Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Generations”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,027 records · Page 57Linked to original sources
PubMed1975

Thermal fields and heat generation effects in tissue, awake and under halothane anesthesia.

In order to further document the heat generation terms used in models predicting heat transmission in tissue, a series of temperature fields were generated and measured in cat brain with an implantable cylindrical source and thermocouple apparatus. The experimental technique allowed measurements to be made under fully awake in vivo conditions as well as for 3 to 45% levels of halothane anesthesia. Fields resulting from probe forcing function temperatures of 4 degrees C, 18 degrees C, and 28 degrees C were warmer in the anesthetized tissue indicating an increase in heat generation resulting from blood flow and metabolic heat. Values of the heat generation were obtained by applying the Bio-Heat Equation directly to the experimental data. A simple blood flow heat generation model gave a reasonable prediction of the heat generation in a temperature range lower than 3 to 4 degrees C below the inlet blood temperature, and with a Q10 equals 3 variation of blood flow rate with temperature. Results also indicate that the heat generation effect under halothane anesthesia conditions are such that the use of the apparent property concept in thermal modeling may not be valid.

Anesthesia, Inhalation↗
PubMed1998

Free radicals generation by granulocytes from men during bed rest.

Phagocytes (granulocytes and macrophages) are one of the most important sources of reactive oxygen species (ROS) in the human body. A stimulated phagocyte reaches within a dozen of seconds the functional state known as the respiratory burst. This phenomenon includes three interrelated processes: 1) a several fold increase in the oxygen uptake, 2) generation of large amounts of ROS, and 3) stimulations of glucose metabolism via the pentose phosphate shunt. The main ROS generated during phagocytosis is the superoxide radical anion O2-. The reaction of dismutation of O2- generates hydrogen peroxide (H2O2). O2- and H2O2 do not have strong cytocidal proerties but are supbstrates for the generation of more active biologically ROS, especially the hydroxyl radical (OH) and hypochlorous acid (HOCl). A stimulated phagocyte (especially neutrophil) generates also vast amounts of nitric oxide (NO-). NO- may react with the superoxide radical anion forming peroxynitrate (ONOO-). Reactivity of ONOO- is comparable to that of the hydroxyl radical. ONOO- plays probably a very important role in the so-called oxygen-dependent killing mechanisms during phagocytosis. The role of NO- in the process of phagocytosis is unclear. However, NO-, apart from other biological functions, inhibits aggregation and adhesion of blood platelets. Morevover, it seems to participate in the slefregulation of granulocyte cativity (probably limiting excessive inflammative reaction). Excess of ROS generated by phagocytes may damage biologically important macromolecules. Membrane lipids are particularly vulnerable to peroxidation. It leads to alterations in membrane fluidity and permeability. ROS excreted to the environment of a phagocyte may impair functions of other morphotic elements of blood (erythrocytes and thromobcytes) in this way. Bed rest covers two conditions: 1) limitation of motoric activity (hypodynamia) and 2) restraining the pressure on bones along parallelly to their long axes (hypogravia). Under bed rest conditions organism is subject to many harmful changes. I.a., bed rest affects also leukocyte functions. However, we were not aware of any sutdies concerning the effect of bed rest on the respiratory burst of granulocytes. This study was aimed at an examination of the effect of bed rest on the generation of O; and H2O2 by neutrophils (PMNL).

Adult↗
PubMed2001

[Modeling the periodically-changing predictable response to mutagen exposure in CBA/LacY mice in a successive inbred generations].

A hypothesis on the genetic determination of periodic fluctuations of the sensitivity to the mutagen thioTEPA in successive inbred generations of mice has been earlier put forward. This study was the initial stage of testing this hypothesis. The mouse strain CBA/LacY was divided into two substrains, which differed in the rate of generation change. As a result, two colonies of isogenic mice differing by 10-12 generations with respect to the inbred age were obtained. Both the rate and range of variations in the mutagen sensitivity (four generations per period of the cycle and 20-40% of cells with chromosome aberrations after the standard dose of 2.5 mg/kg of thioTEPA, respectively) in 19 generations of the "fast" substrain agreed with earlier data. The response of the "slow" substrain corresponded to the expected response of the "fast" substrain after the given number of generations. In the mice of generations F142 and F146 that lived simultaneously and differed in thioTEPA sensitivity, the effects of the carcinogen benzo[a]pyrene (BaP) were significantly different. The levels of these effects corresponded to the levels of the responses to thioTEPA. The data obtained agree with the hypothesis tested.

Animals↗
PubMed2002

Local generation of fast ripples in epileptic brain.

Aperiodic high-frequency oscillations (>100 Hz) reflect a short-term synchronization of neuronal electrical activity. It has been shown in the epileptic brain that spontaneous oscillations in the frequency range of 250-600 Hz reflect action potential population bursts of synchronously discharging neuronal clusters. These oscillations occur in the early stages of epileptogenesis in areas adjacent to the brain lesion and may trigger the formation of seizure-generating neuronal networks. We studied the extent of the area generating oscillations in the frequency range of 250-600 Hz [fast ripples (FRs)] in intrahippocampal kainic acid-treated rats with spontaneous seizures, by analyzing voltage versus depth profiles of FRs in hippocampal and parahippocampal areas in freely moving animals and by spatial mapping in hippocampal slice preparations in vitro. The strength of inhibition was compared in areas with and without FRs using a paired-pulse paradigm. The extent of the areas generating FRs did not exceed 1 mm(3). The areas generating FRs became broader after the application of the GABA(A) receptor antagonist bicuculline. Paired-pulse fast inhibition at 15-30 msec intervals was similar in areas generating FRs and areas not generating FRs. Our data illustrate that hypothesized clusters of highly interconnected neurons are capable of overcoming interneuron feedback inhibition, resulting in generation of epileptiform bursts, eventually leading to seizure activity.

Action Potentials↗
PubMed2002

Generation of effective antitumor vaccines using photodynamic therapy.

Preclinical studies have shown that photodynamic therapy (PDT) of tumors augments the host antitumor immune response. However, the role of the PDT effect on tumor cells as opposed to the host tissues has not been determined. To test the contribution of the direct effects of PDT on tumor cells to the enhanced antitumor response by the host, we examined the immunogenicity of PDT-generated murine tumor cell lysates in a preclinical vaccine model. We found that the PDT-generated tumor cell lysates were potent vaccines and that PDT-generated vaccines are more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation, and unlike other traditional vaccines, PDT vaccines do not require coadministration of an adjuvant to be effective. PDT vaccines are tumor specific and appear to induce a cytotoxic T-cell response. We have demonstrated that although both UV and PDT-generated tumor cell lysates are able to induce phenotypic DC maturation, only PDT-generated lysates are able to activate DCs to express IL-12, which is critical to the development of a cellular immune response. Our results show that PDT effects on tumor cells alone are sufficient to generate an antitumor immune response, indicating that the direct tumor effects of PDT play an important role in enhancing that host antitumor immune response. These studies also suggest that in addition to the role of PDT as a therapeutic modality, PDT-generated vaccines may have clinical potential as an adjuvant therapy.

Animals↗
PubMed2002

Effect of heparin on TAFI-dependent inhibition of fibrinolysis: relative importance of TAFIa generated by clot-bound and fluid phase thrombin.

Heparin has been proposed to enhance thrombolysis by inhibiting thrombin-dependent generation of activated TAFI (thrombin activatable fibrinolysis inhibitor), a carboxypeptidase that inhibits fibrinolysis. We evaluated the effect of heparin in an in vitro thrombolysis model consisting of a radiolabelled blood clot submerged in defibrinated plasma. Fibrinolysis was induced by adding t-PA (250 ng/ml) and calcium to the plasma bath. Control experiments indicated that thrombin generation induced by recalcification caused significant TAFI activation and inhibited clot lysis. Heparin (up to 1 U/ml), added to the plasma bath, failed to enhance clot lysis. Thrombin generation in the fluid phase was totally inhibited by heparin at concentrations > 0.5 U/ml. In contrast, thrombin generation on the clot surface was not inhibited by heparin (1 U/ml). TAFIa generation did occur in heparin-containing samples (1 U/ml) and amounted to about 10% of TAFIa formed in control samples. This low amount of TAFIa did exert antifibrinolytic activity as indicated by the observation that the addition of a specific TAFIa inhibitor (PTI) along with heparin enhanced clot lysis. Hirudin (10 micrograms/ml), at variance with heparin, inhibited clot-bound thrombin and enhanced clot lysis. These data show that heparin is unable to stimulate fibrinolysis through a TAFI-dependent mechanism, most likely because of its inefficiency in inhibiting thrombin generation on the clot surface. Moreover, they suggest that clot-bound thrombin plays a major role in TAFI-mediated inhibition of fibrinolysis through "localized" TAFIa generation.

Blood Coagulation↗
PubMed2003

Correlates of thrombin generation in patients with advanced prostate cancer.

Thrombin generation is increased in men with advanced prostate cancer. Thrombin has the ability to interact with, and affect the biology of, a variety of cell types including prostate cancer cell lines. We therefore looked for correlations between thrombin generation and other markers of disease activity in spot urine samples obtained from men with advanced prostate cancer. Excretion of part of the prothrombin activation peptide F(1+2) (called here iF2), interleukin-6 (IL-6), the bone turnover marker deoxypyridinoline (DpD), and vascular endothelial growth factor (VEGF) were quantitated in spot urine samples collected from 37 men with hormone-refractory prostate cancer. Following log transformation of the data, significant correlations were found by univariate analysis between the excretion of a marker of thrombin generation (iF2) and IL-6, DpD and VEGF, as well as between IL-6 and DpD or VEGF excretion. No correlation was found between any marker and serum PSA level. After multivariate analysis, a significant correlation remained between thrombin generation and IL-6 excretion. Analysis of a second urine specimen obtained from 19 of the subjects 1 to 7 months after the first also revealed a significant correlation between thrombin generation and IL-6, DpD, and VEGF excretion. These data provide evidence of a correlation between thrombin generation/coagulation system activation and IL-6 generation in patients with cancer. They provide a rationale for studying the effects of inhibitors of thrombin generation upon the biology of prostate cancer.

Amino Acids↗
PubMed1976

In vitro generation of suppressor cell activity: suppression of in vitro induction if cell-mediated cytotoxicity.

It was observed that when normal mouse spleen cells were cultured alone in vitro (precultured) for 3 to 7 days, these cells lost the ability to generate cell-mediated cytotoxicity (CML) during subsequent in vitro sensitization with allogeneic spleen cells, trinitrophenyl (TNP)-modified syngeneic spleen cells, or syngeneic tumor cells. These precultured cells, which were themselves unable to generate CML, were also shown in mixing experiments to suppress, actively, the generation of CML by freshly explanted spleen cells. Suppression occurred at the sensitization phase of CML, and not at the effector level; supernatants from suppressive precultured cells were not suppressive. Suppression was totally abrogated by the treatment of spleen cells with a T cell-specific rabbit anti-mouse brain serum and complement (RalphaMB+C) either before or after preculturing, suggesting that a T cell eas essential both to the generation of suppressor activity and to its expression. Suppressor activity was entirely absent in precultured nylon wool column-nonadherent spleen cells, a T cell-enriched population containing most of the RalphaMB+C-sensitive cells in the spleen. Precultured nylon column-adherent cells (T cell-depleted) did have suppressive activity, and a mixture of nylon-adherent and nylon-non-adherent cells was a suppressive after preculture as the precultured unseparated spleen. Moreover, the ability of nylon-adherent spleen cells to generate suppressive activity during preculturing was abrogated by treatment with RalphaMB+C. Thus, the "spontaneous" generation of CML-suppressive activity was dependent upon a limited subpopulation of splenic T cells isolated in the nylon column-adherent fraction. The relationship of these data to a previously described synergy between subpopulations of normal spleen in the generation of CML is discussed, and the findings related to other suppressor systems described in the literature.

Animals↗
PubMed1992

Extended-spectrum (second- and third-generation) cephalosporins.

The extended-spectrum cephalosporins provide better activity against gram-negative bacilli and anaerobes than first-generation agents. Cefoxitin and cefotetan (second-generation) and ceftriaxone (third-generation) have excellent activity against B. fragilis and are useful in the treatment of postoperative infections and pelvic inflammatory disease. The extended-spectrum cephalosporins are as efficacious as first-generation agents for prophylaxis of cesarean section and hysterectomy. The first-generation drugs, such as cefazolin, are considerably less expensive than these newer compounds, however, making first-generation agents the drugs of choice when used for prophylaxis. The majority of the third-generation agents should be reserved for the treatment of meningitis and resistant nosocomial infections.

Bacterial Infections↗
PubMed1992

New generation RIBA hepatitis C strip immunoblot assays.

Second generation hepatitis C virus (HCV) Elisas are currently in use in Europe and have been submitted for approval in the United States. These new assays contain additional antigens from the putative nucleocapsid and NS-3 regions of the HCV genome in addition to the c100-3 antigen present in first generation Elisas. A supplementary test, the second generation RIBA (Chiron Co trademark) HCV strip immunoblot assay (2-RIBA HCV SIA) has also been developed. The strip immuno-blot assay uses four recombinant HCV antigens (5-1-1 [NS-4], c100-3 [NS-4], c33c [NS-3], and c22-3 [NS-3 [nucleocapsid]) slot blotted on nitrocellulose. Screening of random volunteer blood donors with the Ortho (Ortho Diagnostic Systems trademark) second generation HCV Elisa (2-Ortho HCV Elisa) indicates that a substantial change in the repeat reactive donor population is observed with the new test. Two notable features of this change are: i) a large number of samples reactive in the 2-RIBA HCV SIA for the second generation antigens, c33c and c22-3, are detected by the 2-Ortho HCV Elisa; ii) the percentage of 2-Ortho HCV Elisa reactive specimens found indeterminate (reactive for only one HCV antigen) by the 2-RIBA HCV SIA is higher than in first generation HCV Elisas (approximately 25 versus 5%). In addition, 2-ortho HCV Elisa repeat reactive, 2-RIBA HCV SIA indeterminate samples are dominated by reactivity to c22-3 instead of c100-3 which is the case for first generation HCV Elisa repeat reactive samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme-Linked Immunosorbent Assay↗
PubMed2004

[Comparison of clinical features of severe acute respiratory syndrome among different transmission generations].

OBJECTIVE: To investigate the differences among various transmission generation of severe acute respiratory syndrome (SARS) by comparing the corresponding clinical data. METHODS: The clinical data of 84 patients with SARS were retrospectively studied, 66 women and 18 men, mean age (29.2 +/- 10.3) years old, 96.4% of whom were health care workers. All subjects had exposure to a source patient and the epidemic progressively propagated in a short time. For the infectious chain, we defined these patients who had exposure to a source patient as the primary cases, which included 35 patients (41.7%). Patients who got the disease by exposure to the primary cases were defined as secondary cases, which included 34 patients (40.5%). Similarly, the tertiary cases included 15 patients (17.9%). RESULTS: (1) No statistical differences in age, sex ratio, incubation period and hospitalization duration among various infectious generations were found (P > 0.05). (2) With descending in infectious generations, the initial temperature lowered, and cases with cough decreased (P < 0.05) with no statistical differences in the peak temperature, other accompanying symptoms and leukopenia (P > 0.05). (3) With descending in infectious generations, the course from the appearance of pulmonary lesions to their resolution shortened (P < 0.05). No differences were found in the maximal involved pulmonary fields, duration from initial fever to appearance of pulmonary lesions and course from the initial pulmonary lesions to their peak among the above three generations (P > 0.05). (4) No statistical differences were found in ways of oxygen therapy and classes of antibiotics prescribed (P > 0.05). With descending in infectious generation, cases treated with methylprednisolone, human gamma-immunoglobulin, interferon-alpha, and antiviral drugs (oral ribavirin or oseltamivir) increased (P < 0.05) and the duration of their use also increased (P < 0.05). CONCLUSIONS: With descending in infectious generations, the clinical features of SARS may become ameliorated.

Adolescent↗
PubMed2005

Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation.

Vitamin K3 (VK3) is a well-known anticancer agent, but its mechanism remains elusive. In the present study, VK3 was found to simultaneously induce cell death, reactive oxygen species (ROS) generation, including superoxide anion (O2*-) and hydrogen peroxide (H2O2) generation, and histone hyperacetylation in human leukemia HL-60 cells in a concentration- and time-dependent manner. Catalase (CAT), an antioxidant enzyme that specifically scavenges H2O2, could significantly diminish both histone acetylation increase and cell death caused by VK3, whereas superoxide dismutase (SOD), an enzyme that specifically eliminates O2*-, showed no effect on both of these, leading to the conclusion that H2O2 generation, but not O2*- generation, contributes to VK3-induced histone hyperacetylation and cell death. This conclusion was confirmed by the finding that enhancement of VK3-induced H2O2 generation by vitamin C (VC) could significantly promote both the histone hyperacetylation and cell death. Further studies suggested that histone hyperacetylation played an important role in VK3-induced cell death, since sodium butyrate, a histone deacetylase (HDAC) inhibitor, showed no effect on ROS generation, but obviously potentiated VK3-induced histone hyperacetylation and cell death. Collectively, these results demonstrate a novel mechanism for the anticancer activity of VK3, i.e., VK3 induced tumor cell death through H2O2 generation, which then further induced histone hyperacetylation.

Acetylation↗
PubMed2005

[A Generator of Mono-energetic Electrons for Response Test of Charged Particle Detectors.].

We designed and fabricated a generator of mono-energetic electrons for the response test of charged particle detectors, which is used to measure fragmented particles of the carbon beam for cancer therapy. Mono-energetic electrons are extracted from (90)Sr by analyzing the energy of beta rays in the generator with a magnetic field. We evaluated performance parameters of the generator such as the absolute energy, the energy resolution and the counting rates of extracted electrons. The generator supplies mono-energetic electrons from 0.5MeV to 1.7MeV with the energy resolution of 20% in FWHM at higher energies than 1.0MeV. The counting rate of electrons is 400cpm at the maximum when the activity of (90)Sr is 298kBq. The generator was used to measure responses of fragmented-particle detectors and to determine the threshold energy of the detectors. We evaluated the dependence of pulse height variation on the detector position and the threshold energy by using the generator. We concluded this generator is useful for the response test of general charged particle detectors.

Beta Particles↗
PubMed1991

Processing of an endogenous protein can generate MHC class II-restricted T cell determinants distinct from those derived from exogenous antigen.

Class II MHC molecules on the surface of an APC present immunogenic peptides derived mainly from exogenous proteins to CD4+ T cells. During its transport to the cell surface, class II molecules intersect the endocytic pathway where they acquire peptides derived from endocytosed proteins. However, class II-restricted presentation of endogenously derived peptides can also occur. The current studies were undertaken to examine the ability of different types of APC to generate and present four different T cell determinants derived from an endogenous, nonsecreted, truncated form of hen-egg white lysozyme (HEL[1-80]-Kk). This was compared with the ability of these APC to generate the same determinants from exogenous HEL. All the peptides derived from endogenous HEL[1-80]-Kk tested, were presented by B cells to HEL-specific T cell hybridomas with an efficiency similar to presentation of the same determinants from exogenous HEL. In contrast, an I-Ak-bearing rat fibroblast was unable to generate the HEL peptide 25-43 from exogenous HEL, but could efficiently produce it from endogenous HEL[1-80]-Kk. The results indicate first, that peptides derived from an endogenous Ag can be presented by MHC class II molecules with an efficiency comparable to that of the presentation of the exogenous Ag. Second, that Ag-presenting B cells can generate the same repertoire of antigenic peptides from endogenous Ag as those generated from the exogenous protein. And third, that in contrast to B cells, certain "nonprofessional" APC can generate, from an endogenous protein, T cell determinants distinct from those generated after endocytosis of the exogenous protein. These results suggest that processing of exogenous and endogenous Ag by different APC take place in different intracellular compartments.

Animals↗
PubMedDate not supplied

Recent advances in depression across the generations.

This Editorial presents recent research on the transmission of depression across three generations and discusses the implications for improving detection, treatment and prevention and for identifying important subgroups for biological studies. It reports a case-control study of three generations at high or low risk for major depression. The first two generations were followed longitudinally for 20 years and were assessed blind to the clinical status of the other generations. Depression is highly familial across three generations. Over 60% of grandchildren (average age 12 yrs.) with two generations affected with depression already have some psychopathology. Anxiety disorders are usually the first presentation before puberty with an increase in depression in adolescents, especially among girls. New opportunities for early detection and treatment exist. Families with three generations affected with depression present a potentially important group for biological, genetic and neuroimaging studies.

Adolescent↗
PubMed1991

Vascular nitric oxide-generating activities for organic nitrites and organic nitrates are distinct.

Like organic nitrates, the organic nitrites are assumed to undergo vascular metabolic activation to nitric oxide (NO) to produce vasodilating activity, but this assumption has never been examined. In this study, isobutyl nitrite and amyl nitrite were incubated with subcellular fractions of bovine coronary arterial smooth muscle at 37 degrees C, and NO generation was assessed by redox chemiluminescence assay of headspace NO. Bovine vascular subfractions exhibited substantial and significant catalytic activity for NO generation towards both organic nitrite substrates, and NO-generating activity could be inhibited by heating and irradiation. These observations suggest that organic nitrites are converted enzymatically to NO in vascular smooth muscle. Analysis of marker enzyme activities suggested that the primary NO-generating activity was associated with the cytosol, whereas a distinct, but relatively minor NO-generating activity was also identified in the microsomal fraction. The cytosolic and microsomal NO-generating activities exhibited different temperature dependencies for heat-induced inhibition of activity. The molecular weights of the NO-generating enzymes, determined by radiation inactivation target-size analysis, were 263 kDa (95% confidence interval: 236-298 kDa) for the cytosolic enzyme and 79 kDa (95% confidence interval: 54-148 kDa) for the microsomal enzyme. Previous studies in this laboratory have shown that the representative organic nitrate, nitroglycerin (NTG), is metabolized to NO by an enzyme associated with the plasma membrane of bovine vascular smooth muscle cells. Thus, the enzymes responsible for vascular bioconversion of organic nitrates and organic nitrites to NO are apparently different.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyl Nitrite↗
PubMedDate not supplied

[Life-span in generations of chronic irradiated Drosophila wild type isogenic and geterogenic strains].

With the goal to study radioadaptation on life-span and observe the role in this phenomenon of genotype, we investigated the dynamics of life-span in 14 consistent generations after chronic gamma-irradiation in heterogenic (Canton-S) and isogenic (Oregon-R spa) Drosophila wild type strains. The gamma-source was 226Ra in dose 60 cGy per generation. The animals kept in standard conditions (25 degrees C and 12 h lighting). Was shown, that the dynamics of median life-span in wild type strains Canton-S and Oregon-R spa was different and the character of alterations depends on genetic heterogeneity. After chronic irradiation in generations in heterogenic line Canton-S since 5 generation cyclic life-span oscillations disappeared, values of median life-span leave on a plateau. Since the 8th generation the life-span values of irradiated populations exceeded all the control values. As a result of the irradiation practically in all generations in isogenic line Oregon-R spa occurs increasing of life-span with the comparing to non-irradiated control. This is possible due to the positive influence of radio-induced heterogeneity on the life-span of isogenic strain. Thus, chronic irradiation led to violation of natural cyclic dynamics of Drosophila life-span in heterogenic strain, discovered in the end 80-s' years by F. Lints and D. Ismaylov. Irradiation of isogenic strain led to increasing of life-span in all generations.

Animals↗
PubMed1990

Alterations of ribonucleotide reductase activity following induction of the nitrite-generating pathway in adenocarcinoma cells.

The murine adenocarcinoma cell line TA 3 synthesized nitrite from L-arginine upon stimulation with gamma-interferon (IFN-gamma) associated with tumor necrosis factor (TNF), and/or bacterial lipopolysaccharide (LPS), but not with IFN-gamma, TNF, or LPS added separately. Induction of the NO2(-)-generating activity caused an inhibition of DNA synthesis in TA 3 cells. This inhibition was prevented by the L-arginine analog N omega-nitro-L-arginine, which inhibited under the same conditions nitrite production by TA 3 cells. The TA 3 M2 subclone, selected for enhanced ribonucleotide reductase activity, was found to be less sensitive than the wild phenotype TA 3 WT to the cytostatic activity mediated by the NO2(-)-generating system. Cytosolic preparations from TA 3 M2 cells treated for 24 or 48 h with IFN-gamma, TNF, and LPS exhibited a reduced ribonucleotide reductase activity, compared to untreated control cells. No reduction in ribonucleotide reductase activity was observed when N omega-nitro-L-arginine was added to treated cells. Addition of L-arginine, NADPH, and tetrahydrobiopterin into cytosolic extracts from 24-h treated TA 3 M2 cells triggered the synthesis of metabolic products from the NO2(-)-generating pathway. This resulted in a dramatic inhibition of the residual ribonucleotide reductase activity present in the extracts. The inhibition was reversed by NG-monomethyl-L-arginine, another specific inhibitor of the NO2(-)-generating activity. No L-arginine-dependent inhibition of ribonucleotide reductase activity was observed using extracts from untreated cells that did not express NO2(-)-generating activity. These results demonstrate that, in an acellular preparation, molecules derived from the NO2(-)-generating pathway exert an inhibitory effect on the ribonucleotide reductase enzyme. This negative action might explain the inhibition of DNA synthesis induced in adenocarcinoma cells by the NO2(-)-generating pathway.

Adenocarcinoma↗