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Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

ABSTRACT: We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations.

SUBMITTER: Nikula P

PROVIDER: S-EPMC1145010 | biostudies-other | 1985 Jun

REPOSITORIES: biostudies-other

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Methylglyoxal-bis-guanylhydrazone inhibits osteopontin expression and differentiation in cultured human monocytes.

Project description:Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 ?M of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.

| S-EPMC5851547 | biostudies-literature

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone.

Project description:UnlabelledMacrophages are a target for infection with HIV and represent one of the viral reservoirs that are relatively resistant to current antiretroviral drugs. Here we demonstrate that methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine analog and potent S-adenosylmethionine decarboxylase inhibitor, decreases HIV expression in monocytes and macrophages. MGBG is selectively concentrated by these cells through a mechanism consistent with active transport by the polyamine transporter. Using a macrophage-tropic reporter virus tagged with the enhanced green fluorescent protein, we demonstrate that MGBG decreases the frequency of HIV-infected cells. The effect is dose dependent and correlates with the production of HIV p24 in culture supernatants. This anti-HIV effect was further confirmed using three macrophage-tropic primary HIV isolates. Viral life cycle mapping studies show that MGBG inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages.ImportanceOur work demonstrates for the first time the selective concentration of MGBG by monocytes/macrophages, leading to the inhibition of HIV-1 expression and a reduction in proviral load within macrophage cultures. These results suggest that MGBG may be useful in adjunctive macrophage-targeted therapy for HIV infection.

| S-EPMC4645666 | biostudies-literature

Direct Targeting of Macrophages With Methylglyoxal-Bis-Guanylhydrazone Decreases SIV-Associated Cardiovascular Inflammation and Pathology.

Project description:BackgroundDespite effective combination antiretroviral therapy, HIV-infected individuals develop comorbidities, including cardiovascular disease, where activated macrophages play a key role. To date, few therapies target activated monocytes and macrophages.MethodsWe evaluated a novel oral form of the polyamine biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone (MGBG) on cardiovascular inflammation, carotid artery intima-media thickness (cIMT), and fibrosis in a simian immunodeficiency virus infection model of AIDS. Eleven simian immunodeficiency virus-infected animals received MGBG (30 mg/kg) once daily and 8 received a placebo control both beginning at 21 days postinfection (dpi). Animals were time sacrificed at 49 days post infection (dpi), when their matched placebo controls developed AIDS (63, 70, 77, 80), or at the study end-point (84 dpi). Aorta, carotid artery, and cardiac tissues were analyzed. Quantitative analyses of macrophage populations and T lymphocytes were done and correlated with cIMT and fibrosis.ResultsMGBG treatment resulted in 2.19-fold (CD163), 1.86-fold (CD68), 2.31-fold (CD206), and 2.12-fold (MAC387) decreases in macrophages in carotid arteries and significant 2.07-fold (CD163), 1.61-fold (CD68), 1.95-fold (MAC387), and 1.62-fold (CD206) decreases in macrophages in cardiac tissues. cIMT (1.49-fold) and fibrosis (2.05-fold) also were significantly decreased with MGBG treatment. Numbers of macrophage and the degree of fibrosis in treated animals were similar to uninfected animals. A positive correlation between decreased macrophage in the carotid artery and cIMT, and cardiac macrophages and fibrosis was found.ConclusionsThese data demonstrate that directly targeting macrophages with MGBG can reduce cardiovascular inflammation, cIMT, and fibrosis. They suggest that therapies targeting macrophages with HIV could be used in conjunction with combination antiretroviral therapy.

| S-EPMC5370195 | biostudies-literature

Inhibition of spermidine formation in rat liver and kidney by methylglyoxal bis(guanylhydrazone).

Project description:The effect of methylglyoxal bis(guanylhydrazone), a substance known to inhibit putrescine-dependent S-adenosyl-l-methionine decarboxylase, on polyamine metabolism in liver and kidney was investigated. Almost complete inhibition of the incorporation of putrescine into spermidine was obtained up to 8h after administration of 80mg of methylglyoxal bis(guanylhydrazone)/kg body wt. by intraperitoneal injection. However, by 20h after administration of the inhibitor spermidine synthesis was resumed. Considerable accumulation of putrescine occurred during this period (up to 3 times control concentrations in both tissues), but there was only a slight fall in the spermidine content. These results suggest that the putrescine-activated S-adenosyl-l-methionine decarboxylase plays an essential role in spermidine biosynthesis in rat liver and kidney, and the possibility of using methylglyoxal bis(guanylhydrazone) to study the role of polyamine synthesis in growth is discussed.

| S-EPMC1177618 | biostudies-other

Diminished excretion of polyamines from BHK-21/C13 cells exposed to methylglyoxal bis(guanylhydrazone).

Project description:Methylglyoxal bis(guanylhydrazone) (1,1'-[methylethanediylidine)dinitrilo]diguanidine) inhibited the growth of BHK-21/C13 cells in monolayer cultures. Accumulation of spermidine and spermine was inhibited, whereas the accumulation of putrescine was increased. The intracellular spermidine/spermine molar ratio decreased conly slightly after exposure of the cells to 20 micrometer-methylglyoxal bis(guanylhydrazone) for 1 day. Cells incubated in the presence of the drug released less polyamine into the culture medium that did control cells, the polyamine released consisting almost exclusively of spermidine, both free and as a conjugated form.

| S-EPMC1185917 | biostudies-other

Acetylation of spermidine and methylglyoxal bis(guanylhydrazone) in baby-hamster kidney cells (BHK-21/C13).

Project description:Treatment of BHK-21/C13 cells with methylglyoxal bis(guanylhydrazone) (MGBG) induced the cytosolic form of spermidine N1-acetyltransferase. It stabilized the enzyme against proteolytic degradation, but the drug did not affect the enzyme activity in vitro. MGBG was itself acetylated by BHK-21/C13 cells, but at only one-tenth the rate at which spermidine was acetylated. Acetylation occurred almost exclusively in the nuclear fraction. The product was identified as N-acetyl-MGBG by h.p.l.c., by using [3H]acetyl-CoA and [14C]MGBG as co-substrates. The results suggest that the acetylation of MGBG by BHK-21/C13 cells occurs by a different acetyltransferase enzyme from that which acetylates spermidine.

| S-EPMC1149278 | biostudies-other

Intracellular putrescine and spermidine deprivation induces increased uptake of the natural polyamines and methylglyoxal bis(guanylhydrazone).

Project description:Inhibition of polyamine synthesis by alpha-difluoromethylornithine in cultured Ehrlich ascites-carcinoma cells rapidly enhanced the uptake of exogenous putrescine, spermidine and spermine from the culture medium. In tumour cells exposed to the drug for 2 days, the intracellular concentration of spermidine was decreased to less than 10% of that found in untreated cells. However, the strikingly stimulated transport system brought the concentration of spermidine to the control values in less than 2h after supplementation of the cells with micromolar concentrations of the polyamine. In the absence of polyamine deprivation, tumour cells did not accumulate extracellular polyamines to any appreciable extent. Ascites-tumour cells deprived of putrescine and spermidine likewise concentrated methylglyoxal bis(guanylhydrazone) [1,1'-[methylethanedylidine)dinitrilo]diguanidine] at a greatly enhanced rate. A previous "priming of tumour cells with difluoromethylornithine followed by an exposure of the cells to methylglyoxal bis(guanylhydrazone) resulted in a marked and rapid anti-proliferative effect.

| S-EPMC1162421 | biostudies-other

Specific inhibition of the enzymic decarboxylation of S-adenosylmethionine by methylglyoxal bis(guanylhydrazone) and related substances.

Project description:Methylglyoxal bis(guanylhydrazone) {1,1'-[(methylethanediylidene)-dinitrilo]diguanidine} is a very potent inhibitor of putrescine-activated S-adenosylmethionine decarboxylases from many different mammalian tissues, including sublines of mouse L1210 leukaemia that are resistant to the drug as well as sublines that are sensitive. The inhibition of purified rat ventral prostate S-adenosylmethionine decarboxylase is competitive with respect to the S-adenosylmethionine substrate, and is much greater in the presence than in the absence of the activator putrescine. Inhibition by the drug depends, among other things, on the nature of the aliphatic amines that can serve as stimulators of rat prostate S-adenosylmethionine decarboxylase. Effects of some congeners of methylglyoxal bis(guanylhydrazone) on the enzyme are described.

| S-EPMC1166290 | biostudies-other

Effects of polyamines and methylglyoxal bis(guanylhydrazone) on hepatic nuclear structure and deoxyribonucleic acid template activity.

Project description:1. The interaction of polyamines and methylglyoxal bis(guanythydrazone) (1, 1'-[(methylethanediylidene)-dinitrilo]diguanidine) with isolated rat liver nuclei was investigated by electron microscopy. 2. At 4mM, putrescine was without effect; however, spermidine, spermine or methylglyoxal bis(guanythydrazone) resulted in dispersed chromatin and alterations in nucleolar structure. In addition, spermidine or methylglyoxal bis(guanylhydrazone) caused marked aggregation of interchromatin granules. 3. The DNA template property of calf thymus DNA was examined by using DNA polymerases from Escherichia coli, Micrococcus lysodeikticus and calf thymus in the presence of 0-5 mM-amine. 4. In the presence of DNA polymerase, spermine or methylglyoxal bis(guanylhydrazone) inhibited activity, whereas putrescine or spermidine had much less effect or in some cases stimulated [3H]dTMP incorporation. 5. Template activity which was inhibited by spermine or methylglyoxal bis(guanylhydrazone) could be partially restored by additional DNA or enzyme. 6. When mixed with calf thymus DNA, calf thymus histone inhibited template activity as measured with E. coli DNA polymerase. The template activity of such a 'histone-nucleate' could not be restored by putrescine, spermidine, spermine or methylglyoxal bis(guanylhydrazone). 7. DNA template activity of isolated rat liver nuclei was tested by using E. coli DNA polymerase. None of the amines was able to increase the template activity of the nuclear DNA in vitro.

| S-EPMC1172397 | biostudies-other

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic ?-Cells.

Project description:To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic ?-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 ?M) for 48 h and then treated with 2 mM MG for 8 h. The effects of CA and MG on INS-1 cells were evaluated using the following: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; glyoxalase 1 (Glo-1) expression via Western blot and enzyme activity assays; Nrf-2, nuclear factor erythroid 2-related factor 2 protein expression via Western blot assay; reactive oxygen species (ROS) production assay; mRNA expression of mitochondrial dysfunction related components (UCP2, uncoupling protein 2; VDAC1, voltage-dependent anion-selective channel-1; cyt c, cytochrome c via quantitative reverse transcriptase-PCR; mitochondrial membrane potential (MMP); adenosine triphosphate (ATP) synthesis; glucose-stimulated insulin secretion (GSIS) assay. The viability of INS-1 cells was maintained upon pre-treating with CA before exposure to MG. CA upregulated Glo-1 protein expression and enzyme activity in INS-1 cells and prevented MG-induced ROS production. Mitochondrial dysfunction was alleviated by CA pretreatment; this occurred via the downregulation of UCP2, VDAC1, and cyt c mRNA expression and the increase of MMP and ATP synthesis. Further, CA pre-treatment promoted the recovery from MG-induced decrease in GSIS. These results indicated that CA could be employed as a therapeutic agent in diabetes due to its ability to prevent MG-induced development of insulin sensitivity and oxidative stress-induced dysfunction of ?-cells.

| S-EPMC7554990 | biostudies-literature

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