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At least 19 recordsLinked to original sources
PubMed1992

Fiber differentiation of the human laryngeal muscles using the inhibition reactivation myofibrillar ATPase technique.

The aim of the present study was to further subdivide the type II fibers of the human thyroarytenoid and posterior cricoarytenoid muscles by means of a modified myosin ATPase reaction. In order to understand the functioning of these highly strained muscles better, it is important to know the respective percentage of fatigue-resistant type IIA fibers and fatigable type IIB fibers. The material comprised the larynges of seven laryngectomized males aged between 45 and 70 years and four laryngectomized females aged between 39 and 72 years. After having been frozen in nitrogen, 10-microns-thick sections were cut from the laryngeal muscles in a cryostat. The pH-lability of the enzyme that can be utilized in a classical myosin ATPase reaction permits a differentiation between fiber types I, IIA and IIB. Evidently, this is not possible with every human muscle. The fiber types IIA and IIB of the thyroarytenoid and the posterior cricoarytenoid muscles could be clearly distinguished by means of the inhibition reactivation myofibrillar ATPase technique. Using this method, the myosin ATPase enzyme was initially inhibited by hydroxymercuribenzoate and subsequently reactivated by cysteine. Regarding the incidence of type I and IIA fibers, there was a statistically significant difference between the thyroarytenoid and the posterior cricoarytenoid muscles. The type IIA fiber content was statistically significantly higher in the arytenoid muscle than in the posterior cricoarytenoid muscle. The percentage of type IIB fibers was low, not only in the thyroarytenoid muscle and the posterior cricoarytenoid muscle but also in the other laryngeal muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1976

Peripheral leukocyte migration inhibition reactivity to breast cancer antigens in patients with breast cancer and in normal controls.

The peripheral leukocyte migration inhibition test has been used to assess cellular immunity to soluble antigen extracts of breast cancer in patients and normal controls. In sequential tests over several weeks, 23 of 23 patients with breast cancer in remission reacted intermittently, with 67 of 139 tests (48%) being positive (greater than or equal to 20% migration inhibition). Similarly, 6 of 10 patients in relapse reacted intermittently showing 16 of 61 positive tests (26%) and 126 of 129 normal females reacted intermittently showing 135 of 512 positive tests (26%). The mean percentage of migration inhibition for all tests in patients in remission was 16.4 +/- 1.2% and that for normal controls was 7.2 +/- 0.7%; this difference was highly significant (p less than 0.001). The value for all tests in patients with relapse was 11.8 +/- 1.4%; this was statistically lower than that for patients in remission (p less than 0.05) but statistically higher than that for normal controls (p less than 0.05). A few normal women, some with high risk factors such as a strong family history and/or fibrocystic and proliferative disease, had a mean percentage of migration inhibition value in the range of that for patients with breast cancer. Mean values of sequential tests may be a more meaningful index of cellular immunity against breast cancer antigen in all groups.

Breast Neoplasms↗
PubMed2025

PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors.

Immunotherapy modalities have revolutionized cancer treatment for a number of metastatic and treatment-refractory tumor types. Still, many malignancies that lack T cell infiltration and are termed immunologically "cold" fail to respond to these modalities. One approach to increase tumor immunogenicity has been to induce stimulator of interferon gene (STING) and downstream interferon signaling that is often dysregulated in cold tumors. Despite some early success of STING agonists in preclinical cancer models, these approaches have not been successful in the clinic due to poor tumor penetrance and systemic toxicities. Here, we performed a genome-wide CRISPR screen to uncover therapeutic targets to activate STING expression in human tumors. We identified the lysosomal hydrolase Palmitoyl Protein Thioesterase1 (PPT1) as a negative regulator of STING highly expressed in cold ovarian and prostate tumors. Genetic or pharmacological PPT1 suppression increased STING protein stability and its downstream activation of interferon and inflammatory cytokine signaling to enhance T cell migration. Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors "hot" and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8+ T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors.

Membrane Proteins↗
PubMed1979

Inhibition of trypsin and chymotrypsin by thiols. Biphasic kinetics of reactivation and inhibition induced by sodium periodate addition.

Biphasic kinetic data were obtained when trypsin (EC 3.4.21.4) which had previously been complexed with a thiol-containing inhibitor (present in Ehrlich ascites tumour cells) was incubated with incremental additions of periodate. At low concentrations of periodate the trypsin was re-activated whilst at higher concentrations of periodate the trypsin was irreversibly inhibited. This biphasic reactivation followed by inhibition was also demonstrated when trypsin was first inhibited by dithiothreitol and followed by incremental addition of periodate. Similar results were obtained with chymotrypsin (EC 3.4.21.1). Incremental additions of either dithiothreitol or periodate caused inhibition of both these enzymes. The biphasic kinetic data can be explained in terms of reduction and oxidation of a significant disulphide bond in both trypsin and chymotrypsin which can be cleaved by thiols in a disulphide exchange reaction [1]. This bond is thought to maintain the active centres of each of these enzymes in a conformation sterically favourable for enzymic cleavage of specific peptide bonds in the protein substrates (polymeric collagen fibrils and casein) employed in this study.

Animals↗
PubMed1991

Anti-C-reactive protein inhibits the calcium-dependent stage of natural killer cell activation.

The studies described in this publication were designed to determine which stage of the NK lytic mechanism is inhibited by anti-C-reactive protein (CRP). Although anti-CRP prevents target cell lysis, it does not block E:T cell conjugate formation. In parallel experiments, the number of conjugates observed in the presence of anti-CRP was normal, whereas the number of target cells killed by this same group of effector cells was greatly inhibited. Since an early stage of NK-mediated lysis requires calcium, conjugates can be synchronized by incubating effector and target cells in the absence of calcium. When conjugates were formed in the absence of calcium, and anti-CRP and calcium were then added to cultures at the same time, anti-CRP inhibited maximally. Anti-CRP continued to inhibit somewhat throughout the calcium-dependent stage but did not block lysis when added after the completion of calcium requiring events. Events that are blocked by anti-CRP must be required for the generation of NK cytotoxic factor because anti-CRP blocks the production of this factor. Once generated, however, anti-CRP does not block the activity of NK cytotoxic factor. This evidence indicates that anti-CRP blocks NK-mediated lysis at the calcium dependent stage of lysis. Events that follow this stage in the lytic process are also inhibited.

Antibodies, Monoclonal↗
PubMedDate not supplied

Modification of cerebrovascular CO2 reactivity by inhibition of dopamine beta-hydroxylase.

The influence of sympathetic nervous activity on cerebral circulation and cerebrovascular CO2 reactivity was investigated through inhibition of dopamine beta-hydroxylase (DBH). A PO2 electrode, a PCO2 electrode and a plate-type thermocouple-flowmeter were placed on the pial surface of the cat brain. Cerebrocortical PO2, PCO2, cerebrocortical blood flow and arterial blood pressure were continuously recorded before, during and after intracarotid infusion of 10 mg/kg of fusaric acid, a potent DBH inhibitor. The effects of 5% CO2 inhalation and hyperventilation were measured before and after the inhibition of DBH. Following the intracarotid infusion of fusaric acid, cerebrocortical PO2 and cerebrocortical blood flow increased significantly. After the inhibition of DBH, the degree of the increase in cerebrocortical PO2 during 5% CO2 inhalation was enhanced while the degree of the decrease in cerebrocortical PO2 during hyperventilation did not show any significant change. The cerebral vasodilatation caused by fusaric acid suggests that the sympathetic nervous system takes part in the resting tone of cerebral blood vessels. The increase in the cerebrovascular CO2 reactivity produced by the inhibition of DBH suggests that the sympathetic nervous system modifies cerebrovascular CO2 reactivity.

Animals↗
PubMed1978

Effects of a stimulant drug on extraversion level in hyperactive children.

7 hyperactive children in a pilot study, and 15 hyperactive and 15 non-hyperactive control children in a later study, were assessed for salivation to lemon juice stimulation, reactive inhibition on an audio-vigilance task, and visual-motor maze errors. Hyperactive children were tested under stimulant drug and nondrug conditions and nonhyperactive children twice under nondrug conditions. Pilot study hyperactive children displayed significantly fewer maze errors and somewhat greater salivation and lesser reactive inhibition levels under the drug than the nondrug conditions. Follow-up study control children did not differ significantly between test occasions on any measure, while the hyperactive children displayed significantly fewer maze errors, more salivation, and less reactive inhibition under the stimulant drug, indicating significant decreases in extraversion after the stimulant drug.

Adolescent↗
PubMed1976

Transcendental Meditation and fine perceptual-motor skill.

30 college male meditators had a 20-min. meditation followed by a 6-min. waking phase prior to 5-min. continuous practice on the pursuit rotor task. This was followed by a 4-min. rest then a further 2-min. of pursuit rotor practice. A similar group of college males who were non-meditators (N = 30) followed the same procedures except that instead of meditating they sat quietly for the initial 20-min. period. The expectations that Transcendental Meditation would (a) facilitate learning and performance; (b) cause less within-subject variability; and (C) cause less reactive inhibition, (c) cause less reactive inhinition, were not upheld by the results. With the exception of performance, which was significantly lower for the meditators, the two groups were no different. Thus, it appears that certain reported physiological and psychological benefits that are attributed to the practice of Transcendental Meditation (such as less anxiety, greater consistency, more awareness, altertness, and attention) are not manifested in the present behavioral test of perceptural-motor function. In fact, in terms of performance, the meditators seemed to be at a disadvantage.

Adolescent↗
PubMed1992

C-reactive protein inhibits intracellular calcium mobilization and superoxide production by guinea pig alveolar macrophages.

C-reactive protein (CRP) is a prototypical acute-phase reactant, the humoral and plasma concentrations of which rise dramatically after tissue injury or inflammation. The effects of CRP on superoxide production and intracellular calcium mobilization by guinea pig alveolar macrophages challenged with platelet-activating factor (PAF), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and phorbol 12-myristate 13-acetate (PMA) were studied. CRP by itself did not activate alveolar macrophages up to a concentration of 100 micrograms/ml, whereas it inhibited superoxide production in a time- and dose-dependent manner with median inhibitory concentration (IC50) values of 4.2 +/- 0.3, 3.0 +/- 0.2, and 3.2 +/- 0.3 micrograms/ml for PAF (10(-7) M), fMLP (10(-7) M), and PMA (10(-9) M), respectively. When CRP was incubated with the agonists before addition to cells, it inhibited PMA-, PAF-, and to a lesser extent fMLP-induced superoxide production. CRP also attenuated the rise in intracellular free calcium levels evoked by fMLP or PAF in a dose-dependent manner. These findings suggest that CRP may play a role in attenuating tissue damage secondary to activation of alveolar macrophages by inhibiting superoxide generation and mobilization of intracellular free calcium.

Animals↗
PubMed1991

Redox reactive reagents inhibiting and inactivating choline acetyltransferase.

3-Trimethylammoniomethyl catechol and N,N-dimethylepinephrine (catecholine) are redox reactive reagents which possess quaternary ammonium functional groups and the capacity to inhibit or inactivate choline binding macromolecules which mediate cholinergic neuronal function. Earlier studies reported the synthesis of 3-trimethylammoniomethyl catechol and demonstrated its redox-dependent covalent inactivation of the nicotinic acetylcholine receptor (Nickoloff et al., Biochemistry 24, 999-1007 (1985)]. Here we present the synthesis of catecholine and show that both 3-trimethylammoniomethyl catechol and catecholine are weak noncompetitive inhibitors (Ki = 15 +/- 6 and 25 +/- 4 mM, respectively) of choline acetyltransferase (EC 2.3.1.6). Both agents irreversibly inactivate the enzyme.

Animals↗
PubMed1979

Regulation of pyruvate dehydrogenase by insulin action.

In animal tissues the pyruvate dehydrogenase complex is regulated by product inhibition and by a phosphorylation-dephosphorylation cycle catalysed by a kinase and a phosphatase. Physiologic and molecular aspects of this regulation are reviewed, and the results of recent studies are described. Insulin deficiency in the rat (diabetes or starvation) is shown to inhibit the conversion of inactive (phospho-) complex into active (dephospho-) complex by the phosphatase by an effect on the substrate for the phosphatase (phosphorylated complex). This change is stable and persists during isolation, incubation, and extraction of mitochondria or purification of phosphorylated complex. The subunit ratios in the purified pig heart pyruvate dehydrogenase complex and the stoichiometry of phosphorylations have been determined by radioamidination and incorporation of 32P. The ratios of decarboxylase tetramer (alpha 2, beta 2) : dihydrolipoyl acetyltransferase monomer : dihydrolipoly dehydrogenase monomer were 1:1:0.5. Inactivation of the complex was accomplished by incorporation of a single phosphate into one alpha subunit of the decarboxylase tetramer. Two further phosphates are then incorporated and these additional phosphorylations inhibit reactivation of the complex by the phosphate. It is suggested that multisite phosphorylations may inhibit reactivation of the complex by the phosphatase in diabetes and in starvation.

Animals↗
PubMed1992

Baroreceptor reflexes and vascular reactivity during inhibition of nitric oxide synthesis in conscious rabbits.

The effect of the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (NOLA) on vascular reactivity and the baroreceptor heart rate reflex was examined in chronically instrumented conscious rabbits. NOLA (15 mg/kg i.v.) significantly increased mean arterial pressure and hindlimb vascular resistance and decreased heart rate. Increases and decreases in arterial pressure were produced by the intravenous injection of phenylephrine and sodium nitroprusside respectively and the values obtained relating mean arterial blood pressure to heart rate were fitted to a sigmoid curve. NOLA significantly reduced the lower plateau of the arterial pressure--heart rate curve but did not significantly affect baroreceptor sensitivity. Depressor and hindlimb vasodilator responses to acetylcholine were significantly impaired by NOLA whereas responses to sodium nitroprusside were significantly enhanced. The pressor and hindlimb vasoconstrictor responses to phenylephrine were significantly enhanced in the presence of NOLA. We conclude that the bradycardia produced by NOLA does not result from a change in baroreceptor sensitivity. The continuous generation of NO appears to be important in regulating basal vascular resistance and in modulating vascular reactivity to both vasodilator and vasoconstrictor agents.

Acetylcholine↗
PubMed1976

[Mitotic activity changes in the corneal epithelium of rats of different ages following exposure to pain].

A study was made of pain stimulus (amputation of 1/3 of the tail) on the mitotic activity in the corneal epithelium of 21-day fetuses, 1-, 3-, 4-, 5-, 7-, 10-, 15-, 20- and 25-day rats. In 45 minutes after the infliction of trauma no significant change was seen in the cornea of the fetuses and of the one-day-old ratlings. A gradual establishment of the reactive inhibition of mitoses in response to pain occurred between the 3rd and the 10th day of postnatal development. This reaction became more intense after the 10th day, reaching the maximum by the 25th day. Reactive inhibition of the mitotic activity was connected with the inhibition of the entrance of cells into mitosis.

Age Factors↗
PubMed1976

[Studies on the pH-dependence, inhibition and reactivation of angiotension II-amide splitting enzymes in human erythrocytes (author's transl)].

Aminopeptidase activity of three fractions of human erythrocytes (membranes free of hemoglobin; hemolysate free of membranes; enzyme protein fraction made free of hemoglobin by DEAE-cellulose) was measured by a NADH dependent optical test using asparaginyl1-angiotension II-amide as substrate. 1. From the enzyme protein fraction 6 subfractions were obtained by (NH4)2SO4 precipitation. By measuring enzyme kinetics at three different pH-values (pH 5,0; 7,0; 8,0) with and without addition of the effectors Na2EDTA and Ca++ the existence of 6 different enzymes could be demonstrated. 2. The aminopeptidase activity of the hemolysate made free of membranes could be inhibited by diisopropylfluorphosphate and p-chloromercuribenzoate at three different pH-values (pH 5,0; 6,5; 7,0; 8,0 and 6,5; 7,0; 8,0 respectively). 3. A reduction of enzymatic activity of 20% was found after incubation at 37degreesC for two hours.

Calcium↗
PubMed1992

Renaturation of a single-chain immunotoxin facilitated by chaperones and protein disulfide isomerase.

B3(Fv)-PE38KDEL, a recombinant immunotoxin, forms inclusion bodies when produced in Escherichia coli. In renaturation experiments, nonspecific aggregation of non-native polypeptide chains, and the formation of incorrect disulfide linkages lead to inactive molecules. To prevent these side reactions, we added molecular chaperones and protein disulfide isomerase (PDI) to the refolding buffer. Both DnaK and GroEL/S influenced the reactivation process. GroEL alone inhibited reactivation, but in the presence of ATP, GroEL and GroES significantly increased the yield of active protein. DnaK also increased the yield of properly folded protein and the stimulating effect of DnaK was also observed using immobilized DnaK, which can be used repeatedly without significant loss of activity. PDI, which catalyzes disulfide bridging of proteins, also stimulated reactivation of the immunotoxin. Under optimum conditions, reactivation yields in the presence of PDI were about twice that obtained with nonenzymatic disulfide bond formation. Furthermore, DnaK and PDI were additive when renaturation was performed in the presence of both proteins.

Antibodies, Monoclonal↗