Introduction: Amine oxidases and polyamines in biological systems

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spermine oxidation products induce mitochondrial alterations on tumor cells

Spermine Oxidation Products Induce Mitochondrial Alterations on Tumor Cells Cytotoxic products of polyamines generated in situ by an enzyme-catalyzed reaction may be useful as a new avenue in combating cancer. This study demonstrates that multidrug resistant (MDR) cancer cells (colon adenocarcinoma and melanoma) are significantly more sensitive than the corresponding wild type (WT) ones to hydrogen peroxide and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. Transmission electron microscopy (TEM) observations showed the major ultrastructural alterations of the mitochondria. These were more pronounced in MDR than in WT cells. After treatment with BSAO/spermine a higher mitochondrial membrane depolarization and an increased mitochondrial activity in drug-resistant cells were observed. The results suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death, mainly in multidrug resistant cell lines

Glucose, glutathione, and cellular response to spermine oxidation products

Bovine serum amineoxidase (BSAO) oxidatively deaminates polyamines, which contain primary amine groups with formation of several toxic products, H2O2, and aldehyde(s). We evaluated the role of glucose metabolism via the pentose phosphate cycle and the level of intracellular glutathione on cytotoxicity induced by each of the toxic products in Chinese hamster ovary (CHO) cells. Glucose protected cells against cytotoxicity in the presence of BSAO at low spermine concentrations (< 50 mu M), where H2O2 was the only toxic species present. When catalase was present, cytotoxicity is attributed to spermine-derived aldehyde(s). Glucose did not protect cells against cytotoxicity induced by spermine-derived aldehyde(s), nor by the aldehyde acrolein. Hydrogen peroxide produced by spermine and BSAO stimulated pentose cycle activity, whereas the aldehyde(s) did not. Depletion of intracellular glutathione with L-buthionine sulfoximine (1 mM, 24 h) sensitized cells to the cytotoxic effects of both H2O2 and the aldehyde(s) produced by spermine and BSAO. The pentose cycle and the glutathione redox cycle have an important role in protection against H2O2 generated from spermine oxidation. Glutathione appears to have a role in protecting cells against cytotoxicity attributed to spermine-derived aldehyde(s), most likely by conjugation in a reaction catalyzed by glutathione S-transferase, whereas metabolism of glucose via the pentose cycle did not. The metabolism of both glucose and glutathione, affect the cellular response to H2O2 and aldehyde(s) derived from spermine, although different pathways are involved

Management of anterior chamber dislocation of a dexamethasone intravitreal implant: a case report

Background Ozurdex is a 700 mcg dexamethasone intravitreal implant, approved for the management of macular edema secondary to retinal vein occlusion, and other related pathoglogiesAnterior chamber dislocation of Ozurdex represents an uncommon complication of the intravitreal injection, which can be managed by repositioning the implant into the vitreous cavity. We describe the case of a successful repositioning of an Ozurdex implant by mobilization and subsequent balanced saline solution injection in the anterior chamber. Case presentation An 83-year-old white woman presented to our Emergency Unit complaining of pain and vision loss in herright eye lasting a week. Her anamnesis revealed a history of persistent cystoid macular edema after phacoemulsification with scleral-fixated posterior chamber intraocular lens implantation, recently treated with an intravitreal Ozurdex implant. She also took a long-distance flight 2 days after the injection. An anterior segment examination showed corneal edema and the rod implant adherent to corneal endothelium. To avoid corneal decompensation, we opted for a implant repositioning. Under topical anesthesia, a 30-gauge needle was introduced through a limbar incisionto mobilize the dislocated rod. Balanced saline solution was injected, with a successful repositioning of the implant into the vitreous cavity. Topical 5 % hypertonic saline solution and 0.2 % betamethasone associated with 0.5 % chloramphenicol drops were administered four times a day. To prevent redislocation of the Ozurdex implant, she was instructed to avoid prone position, any kind of physical effort, and not to undertake long-distance flights during the first postoperative week. One week after surgery, an anterior segment examination showed an improvement of corneal edema. Funduscopy showed that the Ozurdex implant was settled into the vitreous cavity. Conclusions Anterior chamber dislocation of Ozurdex from the vitreous cavity is rare. In our patient, in addition to the posterior capsule tearing, the long-distance flight could have contributed to implant dislocation. Repositioning of the implant is necessary to avoid endothelial decompensation. It can be carried out by using saline balanced solution with the same efficacy as other surgical procedures reported in the literature. A possible disadvantage of this procedure could be implant migration

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts to H(2)O(2) and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic than exogenous H(2)O(2) and acrolein, even thou-h their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Both wild-type and MDR cells, after pre-treatment with MDL 72527, an inactivator of polyamine oxidase and a lysosomotropic compound, show to be sensitized to subsequent exposure to BSAO/spermine. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this work that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by MDL 72527. Owing to its lysosomotropic effect, pre-treatment with MDL 72527 amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Since it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells, it is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting

Agmatine prevents the Ca2+-dependent induction of permeability transition in rat brain mitochondria

The arginine metabolite agmatine is able to protect brain mitochondria against the drop in energy capacity by the Ca(2+)-dependent induction of permeability transition (MPT) in rat brain mitochondria. At normal levels, the amine maintains the respiratory control index and ADP/O ratio and prevents mitochondrial colloid-osmotic swelling and any electrical potential (DeltaPsi) drop. MPT is due to oxidative stress induced by the interaction of Ca(2+) with the mitochondrial membrane, leading to the production of hydrogen peroxide and, subsequently, other reactive oxygen species (ROS) such as hydroxyl radicals. This production of ROS induces oxidation of sulfhydryl groups, in particular those of two critical cysteines, most probably located on adenine nucleotide translocase, and also oxidation of pyridine nucleotides, resulting in transition pore opening. The protective effect of agmatine is attributable to a scavenging effect on the most toxic ROS, i.e., the hydroxyl radical, thus preventing oxidative stress and consequent bioenergetic collapse

Trophic and neurotrophic factors in human pituitary adenomas (Review)

The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in functional or non-functional, depending on their hormonal activity. Some trophic and neurotrophic factors seem to play a key role in the development and maintenance of the pituitary function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. Several lines of evidence suggest that trophic and neurotrophic factors may be involved in pituitary function, thus suggesting a possible role of the trophic and neurotrophic factors in the normal development of pituitary gland and in the progression of pituitary adenomas. Additional studies might be necessary to better explain the biological role of these molecules in the development and progression of this type of tumor. In this review, in light of the available literature, data on the following neurotrophic factors are discussed: ciliary neurotrophic factor (CNTF), transforming growth factors β (TGF‑β), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), vascular endothelial growth inhibitor (VEGI), fibroblast growth factors (FGFs) and epidermal growth factor (EGF) which influence the proliferation and growth of pituitary adenomas

Tyrosine phosphatase activity in mitochondria: presence of Shp-2 phosphatase in mitochondria

Tyrosine phosphorylation by unidentified enzymes has been observed in mitochondria, with recent evidence indicating that non-receptorial tyrosine kinases belonging to the Src family, which represent key players in several transduction pathways, are constitutively present in mitochondria. The extent of protein phosphorylation reflects a coordination balance between the activities of specific kinases and phophatases. The present study demonstrates that purified rat brain mitochondria possess endogenous tyrosine phosphatase activity. Mitochondrial phosphatases were found to be capable of dephosphorylating different exogenous substrates, including paranitrophenylphosphate, P-32-poly(Glu-Tyr)(4:1) and P-32-angiotensin. These activities are strongly inhibited by peroxovanadate, a well-known inhibitor of tyrosine phosphatases, but not by inhibitors of alkali or Ser/Thr phosphatases, and mainly take place in the intermembrane space and outer mitochondrial membrane. Using a combination of approaches, we identified the tyrosine phosphatase Shp-2 in mitochondria. Shp-2 plays a crucial role in a number of intracellular signalling cascades and is probably involved in several human diseases. It thus represents the first tyrosine phosphatase shown to be present in mitochondria