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PubMed2000

Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues.

Sulfonylureas are widely used to stimulate insulin secretion in type 2 diabetic patients because they close adenosine triphosphate-sensitive potassium (K(ATP)) channels in the pancreatic beta-cell membrane. This action is mediated by binding of the drug to the sulfonylurea receptor (SUR1) subunit of the channel. K(ATP) channels are also present in a range of extrapancreatic tissues, but many of these contain an alternative type of SUR subunit (SUR2A in heart and SUR2B in smooth muscle). The sulfonylurea-sensitivity of K(ATP) channels containing the different types of SUR is variable: gliclazide and tolbutamide block the beta cell, but not the cardiac or smooth muscle types of K(ATP) channels with high affinity. Glibenclamide and glimepiride, on the other hand, block channels containing SUR1 and SUR2 with similar affinity. The reversibility of the different sulfonylureas also varies. Tolbutamide and gliclazide produce a reversible inhibition of Kir6.2/SUR1 and Kir6.2/SUR2 channels, whereas glibenclamide has a reversible effect on cardiac, but not beta-cell, K(ATP) channels. In this article, we summarize current knowledge of how sulfonylureas act on K(ATP) channels containing the different types of sulfonylurea receptor, and discuss the implications of these findings for the use of sulfonylureas in the treatment of diabetes mellitus.

Adenosine Triphosphate↗

PubMed1975

Egg sensitivity and eczematous manifestations in breast-fed newborns with particular reference to intrauterine sensitization.

In 10 newborn breast-fed infants with eczematous manifestations, sensitivity to egg was confirmed by indirect elimination and provocation tests in the mother and direct provocation and elimination tests in the infant in the weaning period. In almost all of the mothers hemagglutinating antibody titers against egg were high in the amniotic fluid. The role of intra-uterine sensitization to food in the etiology of eczematous manifestations in newborn breast-fed infants is discussed.

Adult↗

PubMed2001

Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide.

Members of the bcl-2 gene family and endogenous inhibitors of cyclin-dependent kinases participate in the regulation of apoptosis and cell cycle in a diverse range of cell types and are implicated in the development of hormone refractory prostate cancer and resistance to anti-cancer therapy. The expression of several of these genes can be regulated by steroid hormones and related agents via their nuclear receptors. However, insufficient information considering the protein expression after the treatment by hormone antagonists is available. The aim of this study was to evaluate the expression of anti- and pro-apoptotic proteins, (Bcl-2, Bax), and to correlate this with the appearance of some nuclear receptors and cell cycle related proteins in androgen sensitive and androgen insensitive prostate cancer cell lines, LNCaP and DU-145, after the treatment by androgen antagonist bicalutamide. Our results revealed that androgen receptor (AR) expression in LNCaP cells decreased, however in DU-145 cells AR slightly increased following anti-androgen treatment. The same agent stimulated expression of p21Waf1/Cip5 and p27Kip1 in LNCaP, as well as in DU-145 cell lines. Bcl-2 level increased slightly in LNCaP cells and, in DU-145 cells was almost undetectable. Bax expression was not changed in LNCaP but significantly decreased in DU-145 cells. Similarly, retinoid X receptor beta (RXRbeta) level was significantly down regulated after 24 hours in DU-145 and also in LNCaP cells after 72 hours. These results confirm that androgen withdrawal therapy employing anti-androgens may elicit different signalling pathways in various types of prostate cancer that may be dependent on AR status and AR sensitivity.

Androgen Antagonists↗

PubMed2002

Cytokine production induced by low-molecular-weight chemicals as a function of the stimulation index in a modified local lymph node assay: an approach to discriminate contact sensitizers from respiratory sensitizers.

In general, contact sensitizers have been shown to selectively induce Th1 immune responses, such as interferon-gamma (IFN-gamma) production, whereas Th2 responses, such as interleukin (IL)-4 production, were seen after exposure to respiratory allergens. However, these features may be dependent on the dose of the particular allergen. Therefore, the aim of the present study was to investigate the distinction between contact sensitizers and respiratory allergens, by establishing dose-dependent cytokine profiles. The contact allergens 2,4- dinitrochlorobenzene (DNCB), hexyl cinnamic aldehyde (HCA), and oxazolone (OXA, 4-ethoxymethylene 2-phenyloxazol-5-one) as well as the respiratory allergens fluorescein 5-isothiocyanate, phthalic anhydride, toluene diisocyanate, and trimellitic anhydride were tested. For a range of concentrations, both proliferative responses and cytokine production were established. Estimated concentrations were derived at several stimulation indices (SIs). From the estimated concentrations, IFN-gamma, IL-4, and IL-10 production as a function of stimulation indices were plotted. All four respiratory allergens showed significantly higher IL-4 and IL-10 production patterns compared to the contact allergens. Positive identification of DNCB, HCA, and OXA as contact allergens on the basis of IFN-gamma production was observed only at very high stimulation indices (SI >or= 35) for DNCB and OXA and at low SIs (SI <or= 7) for HCA. We propose that, by direct linkage of proliferation and cytokine production in a dose-response manner, distinguishing contact allergens from respiratory allergens may be improved compared to present approaches.

Administration, Inhalation↗

PubMed2003

[Antimicrobial activity of fosfomycin against beta-lactamase-producing methicillin-sensitive Staphylococcus aureus and methicillin-sensitive coagulase-negative staphylococci].

Antimicrobial activity of fosfomycin (FOM), cefazolin (CEZ), cefmetazole (CMZ), cefotiam (CTM) and piperacillin (PIPC) against clinical isolates of methicillin-sensitive Staphylococcus aureus (MSSA) (beta-lactamase-producing or non-producing) and methicillin-sensitive coagulase-negative Staphylococci (MSCNS) (beta-lactamase-producing or non-producing) were determined to make clear the differences in antimicrobial activity of FOM and beta-lactam antibiotics. The antimicrobial activity of PIPC against beta-lactamase-producing strains of MSSA was lower than that against non-producing ones, judging from the distribution patterns of susceptibility of the strains to PIPC. There were no differences in the antimicrobial activity of FOM, CEZ and CMZ for the producing and non-producing strains. The activity of FOM against MSCNS was comparable to that against MSSA, although those of CEZ, CMZ, CTM and PIPC were decreased. FOM, CEZ, CMZ and CTM showed bactericidal activity against TH4278 (MIC [microgram/ml]: FOM, 1; CEZ, 0.5; CMZ, 1; CTM, 0.5; PIPC, 1) of beta-lactamase-producing MSSA at 1 microgram/ml for 6 h, but PIPC did not at the same condition. FOM and CMZ at MIC suppressed regrowth of the strain, but CEZ, CTM and PIPC did not. In conclusion, FOM, which is not affected by beta-lactamase, demonstrated strong bactericidal activity at low concentration against the beta-lactam-resistant strains due to beta-lactamase production.

Anti-Bacterial Agents↗

PubMed1979

The sensitizing capacity of Compositae plants. III. Test results and cross-reactions in Compositae-sensitive patients.

25 patients known or suspected to be allergic to different Compositae plants were tested epicutaneously with ether extracts of different Compositae species. 14 persons revealed a chrysanthemum hypersensitivity, 2 were allergic to arnica and 2 to camomile. In 1 patient a positive reaction to tansy was obtained. In the case of the chrysanthemum allergy, this was induced occupationally. All other patients had sensitized themselves by non-occupational contact. Cross-reactions were seen to tansy [14], yarrow [11], camomile [10], arnica and sunflower [5]. The components which are responsible for the sensitization as well as for the crossreactions are sesquiterpene lactones.

Chemical Phenomena↗

PubMed2006

Diverse resveratrol sensitization to apoptosis induced by anticancer drugs in sensitive and resistant leukemia cells.

Naturally occurring dietary compound resveratrol (RES), possessing chemopreventive and cytostatic properties, has been shown as potent sensitizer for apoptosis induced by a variety of anticancer drugs. Cell cycle analysis in sensitive promyelocytic leukemia HL60 cell line and its multidrug-resistant variant HL60/VCR (P-gp positive) treated with RES resulted in cell cycle arrest in S-phase in both cell variants. Flow cytometry measurements showed diverse activities of RES in combination with anticancer drugs doxorubicin (DOX), cycloheximide (CHX), busulfan (BUS), gemcitabine (GEM) and paclitaxel (PTX), in some cases resulting in apoptosis induction, preferentially at the expense of S-phase. Thus, RES could become a candidate to enhance the efficacy of combination anticancer therapy in a variety of human cancer cells inclusive leukemias.

Anticarcinogenic Agents↗

PubMed1992

Effects of v-src oncogene activation on radiation sensitivity in drug-sensitive and in multidrug-resistant rat fibroblasts.

Recent work has implicated the activated ras oncogene, whose gene product is a G-protein located in the plasma membrane, as well as the activated raf oncogene, whose gene product is a membrane-associated protein kinase, in contributing to radioresistance. Another transforming oncogene whose gene product is localized to the plasma membrane is v-src. We have examined a rat fibroblast line (RAT-1) infected with an avian sarcoma virus carrying a temperature-sensitive mutation in the v-src tyrosine kinase domain (LA-24). At 40 degrees C, LA-24 cells have a flat morphology and grow as a contact-inhibited monolayer, while at 35 degrees C, LA-24 cells have a transformed morphology, lose contact inhibition, grow in soft agar, and exhibit 3.5-fold higher tyrosine kinase activity. The parental RAT-1 line, not infected by the virus, grows at both temperatures as a contact-inhibited monolayer. This well-characterized system represents a good model for examining the effect of v-src transformation on radiosensitivity. RAT-1 and LA-24 cells grown at 35 and 40 degrees C were irradiated with graded doses of radiation, and clonogenic survival was assayed. For LA-24 cells grown at 35 and 40 degrees C, and for RAT-1 cells grown at 35 and 40 degrees C, calculated D0, n, alpha, and beta values did not differ significantly. To determine whether there might be differences in radiation damage repair capacity too subtle to detect by comparing radiation survival curves, sublethal damage repair capacity was assessed. There was no difference in sublethal damage repair capacity for LA-24 cells grown at 35 or 40 degrees C. Other studies have associated multidrug resistance with radioresistance. We have examined the radiation sensitivity of two colchicine-resistant LA-24 clones with four- to fivefold amplification of the P-glycoprotein gene, which are four-to fivefold more resistant to colchicine than the parental LA-24 line. In these multidrug-resistant clones, v-src activation does appear to increase radiation resistance. This did not appear to be due to alteration in cell cycle kinetics. We conclude that oncogene activation, or even protein kinase activity per se, does not necessarily lead to radiation resistance. Rather, radiation resistance following oncogene activation depends upon the oncogene and cell line studied, and perhaps upon specific protein phosphorylation.

Animals↗

PubMed1991

Changes in airway sensitivity to histamine are not necessarily paralleled by changed sensitivity to acetylcholine.

In allergic asthmatics, it has been shown that airway sensitivity to histamine closely parallels sensitivity to methacholine, a finding which underlies the widely-held view that airway hyperreactivity of asthma is non-selective. We have been interested to evaluate the capacity of various agents to influence reactivity to intravenous injections of both histamine and acetylcholine in the anaesthetized guinea-pig. Intravenous infusion of PAF or (+/-)isoprenaline are procedures which increase airway reactivity to histamine, but leave reactivity to acetylcholine unaffected; by way of contrast, there is comparable enhancement of hyperreactivity to both histamine and acetylcholine following endotoxin infusion. These observations do not accord with the concept that obstruction of the airways per se accounts for changed reactivity of the airways and question the presumption that PAF might be a pivotal mediator of airway hyperreactivity in allergic asthma.

Acetylcholine↗

PubMed1988

Effect of antihistamines on interferon production by leukocytes from sensitized and non-sensitized mice.

The effect of four antihistamines (Intal, Zaditen, Tavegyl, Benzhydramine) on interferon production in mice was investigated. The agents were administered in vivo to ovalbumin-sensitized and non-sensitized mice, or in vitro to isolated peritoneal cell cultures. The cells were induced for interferon production with Newcastle virus. It was shown that Tavegyl and Benzhydramine, both after in vivo and in vitro administration, inhibit interferon production, while Intal and Zaditen had no effect.

Animals↗

PubMedDate not supplied

Sensitivity to aspirin--methods of detection of sensitivity and inducing tolerance state to aspirin.

The paper deals with various methods of detection of bronchoconstrictor and urticaria/angioedema types of sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. The authors consider that anamnesis plays the major part in detection of sensitivity to these drugs. Oral challenge tests should be applied only with the use of acetylsalicylic acid administered at small, increasing doses at intervals not shorter than 24 h. Tolerance to aspirin is elicited using aspirin at 24 hour intervals, beginning with a threshold dose. The authors prefer, however, their own method where a subthreshold dose is the initial one. The protective role of sodium salicylate against aspirin-induced bronchoconstriction is also discussed.

Adult↗

PubMed1989

Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro.

Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.

Animals↗

PubMed1987

Platinum group metal sensitivity: reactivity to platinum group metal salts in platinum halide salt-sensitive workers.

The ability of closely related platinum group metal salts (PGMS) to cross-react with the principal sensitising agent ammonium hexachloroplatinate IV was investigated in refinery workers. Selected subjects were screened by skin prick test, specific RAST, RAST inhibition, and primate PCA tests. These showed--but only in platinum-sensitive subjects--a low prevalence of skin and RAST sensitivity to the other PGMS and limited evidence of hapten specific cross-reactivity.

Animals↗

PubMed1986

[Lymphocyte subpopulations in sensitization and specific immunotherapy in an experiment. Lymphocyte subpopulations in the specific immunotherapy of microbial allergy and subsequent heterologous pollen sensitization].

The influence exerted by the specific immunotherapy (SIT) of delayed hypersensitivity (DH) to staphylococci and subsequent sensitization with tarragon pollen on the level of immunocompetent cells in the blood and lymphoid organs of guinea pigs was studied. On the whole, SIT normalized the characteristics of T- and B-lymphocytes, altered as the result of experimentally induced DH: the content of T-cells in the peripheral blood and the lymph nodes increased, while the number of B-cells in the blood and T gamma-suppressors increased. The subsequent heterologous sensitization with pollen abolished the effect of SIT, inducing the general decrease of the level of T gamma-lymphocytes and enhancing the number of T-lymphocytes in the lymph nodes.

Allergens↗

PubMed1977

[Electron microscopic investigations on the influence of lymphocytes of sensitized and non-sensitized guinea pigs on the visceral yolk sac epithelium of the rat (author's transl)].

Rats on day 19 of pregnancy were intrauterinely injected lymphocytes from guinea-pigs, sensitized or not sensitized to trophoblast antigens of the rat placenta. In the first case locally severe cytolytic effects were observed on the yolk-sac surface, in the second case--the controls--no immune reaction was evident.

Animals↗

PubMed1982

Reactions of epidermal keratinocytes in sensitized and non-sensitized guinea pigs after dichromate exposure: an electron microscopic study.

The reaction in epidermal keratinocytes in sensitized and non-sensitized, normal guinea pigs after dichromate exposure has been investigated by electron microscopy. The results of the investigation show that the morphological alterations in keratinocytes in irritant and contact allergic reactions to dichromate are of a nonspecific nature. This underlines the fact that morphological reactions in the keratinocyte are uniform. The reactions were dose- and time-dependent. The morphology of the contact allergic reaction to dichromate in the guinea pig is consistent with that described for DNCB.

Animals↗

PubMed1980

Temperature sensitive phosphoproteins in rat cells transformed by a temperature sensitive mutant of rous sarcoma virus.

The localization of the src-encoded protein kinase was examined by fractionating cellular extracts from rat cells transformed by a wild type and a temperature-sensitive mutant of Rous sarcoma virus (SR-A 3Y1 and ts68 3Y1 cells). It was found to be specifically localized in the post-microsomal supernatant (PMS) fraction. Furthermore, it was noticed that a protein with a molecular weight of 16,000 (16K-protein) in the PMS fraction was phosphorylated in vitro when the PMS fraction from ts68 3Y1 cells was preincubated at 33 degrees C, but not at 42 degrees C. This protein was phosphorylated when the fraction from SR-A 3Y1 cells was preincubated at 33 degrees C and at 42 degrees C. Similar temperature-sensitive phosphorylation of 16K-protein was also observed in the PMS fraction from ts68 3Y1 cells labeled in vivo with [32P]orthophosphate at 33 degrees C. These results suggest that this 16K-protein might be a candidate for the endogenous acceptor for the src-encoded protein kinase.

Animals↗

PubMed1983

Experimental investigations on sensitivity to nickel present in alloys used in dentistry carried out on guinea pigs previously sensitized to this metal.

Experimental investigation on sensitivity to nickel present in dental alloys has been carried out on guinea pigs previously sensitized to this metal. The metal plates containing nickel have been sutured to the oral mucosa in such a way that condition of alloys contact with mucosa were possible similar to those present in the mouth of the patient wearing fixed prosthesis. The results of macro and micro examination has not shown any morphological differences between experimental and control material.

Animals↗