Interferon % induction

Interferon induction stimulation. Fresh plant juice, in cell culture, was active on mice splenocytes° h... 

Anionic polyelectrolytes have been shown to enhance resistance to bacteria and fungi, enhance immune response, inhibit adjuvent arthritis and either depress or stimulate phagocytic activity of the reticuloendothelial system [458,459]. Carboxylic acid polymers have shown interferon induction, antiviral activity, and tumor growth inhibition [460]. The effects include inhibition of sarcoma, leukemia, polyoma and vesicular stomatitis virus. In one application, the cytotoxicity of bleomycin toward cultured mammalian cells was synergisti-cally enhanced by stirring in the presence of high molecular weight polyfacrylic acid) [461]. 

Lebon, P, M.J. Commoy-Chevalier, B. Robert-Galliot, and C. Chany, Different mechanisms for alpha and beta interferon induction. Virology, 1982.119(2) 504-7. 

Subramaniam, P.S., EE. Cruz, A.C. Hobeika, and H.M. Johnson, Type I interferon induction of the Cdk-inhibitor p21WAFl is accompanied by ordered G1 arrest, differentiation and apoptosis of the Daudi B-cell line. Oncogene, 1998.16(14) 1885-90. 

Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., et al., Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434 (2005) 1035-1040. 

The interferon induction with similar pharmacological effects such as immunization is also connected with an activation of these cells. 

Due to the toxicity of the co-(cyclopolymer) 8, the capability of interferon induction of a great number of polymers has been tested. Thus, interferon is formed by the presence of natural double helix RNA, which occurs in some viruses (Reo-viruses), but also by the synthetically produced complex (40) from poly(inosinic acid) and poly(cytidylic acid) (1 1). An improved and extended interferon induction of such poly(nucleic acid)s can be achieved by complexing with synthetic polycations, as for example diethylaminodextrane (41) or with a polycation (42) of composition 9. 

Pitha and co-wodcers (43) have been able to demonstrate in a series of studies the poly(vinyl uracil) [10] and polyfvinyladenin) [22] to show in fact antiviral activity, but probably no interferon induction. Rather, it has been shown, that these electrically neutral polymers with a molecular weight... 

It seems, however, that only polyanions are chiefly concerned in the interferon induction. Further polymers having anionic groups have been investigated besides poly(nucleic acid)s and co-(cyclopolymers) 8, for which a partial hydrolysis of the anhydride moiety is supposed. Thus, poly(vinylsulfonate)s or polyacrylates have been found to be active, but, polymethacrylates inactive. It has been shown that in the case of acrylic acid copolymers the molecular weight is also of importance in addition to the structure of the polymer chain and the fraction of carboxy groups. The influence of these various parameters has been discussed in detail by De Somer (45). 

Actually it is doubtful that the antiviral properties of polyanions are based only on the interferon induction (46), since several groups have also demonstrated other activities of polyanions. Thus, e.g. poly(vinylsulfonate) has been found to interact with nucleic acids, thus inhibiting their acylation or methylation (47). Tempel (48) has shown that in mice phosphatases can be activated with poly(vinylsulfonate). 

Administration of cycloheximide (60 mg/kg) 1 hr prior to tilorone administration inhibited the interferon response43,44. The inhibition by cycloheximide suggested that protein synthesis was involved in the appearance of interferon in the serum. For a more complete discussion of interferon induction, see the review on synthetic interferon inducers written by DeClercq45. ... 

In discussing the mechanism of antiviral protection and stimulation of interferon production in the mouse, DeClercq and Merigan46 concluded that there was a direct relationship between the extent of protection against vesicular stomatitis virus, the titers of interferon produced and the doses of tilorone. Giron et al.47, however, found no correlation between interferon induction and protection against MM virus in mice. Protection was achieved at doses far below the doses at which detectable interferon was found in the serum. Both findings may be consistent with differing mechanisms of viral inactivation for the two viruses under study. 

Interferon induction in normal and leukemic lymphocyte cultures with tilorone has been observed50. The interferon response observed in normal lymphocyte cultures appeared to be correlated with the toxic effect of tilorone. The effect observed in leukemic cultures required higher concentrations of tilorone, but, similarly, appeared to be related to cell viability. Tilorone has been reported to stimulate production of interferon by itself in mouse embryo fibroblasts and, in combination with poly rl poly rC/DEAE-dextran in mouse L929 cells51. Human foreskin fibroblasts were not stimulated. The degree of synergism between tilorone and the nucleotide-dextran complex was proportional to the concentrations of tilorone and poly rl/poly rC and was influenced by the times of addition of the compounds relative to each other. 

Krueger, R. F., Mayer, G. D., Camyre, K. P., Yoshimura, S. Int. Colloq. Interferon and Interferon Induction, Sept. 14, Leuven, Belgium 1971... 

Some plants have been cultivated by germanium penetration into the plant from its roots and organogermanium pharmaceuticals have been prepared. Cultivation of Sac-charomyces cerevisiae or Ganoderma lucidum in carboxyethylgermanium sesquioxane medium gave a product with antitumor and interferon-inducting activity . 

Hahon N, Booth JA, Flowers L. 1990. Coinhibition of viral interferon induction by benzo[a]pyrene in association with occupation-related particles. Environ Res 52 83-98. 

Only an efficient antiyiral immune reaction can eliminate the hepatitis C virus. In cases of acute HCV infection, minimal (endogenous) interferon-a values are detectable in the serum, i.e. the virus effects a poor interferon induction in the organism. The CD8+ and CD4 T lymphocytes appear to be mainly responsible for virus elimination. The problems of HCV infection lie in the fact that the patient has virtually no chance of spontaneous improvement or even healing with a chronic course of disease, i.e. there is practically no self-limiting factor in a disease process that has become chronic. 

Adinolfi, L.E., Utili, R., Tonziello, A., Rn ero, G. Effects of alpha interferon induction plus ribavirin with or without amantadine in the treatment of interferon nonresponsive chronic hepatitis C a randomized trial. Gut 2003 52 701 -705... 

The dihydro-chloride salt of 2,7-bis(2-(diethylamino)ethoxy)-fluoren-9-one, referred to as tilorone hydrochloride (non-proprietary name) or bis-DEAE-fluorenone, is a broad spectrum antiviral compound44) with antitumor activity45-47). Mayer and coworkers48 49) have identified this compound as an interferon inducer and established a relationship with the antiviral activity. However, recently a lack of correlation between interferon induction and viral protection by tilorone hydrochloride has been reported50). 

Munson et al.41) have recently shown that DEAE-F is effective in inhibiting the established Friend viral leukemia. They believe that interferon induction may not be responsible for the antitumor activity of this compound. This suggests that the virus-associated enzymatic activities, DNA polymerases, may be sensitive towards the action of DEAE-F. Table 21 shows the inhibition of reverse-transcriptase activity from MSV (Moloney) and FLV (Friend) by DEAE-F. 

Our further discussion will be limited to an analysis of the mechanism of interferon induction by... 

Structural Requirements for Interferon Induction by Synthetic Interferon Inducers... 

Table 4. Interferon induction by polycarboxylates structural requirements...

A second structural feature for interferon induction by polycarboxylates is the presence of negative charges. They may be placed in either alternate (PAA) or adjacent (pyran copolymer) position but should occur in a regular and dense sequence. The polyanionic character of the polymer appears to be a prerequisite for interferon induction, antiviral activity and antibacterial activity, since uncharged polymers such as dextran, polyacrylamide, non-carboxylated polyethylene analogues of pyran copolymers and incompletely oxidized amylose were devoid of any of these activities48,49,51,107). 

The structural requirements for interferon induction by synthetic polynucleotides are summarized in Table 5. 

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