scholarly journals Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites

1983 ◽  
Vol 212 (3) ◽  
pp. 895-898 ◽  
Author(s):  
A Kallio ◽  
J Jänne
Keyword(s):  
Diamine Oxidase ◽  
Potent Inhibitor ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Tumour Cells ◽  
Adenosylmethionine Decarboxylase ◽  
Growth Inhibitory ◽  
Sequential Combination ◽  
Marked Accumulation

Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.

Involvement of PKCe in the Negative Regulation of Akt Activation Stimulated by G-CSF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2187-2187
Author(s):  
Hong Liu ◽  
Fan Dong
Keyword(s):  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Signaling Cascades ◽  
Granulocytic Differentiation ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Receptor Mutant

Abstract Granulocyte colony-stimulating factor (G-CSF) supports the proliferation, differentiation and survival of myeloid cells by stimulating the activation of several signaling cascades including the serine/threonine kinase Akt pathway. Akt activation has been shown to be important for G-CSF-induced survival and granulocytic differentiation. Although significant progresses have been made in our understanding of the molecular mechanisms by which Akt is activated, much less is known about the signaling events that negatively regulate Akt activation. Interestingly, G-CSF-induced activation of Akt was completely inhibited when myeloid 32D cells transfected with the wild type G-CSF receptor were incubated with phorbol-12-myristate 13-acetate (PMA), a PKC activator. PMA-mediated inhibition of Akt activation occurred with 5 min and lasted at least 1 hour. Previously, it has been shown that a carboxyl terminally truncated G-CSF receptor (D715), whose expression is associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia (SCN), mediates significantly prolonged Akt activation. Notably, Akt activation by G-CSF in 32D cells expressing the D715 receptor mutant was rapidly downregulated by PMA treatment. The inhibitory effect of PMA on Akt activation was abolished by pretreatment of cells with the specific PKC inhibitor GF109203X, suggesting that PKC-dependent pathway negatively regulates Akt activation. Ro-31-7549, a specific inhibitor of PKCe, also abrogated PMA-mediated inhibition of Akt activation whereas rottlerin and Go6976, inhibitors of PKCd and PKC a/bI,, respectively, displayed no effect. Together, these results identified PKCe as being critically involved in PMA-mediated inhibition of Akt activation. Experiments are currently under way to determine the mechanism by which PKCe downregulates Akt activation and the role of PKCe in the regulation of cell proliferation, differentiation and survival in response to G-CSF.

Possible Role of Dopamine in the Growth Inhibitory Effect of Pentazocine

1983 ◽  
Vol 6 (2) ◽  
pp. 138-144 ◽  
Author(s):  
Indravadan C. Gandhi ◽  
Shailendra Vajpeyee ◽  
Usha H. Shah ◽  
Ram K. Dikshit ◽  
Rajanikant B. Doctor
Keyword(s):  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory

THE ROLE OF PROTON ATPase SPECIFIC INHIBITOR $N,N'$-DICYCLOHEXYLCARBODIIMIDE AND EXTERNAL FORMATE CONCENTRATION ON $E.~COLI$ GROWTH DURING MIXED CARBON SOURCES FERMENTATION AT DIFFERENT pHs.

2021 ◽  
Vol 55 (1 (254)) ◽  
pp. 67-74
Author(s):  
Heghine Kh. Gevorgyan ◽  
Anait V. Vassilian ◽  
Karen A. Trchounian
Keyword(s):  
Regulatory Protein ◽  
Carbon Sources ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
E Coli ◽  
Proton Atpase ◽  
Mutant Strains ◽  
Atpase Inhibition ◽  
Compensatory Effect

This research is focused on the investigation of specific growth rate changes of $E.~coli$ wild type and mutant strains with defect of Hyd, FDH enzymes and FhlA regulatory protein in the presence of $N,N'$-dicyclohexylcarbodiimide (DCCD) and external formate various concentration during co-fermentation of glucose, glycerol and formate at pHs $5.5-7.5.$ The highest value of SGR was observed at pH 7.5. It was revealed that SGR depends on external formate concentration at all pHs. DCCD inhibitory effect was shown mainly at pH 7.5 and partially at pH 6.5 and 5.5. In the case of the F0F1-ATPase inhibition FhlA compensatory effect on SGR was revealed.

Targeting IKK Inhibits Multiple Myeloma (MM) Cell Growth in the Bone Marrow Microenvironment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2351-2351
Author(s):  
Teru Hideshima ◽  
Pierfrancesco Tassone ◽  
Dharminder Chauhan ◽  
Kenji Ishitsuka ◽  
Constantine Mitsiades ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Adhesion ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Bone Marrow Microenvironment ◽  
Thymidine Uptake ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory

Abstract NF-κB is a transcriptional factor promoting tumor cell growth and inhibition of apoptosis via regulating expression of proteins modulating cell cycle and anti-apoptosis. NF-κB is constitutively associated with an inhibitor (IκB), which is phosphorylated by IκB kinase (IKK) upon cell stimulation (ie, TNFα) and subsequently degraded by ubiquitin-proteasome pathway, thereby allowing NF-κB to translocate to nucleus. We have previously shown that an IKK inhibitor PS-1145 partially (20–50%) inhibits MM cell proliferation; however, it inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. Targeting IKKβ is therefore a possible therapeutic option for inhibition of MM cell growth in the bone marrow microenvironment by downregulating NF-κB activity. In this study, we further delineated the biologic significance of IKK inhibition in MM cells using IKKβ specific inhibitor MLN120B (Millennium Pharmaceuticals, Cambridge, MA). MLN120B induced 60–90% growth inhibition in cells from the MM cell lines RPMI8226, RPMI/Dox40, RPMI/LR5, U266, and INA-6; on the other hand, it induced only 25–30% inhibition in MM.1S and MM.1R cells, assessed by 72 h tritiated-thymidine uptake. Importantly, neither IL-6 nor IGF-1 overcomes the growth inhibitory effect of MLN120B in both MM.1S and U266 cells. Interestingly, MLN120B significantly augmented TNFα-induced cytotoxicity in MM.1S cells. We next examined whether MLN120B could enhance the cytotoxicity of other agents. MLN120B augmented growth inhibition triggered by doxorubicin and melphalan in RPMI8226 and IL-6 dependent INA-6 cell line. We therefore studied growth inhibitory effect of MLN120B in the presence of bone marrow stromal cells (BMSCs). MLN120B inhibited 70–80% of constitutive IL-6 secretion from BMSCs, without toxicity. Importantly, MLN120B almost completely blocked stimulation of MM.1S, U266 and INA-4 cell growth and IL-6 secretion from BMSCs induced by binding of tumor cells to BMSCs. Finally, MLN120B overcame the protective effect of BMSCs, cell adhesion mediated drug resistance, against dexamethasone in MM.1S cells. Taken together, our data demonstrate that an IKKβ inhibitor induces cytotoxicity in MM cells in the BM milieu, providing the framework for clinical trials of these novel agents to improve patient outcome in MM.

scholarly journals Effect of methylglyoxal bis(guanylhydrazone) on polyamine metabolism in normal and regenerating rat liver and rat thymus

1973 ◽  
Vol 136 (3) ◽  
pp. 669-676 ◽  
Author(s):  
E. Hölttä ◽  
P. Hannonen ◽  
J. Pispa ◽  
J. Jänne
Keyword(s):  
Rat Liver ◽  
Diamine Oxidase ◽  
Competitive Inhibitor ◽  
Polyamine Metabolism ◽  
Adenosylmethionine Decarboxylase ◽  
Regenerating Rat Liver ◽  
Marked Accumulation ◽  
Sublethal Doses ◽  
Oxidase Reaction

1. Injections of sublethal doses of methylglyoxal bis(guanylhydrazone), a potent inhibitor of putrescine-activated S-adenosylmethionine decarboxylase in vitro, resulted after a few days in an immense increase in the activity of S-adenosylmethionine decarboxylase in normal and regenerating rat liver and in rat thymus. The increase in the activity of S-adenosylmethionine decarboxylase was at least partly due to a marked lengthening of the half-life of the enzyme. 2. In regenerating liver and thymus there was also a moderate stimulation of the activity of ornithine decarboxylase (EC 4.1.1.17) and a marked accumulation of tissue putrescine. 3. Injection of methylglyoxal bis(guanylhydrazone) into the rat also markedly decreased the activity of diamine oxidase (EC 1.4.3.6) in thymus. 4. In no cases where doses of methylglyoxal bis(guanylhydrazone) close to the LD50 dose for the rat were used was it possible to lower tissue spermidine content to any significant extent. 5. Methylglyoxal bis(guanylhydrazone) seemed to act as a competitive inhibitor for the substrate S-adenosylmethionine and as an uncompetitive inhibitor for the activator putrescine in the decarboxylation of S-adenosylmethionine in vitro. 6. In the diamine oxidase reaction, with putrescine as the substrate, methylglyoxal bis(guanylhydrazone) was a non-competitive inhibitor for putrescine.

scholarly journals NMR Based Real-Time Enzyme Kinetics on Estimating the Inhibitory Effect of Sucralose in the Enzymatic Conversion of Sucrose

2020 ◽  
Author(s):  
Justin Vang ◽  
Cheenou Her ◽  
Krish Krishnan
Keyword(s):  
Enzyme Kinetics ◽  
Real Time ◽  
Potent Inhibitor ◽  
Inhibitory Effect ◽  
Lambert W Function ◽  
Enzymatic Conversion ◽  
Experimental Conditions ◽  
Enzymatic Production ◽  
Progress Curve

<p>Sucralose, one of the popular non-caloric artificial sweeteners, has been known to influence the enzymatic conversion of sucrose to glucose and fructose by invertase. In continuing the use of real-time NMR experiments and reaction progress curve analysis to measure enzyme kinetics, here we investigate the role of sucralose as an inhibitor. NMR based kinetic experiments were performed as a function of the substrate concentration for a range of sucralose concentrations, and the results were analyzed by fitting the progress curve to the Lambert-W function. The Michaelis-Menten parameters were then used to estimate the inhibitory constant of sucralose. To estimate the extent of sucralose inhibition on the enzymatic production of glucose, control experiments were performed with lactose as the inhibitor under similar experimental conditions. The results show that sucralose is a much more potent inhibitor than lactose, inhibiting the enzymatic conversion at least seven times more. <b><u></u></b></p>

scholarly journals Phosphoinositide 3-kinase inhibits megalin-mediated transcytosis of thyroglobulin across thyroid epithelial cells at a post-sorting level

2001 ◽  
pp. 477-483 ◽  
Author(s):  
M Marino ◽  
L Chiovato ◽  
S Lisi ◽  
A Pinchera ◽  
RT McCluskey
Keyword(s):  
Low Density Lipoprotein ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Thyroid Cells ◽  
Microbial Product ◽  
Phosphoinositide 3 Kinase ◽  
Rat Thyroid ◽  
Upper Chamber

BACKGROUND: Phosphoinositide 3-kinase (PI3-K) is implicated in various cellular processes involving signaling, including intracellular trafficking. PI3-K has been shown to play a part in both receptor- and non-receptor-mediated transcytosis across cultured kidney cells and undifferentiated thyroid cells. OBJECTIVE: To investigate the role of PI3-K in transcytosis of thyroglobulin (Tg) across differentiated cultured Fisher rat thyroid cells (FRTL-5 cells) - a process known to be mediated by megalin, a member of the low-density lipoprotein receptor family. DESIGN: We studied the effect of the microbial product wortmannin, a specific inhibitor of PI3-K, on transcytosis of Tg across FRTL-5 cells. METHODS: Transcytosis experiments were performed using FRTL-5 cells cultured as tight layers on filters in the upper chamber of dual chambered devices, with megalin expression exclusively on the upper cell surface. Tg was added to the upper chamber and cells were incubated at 37 degrees C. Transcytosed Tg was measured in fluids collected from the lower chamber. To study the role of PI3-K, cells were pre-incubated with wortmannin. RESULTS: Pre-incubation of FRTL-5 cells with wortmannin did not affect Tg binding and uptake, but resulted in a considerable increase in Tg transcytosis (by 40-75%, depending on the concentration of wortmannin), suggesting that PI3-K exerts an inhibitory effect on Tg transcytosis. In experiments in which a monoclonal antibody against megalin was used to reduce Tg transcytosis, pre-incubation with wortmannin did not increase Tg transcytosis from its reduced levels, indicating that PI3-K is involved in the megalin-mediated pathway. Wortmannin did not affect the extent of release of tri-iodothyronine from exogenously added Tg by FRTL-5 cells, which was used as a measure of Tg degradation in the lysosomal pathway, indicating that the effect of PI3-K on transcytosis occurs after diversion of Tg from the lysosomal pathway. CONCLUSIONS: PI3-K exerts an inhibitory role on megalin-mediated Tg transcytosis across cultured thyroid cells. PI3-K action takes place at a post-sorting level, after Tg bypassing of the lysosomal pathway.

scholarly journals THE INFLUENCE OF CORTISONE ON EXPERIMENTAL VIRAL INFECTION

1957 ◽  
Vol 106 (6) ◽  
pp. 883-892 ◽  
Author(s):  
Edwin D. Kilbourne ◽  
Keyword(s):  
Protein Synthesis ◽  
Influenza Virus ◽  
Potent Inhibitor ◽  
Inhibitory Effect ◽  
The Self ◽  
Inhibitory Effects ◽  
Obligate Intracellular ◽  
Intracellular Parasites ◽  
Experimental Viral Infection

Cortisone is a highly potent inhibitor of influenza virus synthesis in the chick embryo, inducing manifest inhibition in doses of 0.1 to 1.0 µg/egg. Inhibition of viral synthesis is only temporarily manifest. As infection continues, the negation by cortisone of the self-limiting effects of viral autointerference obscures the coincident cortisone effect on synthesis. The inhibitory effect of cortisone may be induced late in the course of viral multiplication, after conclusion of the latent period. It is proposed that inhibition of viral synthesis with cortisone is a corollary of the steroid's inhibitory effects on growth and protein synthesis of the infected host. The role of adrenal corticoids in the regulation of infection with obligate intracellular parasites deserves continued investigation.

The interaction of fragment 1 of prothrombin with the membrane surface is a prerequisite for optimum expression of factor Va cofactor activity within prothrombinase

2008 ◽  
Vol 99 (03) ◽  
pp. 511-522 ◽  
Author(s):  
Michael Bukys ◽  
Tivadar Orban ◽  
Paul Kim ◽  
Michael Nesheim ◽  
Michael Kalafatis
Keyword(s):  
Membrane Surface ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Factor Va ◽  
Initial Cleavage ◽  
Membrane Bound ◽  
Cofactor Activity ◽  
Thrombin Formation

SummaryIncorporation of factor (F) Va into prothrombinase directs prothrombin activation by FXa through the meizothrombin pathway, characterized by initial cleavage at Arg320 We have shown that a pentapeptide with the sequence DYDYQ specifically inhibits this pathway. It has been also established that Hir54–65(SO3 -) is a specific inhibitor of prothrombinase.To understand the role of FVa within prothrombinase at the molecular level, we have studied thrombin formation by prothrombinase in the presence of various prothrombin-derived fragments alone or in combination. Activation of prethrombin 1 is slow with cleavages at Arg320 and Arg271 occurring with similar rates. Addition of purified fragment 1 to prethrombin 1 accelerates both the rate of cleavage at Arg320 and thrombin formation.Both reactions were inhibited by Hir54–65(SO3 -) while DYDYQ had no significant inhibitory effect on prethrombin 1 cleavage in the absence or presence of fragment 1. Similarly, activation of prethrombin 2 by prothrombinase,is inhibited by Hir54–65(SO3 -), but is not affected by DYDYQ.Addition of purified fragment 1•2 to prethrombin 2 accelerates the rate of cleavage at Arg320 by prothrombinase. This addition also results in a significant inhibition of thrombin formation by DYDYQ and is concurrent with the elimination of the inhibitory effect of Hir54–65(SO3 -) on the same reaction. Finally, a membrane-bound ternary complex composed of prethrombin 2/fragment 1•2/Hir54–65(SO3 -) is inhibited by DYDYQ. Altogether,the data demonstrate that membrane- bound fragment 1 is required to promote optimum FVa cofactor activity which in turn is translated by efficient initial cleavage of prothrombin by prothrombinase at Arg320.

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