dpp (Mad) and Medea genes. Phenotypic analysis of the new Medea mutations indicates that Medea, like Mad, is required for both embryonic and imaginal disc patterning. Genetic analysis suggests that Medea may have two independently mutable functions in patterning the embryonic ectoderm. Complete elimination of maternal and zygotic Medea activity in the early embryo results in a ventralized phenotype identical to that of null dpp mutants, indicating that Medea is required for all dpp-dependent signaling in embryonic dorsal-ventral patterning. Injection of mRNAs encoding DPP or a constitutively activated form of the DPP receptor, Thick veins, into embryos lacking all Medea activity failed to induce formation of any dorsal cell fates, demonstrating that Medea acts downstream of the thick veins receptor. We cloned Medea and found that it encodes a protein with striking sequence similarity to human SMAD4. Moreover, injection of human SMAD4 mRNA into embryos lacking all Medea activity conferred phenotypic rescue of the dorsal-ventral pattern, demonstrating conservation of function between the two gene products.

Amino Acid Sequence↗

PubMed1997

Antiviral activities of photoactive perylenequinones.

Nine perylenequinones (PQ), including some familiar naturally occurring pigments, were compared for their light-mediated antiviral efficacies. Calphostin C was the most active compound against the two target viruses, herpes simplex virus type 1 and Sindbis virus. Hypocrellins A and B were also very active. However, three cercosporin-like PQ were substantially less active in spite of their high quantum yields of singlet oxygen, whereas phleichrome, another efficient singlet oxygen producer, showed no detectable antiviral activity. One other PQ, which was a very weak singlet oxygen producer, also showed no antiviral activity. None of the active compounds showed significant antiviral activity in the dark. Thus, for some groups of PQ there was correlation between quantum yield of singlet oxygen (1O2) and antiviral efficacy, but there are evidently other structural features of PQ that influence activity.

Animals↗

PubMed1996

Antiviral activities of Nepalese medicinal plants.

In a screening of plants used traditionally in Nepal to treat diseases that could be caused by viruses, methanol extracts from 21 species were assayed for activity against three mammalian viruses: herpes simplex virus, Sindbis virus and poliovirus. Assays were performed in UV-A or visible light, as well as dark. Individual species of Hypericum, Lygodium, and Maesa exhibited impressive antiviral activities, although their selective effects on the three viruses suggested that the antiviral ingredients were different in each extract. In addition, many of the other extracts showed partial inactivation of one or more test viruses.

Animals↗

PubMed1996

Antiviral activities of anthraquinones, bianthrones and hypericin derivatives from lichens.

The antiviral activities of some naturally occurring anthraquinones, bianthrones, and hypericin derivatives were compared by the end-point CPE (viral cytopathic effects) method and plaque assays. Under optimal conditions of exposure to light, hypericin, 7,7'-dichlorohypericin and 5,7-dichloroemodin exhibited strong inhibitory activity against HSV-1 (herpes simplex virus type 1) in both assays. Partial inactivation of the virus was shown by emodin, 7-chloroemodin and 7-chloro-1-O-methylemodin; the bianthrones and other anthraquinones were found to be inactive. Antiviral activity appeared to be positively correlated with increasing substitution of chlorine in the anthraquinone structure. In the absence of light, only hypericin and 7,7'-dichlorohypericin displayed detectable activity.

Anthracenes↗

PubMed1996

Antiviral activities of medicinal plants of southern Nepal.

In a screening of plants used traditionally in Nepal to treat diseases that could be caused by viruses, twenty-one methanol extracts from twenty species were quantitatively assayed for activity against three mammalian viruses: herpes simplex virus, Sindbis virus and poliovirus. Assays were performed in ultraviolet (UV)-A or visible light, as well as dark, and cytotoxicity was also noted. Impressive antiviral activities were exhibited by species of Bauhinia (Fabaceae), Carissa (Apocynaceae), Milletia (Fabaceae), Mallotus (Fabaceae), Rumex (Polygonaceae), Streblus (Moraceae), Terminalia (Combretaceae) and Tridax (Asteraceae). The Carissa extract was the most active, showing activity against all three viruses at a concentration of 12 micrograms/ml. Many of the other extracts showed partial inactivation of one or more test viruses.

Animals↗

PubMed1995

Isolation of the anthropogenic compound fluoranthene in a screening of Chinese medicinal plants for antiviral compounds.

Thirty-one species of medicinal plants used in the treatment of diseases of viral origin in Yunnan Province of China were assayed for inhibition of Sindbis and murine cytomegalovirus in mammalian cell cultures. Sixteen species displayed antiviral activity. A compound, which exhibited long wavelength UV-mediated antiviral activity, was isolated from leaves and twigs of Elsholtzia ciliata (Lamiaceae) using bioassay-guided fractionation and identified as the polycyclic aromatic hydrocarbon, fluoranthene. The discovery of an anthropogenic photosensitizer with antiviral activity in a plant has implications in studies of plants as sources of bioactive constituents.

Antiviral Agents↗

PubMed1994

Identification and characterization of a murine cytomegalovirus gene with homology to the UL25 open reading frame of human cytomegalovirus.

Monoclonal antibody 1B4, previously shown to be protective in vivo and to cross-react with both virally encoded and normal host cell proteins, was used to screen a lambda gt11 cDNA derived from mRNA harvested from mouse embryo fibroblasts 24 hr after infection with murine cytomegalovirus (MCMV). A 700-bp cDNA was identified representing the 5'terminus of a 2460-bp open reading frame (ORF) with significant homology to the human cytomegalovirus UL25 ORF. The UL25 ORF of MCMV potentially encodes an 820 amino acid viral tegument protein with an estimated molecular weight of approximately 90 kDa. Amino acid homology with eukaryotic nucleolins was identified in the acidic N-terminal third of the MCMV UL25 proteins, suggesting that the protein may be involved in transcriptional activation or interactions with chromatin. Northern analysis and S1 nuclease data indicated that the gene is expressed late in infection as an approximately 3-kb transcript and that expression is dependent on viral DNA replication. An epitope recognized by MAb 1B4 was identified using recombinant pGEX plasmids expressing fusion proteins representing the N-terminal region of the MCMV UL25 protein. The identification of the MCMV UL25 ORF as a member of the CMV-specific UL25/UL35 gene family provides an opportunity for the investigation of the role these genes and their products in CMV pathogenesis in an animal model.

Amino Acid Sequence↗

PubMed1994

Antiviral assays on phytochemicals: the influence of reaction parameters.

Investigations of phytochemicals for antiviral activities are assuming greater importance; but little attention has been given to the influence of various reaction parameters. We found that the activities of several known antiviral phytochemicals were profoundly affected by the presence of serum components, but in different ways. Thus, the terthiophene, alpha-terthienyl (alpha-T), was inhibited in a concentration-dependent manner by serum. In the case of a carboxylic acid derivative of alpha-T, the compound appeared to have no antiviral activity at all in the presence of serum, yet in its absence this compound was as effective as alpha-T. In contrast the complex anthraquinone hypericin required a small amount of serum for maximal antiviral activity, although too much was inhibitory. The reactions were also strongly affected by the order of incubation of the components: virus, compound, serum, and light. The antiviral effects were not influenced significantly by temperature, in contrast to a report by other workers, provided the light exposures were controlled. These effects are significant because serum is commonly used in virus assays, and plant extracts often contain polypeptides. Furthermore, when phytochemicals are used in vivo, their effects could be modulated by components of tissues and body fluids.

3T3 Cells↗

PubMed1994

Hypocrellin, from Hypocrella bambuase, is phototoxic to human immunodeficiency virus.

Hypocrellin, a photodynamic perylene quinonoid isolated from the Chinese medicinal fungus Hypocrella bambuase, was evaluated for antiviral activity against the human immunodeficiency virus (HIV-1). Hypocrellin was phototoxic to HIV-1, almost as good as the structurally similar plant pigment hypericin, and like hypericin its activity required visible light. In contrast peroxyhypocrellin had little or no effect on the virus.

3T3 Cells↗

PubMed1994

Photoactive terthiophenes: the influence of serum on anti-HIV (human immunodeficiency virus) activities.

A number of carboxylic acid derivatives of the photoactive terthiophene, alpha-terthienyl, were found to possess impressive UVA-dependent activity against the human immunodeficiency virus, HIV-1; but only when assayed in the absence of serum, indicating that the latter contained interfering components. Good antiviral activity required a high rate of singlet oxygen production, in accordance with previous observations on thiophenes.

Antiviral Agents↗

PubMed1993

Growth and differentiation of human papillomavirus type 31b positive human cervical cell lines.

Human papillomavirus (HPV) containing cell lines derived from human cervical intraepithelial neoplasia (CIN) can offer valuable insights into the role of HPV in cervical neoplasia and can help in the understanding of the cellular changes that fuel the progression toward malignancy. We describe the growth and differentiation properties of an epithelial cell line established from a CIN I lesion. The cell line, designated as CIN 612, contains predominantly episomal copies of HPV 31b deoxyribonucleic acid (DNA). In vitro differentiation in a collagen raft system, growth characteristics, and episomal HPV DNA content of the CIN 612 cell line and two of its subclones were analyzed. Early passage CIN 612 cells differentiate in a manner which resembles the original low-grade intraepithelial lesion. On further passage, these cells exhibit increasingly poor differentiation in vitro. Two subclones with different growth characteristics and morphology were identified. A more rapidly growing, poorly differentiated subclone contains less episomal copies of viral DNA compared to a slower growing and better-differentiated subclone. Cell populations with similar growth characteristics yet different ploidy were observed. The CIN 612 cell line with its episomal copies of viral DNA shows promise for the development of an in vitro culture system for HPV 31b. The isolation of subclones with consistently different growth and differentiation properties in vitro creates an opportunity to identify the cellular events that lead to the progression from low-grade to high-grade cervical neoplasia.

Adult↗

PubMed1993

The importance of light in the anti-HIV effect of hypericin.

The requirement for light in the anti-HIV-1 activity of hypericin was investigated. The hypericin concentration-dependence and light dosage-dependence of the reaction were measured. Under conditions in which hypericin caused substantial inactivation of HIV-1, there was a strict requirement for visible light. Only when the concentration of hypericin approached the cytotoxic level was there an apparent light-independent antiviral effect. This strict light-requirement for the antiviral effect could explain some of the apparently discrepant results reported by other workers. Furthermore if hypericin is contemplated for use in humans, the importance of light must be considered.

Anthracenes↗

PubMed1993

The anti-HIV activity of the phytochemical alpha-terthienyl.

The plant trithiophene, alpha-terthienyl (alpha T), was evaluated for activity against the human immunodeficiency virus (HIV-1). Antiviral activity specifically required long wavelength light (UVA, 320-400 nm). The compound had little or no activity in visible light or in the dark. The anti-HIV effect was UVA-dose dependent and was proportional to the concentration of alpha T, according to several parameters of virus infectivity and replication. The efficacy was decreased to some extent by the presence of bovine serum in the reactions; but under optimal conditions 0.1 microgram/ml. alpha T (3 x 10(-7) M) could inactivate 10(4)-10(5) infectious particles. In contrast poliovirus and Coxsackievirus infectivity were relatively resistant to alpha T + UVA.

Blood↗

PubMed1993

DNA cleavage, antiviral and cytotoxic reactions photosensitized by simple enediyne compounds.

Very potent antibiotic antitumor natural products contain a enediyne moiety which, upon thermal activation, is capable of abstracting hydrogens from DNA. 1,6-Diphenyl-3-hexene-1,5-diyne was selected as a candidate for inducing DNA strand breaks photochemically. Easily interconverted with light, both geometric isomers 1 and 2 were expected to be phototoxic. As anticipated, they photosensitized the production of strand breaks in double-stranded supercoiled pBR322, and in single-stranded M13 DNA. The DNA cleavage reactions were favored by the presence of oxygen and were inhibited by ethanol. Preliminary experiments with the (Z)-isomer indicated moderate light-dependent antiviral activity against human immunodeficiency virus (HIV), Sindbis virus, and mouse cytomegalovirus. The enediynes were cytotoxic to Escherichia coli, a gram-negative organism, to Streptococcus faecalis, a gram-positive organism, to Daphnia magna and to fish (Pimephales promelas), but only in the presence of light. The production of o-terphenyl, the expected product of Bergman cyclization of 1, could not be confirmed. However, both 1 and 2 photosensitized the formation of singlet oxygen and of superoxide anion radical, and photodynamic reactions could have been responsible for some of the phototoxic reactions observed.

3T3 Cells↗

PubMed1993

Biological activities of terthiophenes and polyynes from the Asteraceae.

We evaluated a number of terthiophenes and polyynes, from the Asteraceae, for biological activities against microorganisms, viruses, and tumor cells, with and without the aid of UVA (long wavelength ultraviolet) radiation. The terthiophenes, which represented the basic alpha-terthienyl nucleus with simple side chains, showed impressive UVA-dependent activities, some of which were superior to alpha-terthienyl itself. In contrast, the polyynes had no significant biological activity, with or without UVA. We believe that these terthiophenes would be worthwhile evaluating in animal models of infectious diseases.

Alkynes↗

PubMed1993

The unusual UVA-dependent antiviral properties of the furoisocoumarin, coriandrin.

The novel furoisocoumarin, coriandrin, which was found recently to possess an interesting combination of photobiological properties, was investigated for antiviral activity in the presence and absence of UVA (long-wavelength ultraviolet radiation). In contrast to results obtained with other antiviral furocoumarins, such as 8-MOP (8-methoxypsoralen), coriandrin was much more phototoxic to the RNA-virus Sindbis virus than to the DNA-virus murine cytomegalovirus, although both viruses were substantially more sensitive to this compound than they were to 8-MOP. Human immunodeficiency virus, HIV-1, was also susceptible to coriandrin + UVA. Another unexpected finding was that viruses without membranes were completely resistant to coriandrin. This suggests that a membrane component was a target for the compound. The antiviral activity of coriadrin was profoundly inhibited by serum components in the reaction mixtures, which suggests that the compound may have a strong affinity for certain protein or lipid materials, although maximal interference was only obtained when all components of the reaction mixture, virus, coriandrin and serum, were irradiated simultaneously. Thus it appears that coriandrin has unusual antiviral properties that would not be predicted from its chemical similarity to furocoumarins.

3T3 Cells↗