Anti-parasitic effect of vitamin C alone and in combination with benznidazole against Trypanosoma cruzi.

Background: Drugs currently used for the treatment of Chagas' disease, nifurtimox and benznidazole, have a limited effectiveness and toxic side effects. With the aim of finding new therapeutic approaches, in vitro and in vivo anti-Trypanosoma cruzi activity of vitamin C alone and combined with benznidazole were investigated.

Methodology/principal Findings: The trypanocidal activity on epimastigote and trypomastigote forms was evaluated by counting parasites in a Neubauer chamber after treatment with the compounds.

Effects of volatile anaesthetics on heme metabolism in a murine genetic model of Acute Intermittent Porphyria. A comparative study with other porphyrinogenic drugs.

Background: Acute Intermittent Porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBG-D). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG-D activity 50% diminished) mice.

Methods for the detection of reactive oxygen species employed in the identification of plant photosensitizers.

Over the past ten years, alternative methods for the rapid screening of PSs have been developed. In the present work, a study was undertaken to correlate the phototoxicity of plant extracts on either prokaryotic or eukaryotic cells, with the total oxidation status (TOS) as well as with their ability to produce O. Results demonstrated that the extracts containing PSs that were active either on eukaryotic cells or bacteria increased their TOS after illumination, and that there was a certain degree of positive correlation between the extract phototoxic efficacy and TOS levels.

Pleiotropic effects of 5-aminolevulinic acid in mouse brain.

5-Aminolevulinic acid (ALA) seems to be responsible for the neuropsychiatric manifestations of acute intermittent porphyria (AIP). Our aim was to study the effect of ALA on the different metabolic pathways in the mouse brain to enhance our knowledge about the action of this heme precursor on the central nervous system. Heme metabolism, the cholinergic system, the defense enzyme system, and nitric oxide metabolism were evaluated in the encephalon of CF-1 mice receiving a single (40 mg/kg body mass) or multiple doses of ALA (40 mg/kg, every 48 h for 14 days).

Reversal of the Migratory and Invasive Phenotype of Ras-Transfected Mammary Cells by Photodynamic Therapy Treatment.

Photodynamic therapy (PDT) is a non-thermal technique for inducing tumor damage following administration of a light-activated photosensitizing drug (PS). In a previous work we found that PDT induces cytoskeleton changes in HB4a-Ras cells (human mammary breast carcinoma HB4a cells transfected with the RAS oncogene). In the present work we have studied the migratory and invasive features and the expression of proteins related to these processes on HB4a-Ras cells after three successive cycles of PDT using different PSs: 5-aminolevulinic acid (ALA), Verteporfin (Verte), m-tetrahydroxyphenylchlorin (m-THPC), and Merocyanine 540 (MC).

Haplotype Study in Argentinean Variegate Porphyria Patients.

Background/aims: The porphyrias are genetically heterogeneous diseases, and each mutation is exclusive to one or two families. Among the mutations responsible for variegate porphyria in our country, c.1042_1043insT stands out, since it was described only in Argentina and is present in about 40% of genetically diagnosed families.

Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi.

Trypanosoma cruzi is the causative agent of Chagas' disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity.

Acute intermittent porphyria in Argentina: an update.

Porphyrias are a group of metabolic diseases that arise from deficiencies in the heme biosynthetic pathway. A partial deficiency in hydroxymethylbilane synthase (HMBS) produces a hepatic disorder named Acute Intermittent Porphyria (AIP); the acute porphyria is more frequent in Argentina. In this paper we review the results obtained for 101 Argentinean AIP families and 6 AIP families from foreign neighbour countries studied at molecular level at Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP).

Experimental protoporphyria: effect of bile acids on liver damage induced by griseofulvin.

The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris) was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA), dehydrocholic (DHA), chenodeoxycholic, or ursodeoxycholic (URSO).

The role of cytoskeleton and adhesion proteins in the resistance to photodynamic therapy. Possible therapeutic interventions.

It is known that Photodynamic Therapy (PDT) induces changes in the cytoskeleton, the cell shape, and the adhesion properties of tumour cells. In addition, these targets have also been demonstrated to be involved in the development of PDT resistance. The reversal of PDT resistance by manipulating the cell adhesion process to substrata has been out of reach.

The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy.

The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature.

Cytochrome P450 expression in mouse brain: specific isoenzymes involved in Phase I metabolizing system of porphyrinogenic agents in both microsomes and mitochondria.

Brain cytochrome P450 (CYP) metabolizes a variety of drugs to produce their pharmacological effects within the brain. We have previously observed that porphyrinogenic agents altered CYP levels in brain. The aim of this work was to further study the involvement of mice brain mitochondrial and microsomal Phase I drug metabolizing system when porphyrinogenic agents, such as Enflurane, Isoflurane, allylisopropylacetamide, veronal, ethanol, and Griseofulvin were administered.

Indole acetic acid is responsible for protection against oxidative stress caused by drought in soybean plants: the role of heme oxygenase induction.

Objectives This study was focused on the role of indole acetic acid (IAA) in the defense against oxidative stress damage caused by drought in soybean plants and to elucidate whether heme oxygenase-1 (HO-1) and nitric oxide (NO) are involved in this mechanism. IAA is an auxin that participates in many plant processes including oxidative stress defense, but to the best of our knowledge no information is yet available about its possible action in drought stress. Methods To this end, soybean plants were treated with 8% polyethylene glycol (PEG) or 100 µM IAA.

Trypanocidal activity of thioamide-substituted imidazoquinolinone: electrochemical properties and biological effects.

Three thioamide-substituted imidazoquinolinone, which possess a heterocyclic center similar to tryptanthrin and are named C1, C2, and C3, were studied regarding (a) their in vitro anti-Trypanosoma cruzi activity, (b) their cytotoxicity and electrochemical behaviour, and (c) their effect on cell viability, redox state, and mitochondrial function. The assayed compounds showed a significant activity against the proliferative forms, but only C1 showed activity on the trypomastigote form (for C1, IC50  epi = 1.49 μM; IC50  amas = 1.

Functional Characterization of Five Protoporphyrinogen oxidase Missense Mutations Found in Argentinean Variegate Porphyria Patients.

A partial deficiency in protoporphyrinogen oxidase (PPOX) produces the acute/cutaneous (or mixed) variegate porphyria (VP), the third most frequent porphyria in Argentina. This autosomal dominant disorder is clinically characterized by skin lesions and/or acute neurovisceral attacks. The precise diagnosis of patients with a symptomatic VP is essential to provide accurate treatment.

Light fractionated ALA-PDT enhances therapeutic efficacy in vitro; the influence of PpIX concentration and illumination parameters.

Light fractionation, with a long dark interval, significantly increases the response to ALA-PDT in pre-clinical models and in non-melanoma skin cancer. We investigated if this increase in efficacy can be replicated in PAM 212 cells in vitro. The results show a significant decrease in cell survival after light fractionation which is dependent on the PpIX concentration and light dose of the first light fraction.

The role of salicylic acid in the prevention of oxidative stress elicited by cadmium in soybean plants.

The protective action of salicylic acid (SA) pre-treatment on soybean plants before cadmium (Cd) addition was tested. Oxidative stress parameters, such as TBARS formation, glutathione and chlorophyll content, were altered by Cd, instead no differences were observed in plants only pre-treated with SA. Antioxidant enzymes were affected by Cd treatment, while SA protected against these effects.

Antiparasitic Effect of Vitamin B12 on Trypanosoma cruzi.

A nutritional characteristic of trypanosomatid protozoa is that they need a heme compound as a growth factor. Because of the cytotoxic activity of heme and its structural similarity to cobalamins, we have investigated the in vitro and in vivo effect of vitamin B(12) (or cyanocobalamin) on the different forms of Trypanosoma cruzi. Cyanocobalamin showed a marked antiparasitic activity against epimastigotes (50% inhibitory concentration [IC(50)], 2.

Combined chemotherapy and ALA-based photodynamic therapy in leukemic murine cells.

The effects of combined administration of doxorubicin (DOX) and vincristine (VCR), with 5-aminolevulinic acid photodynamic treatment (ALA-PDT), were analyzed in sensitive murine leukemic cell lines (LBR-) and DOX and VCR chemoresistant LBR-D160 and LBR-V160 cell lines. Low doses of DOX and VCR increased anti-cancer effect of ALA-PDT in LBR-cells. Decrease in cell survival was higher when the combination VCR+ALA-PDT was used compared to DOX+ALA-PDT.

Molecular analysis of the UROD gene in 17 Argentinean patients with familial porphyria cutanea tarda: characterization of four novel mutations.

Porphyria cutanea tarda (PCT) is caused by decreased activity of uroporphyrinogen decarboxylase (UROD) in the liver. The disease usually occurs in adulthood and is characterized by cutaneous photosensitivity, hyperpigmentation, skin fragility and hypertrichosis, due to the accumulation of porphyrins produced by oxidation of uroporphyrinogen and other highly carboxylated porphyrinogens overproduced as a result of the enzyme deficiency. PCT is generally sporadic, but about 20-30% of patients have familial-PCT (F-PCT) which is associated with heterozygosity of mutations in the UROD gene.

ALAS1 gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FOXO1 by vanadate in diabetic mice.

Porphyrias are diseases caused by partial deficiencies of haem biosynthesis enzymes. Acute porphyrias are characterized by a neuropsychiatric syndrome with intermittent induction of hepatic ALAS1 (δ-aminolaevulinate synthase 1), the first and rate-limiting enzyme of the haem pathway. Acute porphyria attacks are usually treated by the administration of glucose; its effect is apparently related to its ability to inhibit ALAS1 by modulating insulin plasma levels.

Mice brain nitric oxide synthase response induced by anaesthetics and other porphyrinogenic drugs.

Porphyrias neuropathophysiology could be related to low levels of heme as a cofactor for nitric oxide synthase (NOS). We examined how anaesthetics and other porphyrinogenic agents affect mice NOS activity and expression. Brain response was differential depending on the cellular fraction analyzed.

The role of 5-aminolevulinic acid in the response to cold stress in soybean plants.

In this study, the possibility of enhancing cold stress tolerance of soybean plants (Glycine max L.) by exogenous application of 5-aminolevulinic acid (ALA) was investigated. ALA was added to the Hoagland solution at various concentrations ranging from 0 to 40 μM for 12 h.

Novel null-allele mutations and genotype-phenotype correlation in Argentinean patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism in which decreased activity of ferrochelatase (FECH) leads to accumulation of protoporphyrin IX (PP IX) in red blood cells, plasma, liver, and bile, and increased PP IX excretion in feces. Clinically, EPP is characterized by photosensitivity that begins in early childhood and includes burning, swelling, itching, and painful erythema in sun-exposed areas. Chronic liver disease is an important complication in a minority of EPP patients, and in some cases liver transplantation has been performed.