Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon inducing activity, antitumor activity and toxicity of poly ICLC (poly IC stabilized with poly L-Lysine and carboxymethyl cellulose) in rodents were studied. SD strain rats were injected intravenously with poly IC or poly ICLC. Interferon in rat plasma was assayed by a plaque reduction method using stomatitis virus. The peak level of plasma interferon of the poly ICLC injection rat was as high as that of poly IC injection rat, and in the former, high level of plasma interferon persisted for 4-12 hours. Next, brain tumor-bearing rats were treated intravenously with poly ICLC and observed for death daily. Weekly treatment with 1 mg/kg of poly ICLC increased the mean survival time although no antitumor effect was observed with poly IC. The LD 50 value of poly IC was 33.5 mg/kg, and that of poly ICLC was 18.6 mg/kg and as to poly ICLC administration, no remarkable side effect was recognized below the dose of 1.5 mg/kg. In clinical trials, poly ICLC was given intravenously at the dose of 0.05-0.2 mg/kg to 9 patients with malignant brain tumor. (6 patients were glioblastoma, 1 was astrocytoma, and 2 were ependymoma.) In 2 patients, poly ICLC was administered once, in 2 patients twice, in 2 patients 3 times, and in 3 patients more than 5 times. The interval of each administration was 7 days. Poly ICLC induced high level of serum interferon (more than 100 reference unit/ml) in all patients and over 100 unit/ml of interferon was maintained for 24 hours. The highest interferon titer induced was 875 unit/ml. The most frequently encountered toxic reaction was fever, which occurred in all cases. The mean peak temperature elevation was 1.9 degrees C, which usually occurred 4-8 hours after drug administration. Modest hypotention was detected in one case. Leucopenia was detected in 3 cases. These abnormalities were all modest, and improved in a few days. As to the effect of poly ICLC, neurological improvement was recognized in 3 cases, and in one of them, remission on CT scan was also recognized.
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PMID:[Effect of interferon inducer (poly ICLC) in the treatment of malignant brain tumor (author's transl)]. 709 65

The carboxyl-terminal Lys-Asp-Glu-Leu (KDEL), or a closely-related sequence, is important for ER localization of both lumenal as well as type II membrane proteins. This sequence functions as a retrieval signal at post-ER compartment(s), but the exact compartment(s) where the retrieval occurs remains unresolved. With an affinity-purified antibody against the carboxyl-terminal sequence of the mammalian KDEL receptor, we have investigated its subcellular localization using immunogold labeling on thawed cryosections of different tissues, such as mouse spermatids and rat pancreas, as well as HeLa, Vero, NRK, and mouse L cells. We show that rab1 is an excellent marker of the intermediate compartment, and we use this marker, as well as budding profiles of the mouse hepatitis virus (MHV) in cells infected with this virus, to identify this compartment. Our results demonstrate that the KDEL receptor is concentrated in the intermediate compartment, as well as in the Golgi stack. Lower but significant labeling was detected in the rough ER. In general, only small amounts of the receptor were detected on the trans side of the Golgi stack, including the trans-Golgi network (TGN) of normal cells and tissues. However, some stress conditions, such as infection with vaccinia virus or vesicular stomatitis virus, as well as 20 degrees C or 43 degrees C treatment, resulted in a significant shift of the distribution towards the trans-TGN side of the Golgi stack. This shift could be quantified in HeLa cells stably expressing a TGN marker. No significant labeling was detected in structures distal to the TGN under all conditions tested. After GTP gamma S treatment of permeabilized cells, the receptor was detected in the beta-COP-containing buds/vesicles that accumulate after this treatment, suggesting that these vesicles may transport the receptor between compartments. We propose that retrieval of KDEL-containing proteins occurs at multiple post-ER compartments up to the TGN along the exocytotic pathway, and that within this pathway, the amounts of the receptor in different compartments varies according to physiological conditions.
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PMID:Localization of the Lys, Asp, Glu, Leu tetrapeptide receptor to the Golgi complex and the intermediate compartment in mammalian cells. 779 12

Many soluble resident proteins of the endoplasmic reticulum share a COOH-terminal Lys-Asp-Glu-Leu (KDEL) sequence. Current opinion favours a model in which these proteins can escape from the endoplasmic reticulum (ER) by bulk flow and are recognized and sorted in the Golgi apparatus by binding to a specific KDEL-receptor, which returns them to the ER. Through biochemical, morphological and mutational analysis we have studied the mechanisms that determine the localization of calreticulin, a soluble 60 kDa KDEL-protein of the ER. Immunogold labelling established the ER localization of calreticulin in transfected and nontransfected COS cells. Although the ER cisternae in transfected cells were enormously dilated and heavily labelled by gold particles we found no significant label in any other compartment. In vivo pulse chase experiments with [35S]methionine followed by biochemical fractionation of calreticulin overexpressing COS cells (50- to 100-fold) revealed that only a minor part of labelled calreticulin leaves the ER. Retrieval from the Golgi was confirmed by a partial redistribution of the endogenous KDEL-receptor as shown by double immunofluorescence. These data suggest a KDEL-independent retention of calreticulin in the ER. Further supporting evidence has come from morphological in vivo studies using calreticulin-transfected and vesicular stomatitis virus (ts045)-infected COS cells. Stimulation of vesicular transport from the ER by releasing the temperature-dependent transport block for the viral G-protein resulted in a small but significant appearance of calreticulin in a post-ER compartment. In contrast a calreticulin mutant, which lacked the Ca(2+)-binding domain but included the KDEL sequence, could escape from the ER to a much higher extent. Secretion of the nonmutated calreticulin was very low (1-2% of total calreticulin in 3 hours) compared to the mutated form (18% in 3 hours). Deletion of the KDEL sequence led to an increase in secretion to 29% over a 3 hour period, which is much less than expected for a secretory protein. Taken together these results strongly support the hypothesis of two independently operating retention/retrieval mechanisms for calreticulin: one providing for direct retention in the ER with a very high capacity and having Ca(2+)-dependent properties; the other a KDEL-based retrieval system for escaped calreticulin present in the Golgi apparatus.
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PMID:Retention and retrieval: both mechanisms cooperate to maintain calreticulin in the endoplasmic reticulum. 787 39

Cationic phthalocyanines with either aluminum or silicon as the central metal were evaluated for their ability to inactivate viruses in red blood cell concentrates (RBCC) photodynamically. In addition, the virucidal potential of a substituted anionic phthalocyanine, aluminum dibenzodisulfophthalocyanine hydroxide (A1N2SB2POH) was evaluated and compared with that of the much studied anionic aluminum tetrasulfophthalocyanine hydroxide (A1PcS4OH). Based on the rate of inactivation of the lipid-enveloped vesicular stomatitis virus (VSV), the virucidal potential of these phthalocyanines was: HOSiPcOSi(CH3)2(CH2)3N+(CH3)3I- (Pc 5) = SiPc[OSi(CH3)2-(CH2)3N+(CH3)3I-]2 (Pc 6) > A1PcOSi(CH3)2(CH2)3N+(CH3)2(CH2)11CH3I- (Pc 21) = A1N2SB2POH = A1PcS4 > HOSiPc[OSi(CH3)2(CH2)3N+(CH3)2(CH2)11CH3I-]2 (Pc 14) > A1PcOSi(CH3)2(CH2)3N+(CH3)3I- (Pc 2). Phthalocyanine ligand 14 and Pc 21 are new phthalocyanines, made by quaternizing known amino analogues. Compared to VSV, the rate of inactivation of Sindbis virus (another model lipid-enveloped virus) was identical when treated in red blood cells (RBC) with Pc 5 and slightly higher when treated with Pc 6 and A1PcS4OH. Treatment of RBCC containing cell-free human immunodeficiency virus (HIV-1) with Pc 5 or A1PcS4OH required 15 min of irradiation to inactivate (> 5 log10 reduction) the virus. The extent of HIV-1 inactivation with A1N2SB2POH was 3.7 log10 after 60 min of red light exposure. The RBC integrity after photosensitization was measured by the ability of the cells to bind to plates coated with poly-L-lysine, (which reflects the retention of the RBC surface negative charges) and hemolysis of the cells over a 7 day storage period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New phthalocyanines for photodynamic virus inactivation in red blood cell concentrates. 793 15

Specific interaction between the nucleocapsid protein (N) and the phosphoprotein (P) of vesicular stomatitis virus (VSV), an important step in the life-cycle of the virus, was studied by using a two-hybrid system. Plasmids encoding P fused with the yeast GAL4 DNA-binding domain (pGALP) and N fused with the herpes simplex virus VP16 transactivating region (pVPN) were transfected into CHO cells along with a reporter plasmid encoding chloramphenicol acetyltransferase (CAT). The ability of N and P to associate in vivo was measured by activation of the CAT gene by the VP16 transactivating region. Transfection of plasmids pGALP and pVPN resulted in a high level of CAT activity, indicating that the N and P portions of the fusion proteins associated very strongly with each other. Progressive C-terminal deletions of the P protein revealed two regions that are important for association with the N protein: the N-terminal acidic domain and the C-terminal basic domain. Phosphorylation of P protein was not required for N-P association. Various deletions and mutations of the N protein revealed the C-terminal 5 amino acids (Val-Glu-Phe-Asp-Lys), in particular the amino acids Val-Glu-Phe, to be critical for N association with P. This two-hybrid system can be used in other viral systems to study the interaction between proteins involved in transcription and replication.
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PMID:Mapping of interacting domains between the nucleocapsid protein and the phosphoprotein of vesicular stomatitis virus by using a two-hybrid system. 823 1

Recently, the vesicular stomatitis virus matrix (M) protein has been shown to be capable of inhibition of host cell-directed transcription in the absence of other viral components (B. L. Black and D. S. Lyles, J. Virol. 66:4058-4064, 1992). M protein is a major structural protein that is known to play a critical role in virus assembly by binding the helical ribonucleoprotein core of the virus to the cytoplasmic surface of the cell plasma membrane during budding. In this study, two M protein mutants were tested to determine whether the inhibition of host transcription by M protein is an indirect effect of its function in virus assembly or whether it represents an independent function of M protein. The mutant M protein of the conditionally temperature-sensitive (ts) vesicular stomatitis virus mutant, tsO82, was found to be defective in its ability to inhibit host-directed gene expression, as shown by its inability to inhibit expression of a cotransfected target gene encoding chloramphenicol acetyltransferase. The ability of the tsO82 M protein to function in virus assembly was similar to that of wild-type M protein, as shown by its ability to complement the group III ts M protein mutant, tsO23. Another mutant, MN1, which lacks amino acids 4 to 21 of M protein demonstrated that the abilities of M protein to inhibit chloramphenicol acetyltransferase gene expression and to localize to the nucleus were unaffected by deletion of this lysine-rich amino-terminal region but that the ability to function in virus assembly was ablated. Thus, the two M protein mutants examined in this study exhibited complementary phenotypes: tsO82 M protein functioned in virus assembly but was defective in inhibition of host-directed gene expression, while MN1 M protein functioned in inhibiting gene expression but was unable to function in virus assembly. These data demonstrate that the role of M protein in inhibition of host transcription can be separated genetically from its role in virus assembly.
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PMID:The role of vesicular stomatitis virus matrix protein in inhibition of host-directed gene expression is genetically separable from its function in virus assembly. 839 15

IFN-gamma is a pleiotropic cytokine that plays a major role in anti-infectious immune responses. The physiologic effects of IFN-gamma are thought to be mediated by the binding of extracellular IFN-gamma to its receptor at the cell surface, thereby triggering an intracellular signaling cascade. In this work, we present evidence for a completely intracellular mechanism for IFN-gamma to induce virus protection. Murine fibroblasts were transfected with the cDNA for murine IFN-gamma, and although no detectable amounts of IFN-gamma were released, these cells were resistant to lysis by the cytolytic vesicular stomatitis virus. In contrast to exogenously added IFN-gamma, the effect of the endogenously produced IFN-gamma was not abolished by treatment with neutralizing Abs. To test whether intracellular signal transduction occurs, an IFN-gamma variant was constructed with the carboxyl-terminal endoplasmic reticulum retention signal Lys-Asp-Glu-Leu (KDEL). Transfection of fibroblasts with this mutant IFN-gamma, anchored in the endoplasmic reticulum, led to virus resistance, thus demonstrating that biologic effects of this protein do not necessarily require binding to the receptor at the cell surface. However, the antiviral state induced by transfection with IFN-gamma-KDEL was strictly dependent on the presence of the IFN-gammaR, since fibroblasts derived from IFN-gammaR-deficient mice (IFN-gammaR -/-) were not rendered virus resistant. The virus resistance induced was accompanied by enhanced expression of 2'-5' oligoadenylate synthetase and constitutive activation of STAT1 (signal transducers and activators of transcription). Hence, autocrinous effects of IFN-gamma in cells naturally producing this cytokine might occur even in the absence of its secretion. The mechanisms involved in signaling appear to be identical with or closely related to those occurring after binding of IFN-gamma to its receptor at the cell surface.
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PMID:Intracellular murine IFN-gamma mediates virus resistance, expression of oligoadenylate synthetase, and activation of STAT transcription factors. 890 36

The existence of specific rabies virus (RV) glycoprotein (G) binding sites on the surfaces of neuroblastoma cells is demonstrated. Spodoptera frugiperda (Sf21) cells expressing G of the RV strain CVS (Gcvs-Sf21 cells) bind specifically to neuroblastoma cells of different species but not to any other cell type (fibroblast, myoblast, epithelial, or glioma). Attachment to mouse neuroblastoma NG108-15 cells is abolished by previous treatment of Gcvs-Sf2 cells with anti-G antibody. Substitutions for lysine at position 330 and for arginine at position 333 in RV G greatly reduce interaction between Gcvs-Sf21 cells and NG108-15 cells. These data are consistent with in vivo results: an avirulent RV mutant bearing the same double mutation is not able to infect sensory neurons or motoneurons (P. Coulon, J.-P. Ternaux, A. Flamand, and C. Tuffereau, J. Virol. 72:273-278, 1998) after intramuscular inoculation into a mouse. Furthermore, infection of NG108-15 cells by RV but not by vesicular stomatitis virus leads to a reduction of the number of binding sites at the neuronal-cell surface. Our data strongly suggest that these specific attachment sites on neuroblastoma cells represent a neuronal receptor(s) used by RV to infect certain types of neurons in vivo.
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PMID:Neuronal cell surface molecules mediate specific binding to rabies virus glycoprotein expressed by a recombinant baculovirus on the surfaces of lepidopteran cells. 944 3

The IFN-tau are type I IFN expressed by the early trophoblast of cattle and sheep but have activity on human cells and have been predicted to have potential therapeutic value. We have compared a series of mutant bovine and ovine IFN-tau with regard to their ability to inhibit the proliferation of Daudi cells and to evoke an antiviral (AV) response in WISH cells. Whereas Daudi cell growth was inhibited by Bo-IFN-tau1 in the 1 nM range, WISH cells were much less responsive, requiring exposure to 150 nM for protection against vesicular stomatitis virus. Replacement of lysines at positions 34, 107, 121, and 132 in Bo-IFN-tau, which are in regions predicted to interact with the type I receptor, led to modest but significant alterations in antiproliferative (AP) and AV activities. Replacement of the lysine residues at 160 and 164 had marked effects on biopotency, with K160 being particularly important. The different IFN-tau were able to activate the transcription factors ISGF3 and AAF (GAF) in Daudi cells at concentrations that correlated reasonably well with their AP potencies. Stat activation occurred in WISH cells in response to approximately 2 nM Bo-IFN-tau1, but ISGF3 formation could not be demonstrated even at the 100-fold higher IFN-tau concentrations that gave viral protection. Pretreatment of WISH cells with Hu-IFN-gamma allowed ISGF3 formation to be observed in response to subsequent treatment with Bo-IFN-tau1 or type I human IFN but did not increase the AV responsiveness of the cells. No evidence was found that IFN-tau elicit uniquely different responses on human cells than type I Hu-IFN, except they are much less potent. The data emphasize the importance of a region near the carboxyl terminus for the functional activity of type I IFN, and that although ISFG3 formation may be necessary, its mere presence is not sufficient to provide an antiviral response.
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PMID:The antiproliferative and antiviral activities of IFN-tau variants in human cells. 945 65

The envelope glycoprotein G of vesicular stomatitis virus induces membrane fusion at acidic pH. A highly conserved amino terminal region spanning residues 123 to 137 has previously been identified as an internal fusion domain. Here we have substituted specific amino acids within a carboxy terminal region, conserved in five vesiculoviruses encompassing residues 395 to 418, and studied the effect of these mutations on membrane fusion at acid pH and pH-dependent conformational change. Substitution of conserved Gly 395, Gly 404, Gly 406, Asp 409, and Asp 411 with Glu, Ala, Ala, Asn, and Asn, respectively, decreased the cell-cell fusion efficiency, as well as reduced the pH threshold of membrane fusion. Mutation of Gly 404 and Asp 409 to Lys and Ala, respectively, abolished the fusion activity. Mutant Gly 404 Lys also showed markedly altered resistance to trypsin digestion at acidic pH. These results suggest that the region between amino acids 395 to 418 is important for the fusogenic activity of the G protein. The possible role of this domain in conformational changes involved in fusion activity of VSV G is also discussed.
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PMID:Mutations in a carboxy-terminal region of vesicular stomatitis virus glycoprotein G that affect membrane fusion activity. 950 Oct 39


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