The trans-sulfuration pathway is a biochemical mechanism that links methionine metabolism to the biosynthesis of cellular redox-controlling molecules, like cysteine, glutathione, and taurine. While there is some knowledge about the metabolic intermediates and enzymes that participate in trans-sulfuration, little is known about the physiological importance of this mechanism. Deficiencies within the trans-sulfuration pathway induces (i) the generation of reactive species of oxygen (ROS) and halogens (RHS), (ii) homocyst(e)ine accumulation, and (iii) the synthesis of proinflammatory molecules by macrophages, and contribute to humans pathologies like atherosclerosis and tumor development. In this review we outline the role of this biochemical pathway in tumor development and analyze current findings on the role of trans-sulfuration in mammalian physiology. The potential relationship between chronic inflammation, and tumor and atherosclerotic development are discussed.

on the effects of cancer chemotherapy on cognitive function in rodent models. Given the increasing concern about cognitive dysfunction in patients receiving chemotherapy, the development of animal models to characterize chemotherapy-induced cognitive impairment has been proposed as a priority for future research (2, 3). Unexpectedly, Lee et al. (1) found an enhancement of both memory and hippocampal synaptic plasticity following several weeks of treatment with cyclophosphamide in rats.We too have used rodent models to investigate the cognitive effects of cyclophosphamide. In contrast to the findings reported by Lee et al. (1), we have observed a transient memory impairment following cyclophosphamide administration in mice. In our experiments, male CF1 mice (70-90 days of age) were trained and tested in step-down inhibitory avoidance conditioning, a type of emotionally motivated, hippocampus-dependent memory task where animals learn to associate a location in the training apparatus with a footshock. Inhibitory avoidance training was carried out as described previously (4). Either 1 day or 1 week before behavioral training, animals were given a systemic injection of cyclophosphamide (8, 40, or 200 mg/kg, i.p.). Control animals were injected with saline. Mice treated with cyclophosphamide at 40 or 200 mg/kg 1 day before training showed significant impairment of 24-hour memory retention when compared with control animals [mean F SE retention test latencies (seconds) were 61.30 F 20.93 in the control group, 80.91 F 25.02 in the group treated with 8 mg/kg cyclophosphamide, 22.0 F 12.02 in the group treated with 40 mg/kg cyclophosphamide, and 12.36 + 2.87 in the group treated with 200 mg/kg cyclophosphamide; both Ps < 0.01 compared with the control group with two-tailed Mann-Whitney U tests; n = 10-11 animals per group]. There was no significant difference among groups in training performance [overall mean F SE training trial latency (seconds) was 12.77 F 1.46; P = 0.16]. A control experiment showed that cyclophosphamide did not affect open field behavior (4), indicating that the impairing effects of cyclophosphamide on inhibitory avoidance could not be attributed to drug-induced alterations in locomotion, motivation, or anxiety (data not shown). Systemic administration of cyclophosphamide (8, 40, or 200 mg/kg, i.p.) did not affect inhibitory avoidance memory when given 1 week before training (data not shown).Our results show that a single administration of cyclophosphamide induces memory impairment in a mice model of aversive conditioning. Further studies are required to characterize cognitive deficits induced by cancer chemotherapy in animal models and investigate the mechanisms underlying the differential effects of cyclophosphamide on memory in different experimental paradigms. In Response: In their Letter to the Editor, Reiriz et al. have questioned the generalization of results that we recently presented about a rodent model to assess cognitive impairments induced by cyclophosphamide and 5-fluorouracil (1). In ...

Gastric cancer is the leading cause of cancer-related death worldwide, and treatment options include surgery and chemotherapy. Because of its prevalence, chemotherapy for gastric cancer treatment represents an active area of pharmacology research, and different small compounds have been used as single treatments or in combination therapy. Unfortunately, chemoresistance is a common phenomenon in gastric cancer cells, and the current arsenal of small compounds used in chemotherapy is not effective for long periods of treatment. Thus, to understand how gastric cancer cells develop chemoresistance and also to find new protein targets and small compounds for gastric cancer treatment, a systems pharmacology-based study was performed using the proteomic and small compounds-protein interaction data available for Homo sapiens. A major physical protein-protein and chemo-protein interaction (PPPI-PCPI) network was obtained, and five subnetworks representing different biological processes were observed. Interestingly, the small compounds currently used to treat gastric cancer converge on the same biological processes, potentially resulting in the development of chemoresistance. This analysis was followed by a network centrality study, which allows for selection of protein targets and/or small compounds, termed bottlenecks, that are defined as central nodes. The bottlenecks control the flow of biological information within the network, and their disruption can break the entire network into small components. From ten major bottlenecks observed within the network, seven bottlenecks represent new protein targets that are suitable for the development of new combinatory drug regimens for gastric cancer treatment.

Biological models have long been used to establish the cytotoxicity and cytostaticity of natural and/or synthetic chemical compounds. Current assay techniques, however, typically require the use of expensive technological equipment or chemical reagents, or they lack adequate testing sensitivity. The poissoner quantitative drop test (PQDT) assay is a sensitive, inexpensive and accurate method for evaluation of cytotoxicity and/or cytostatic effects of multiple chemical compounds in a single experiment. In this study, the sensitivity of the PQDT assay was evaluated in a wild-type Saccharomyces cerevisiae strain using 4-nitroquinoline-N -oxide (4-NQO) and methyl methanesulfonate (MMS), both cytotoxic and genotoxic standard compounds, and cytostatic 5-fluorouracil, an antitumoral drug. Yeast cell colony growth was measured in culture media containing increasing concentrations of the three chemical agents. The results showed that the PQDT assay was able to clearly differentiate the cytotoxic effect of 4-NQO and MMS from the cytostatic effect of 5-fluorouracil. Interestingly, the cytostatic effect of 5-fluorouracil followed an exponential decay curve with increasing concentrations, a phenomenon not previously described for this drug. The PQDT assay, in this sense, can be applied not only for cytotoxic/ cytostatic assays, but also for pharmacodynamic studies using Saccharomyces cerevisiae as a model. Cellular viability following DNA damage has been a topic of intense research in fields, such as genotoxicity, toxicology, carcinogenesis and cancer therapy [1]. Microorganism models can be used to evaluate cellular viability, because they can be easily and inexpensively cultured in the laboratory. Additionally, their small size, simple morphology and large surface area in relation to their size give microorganisms greater sensitivity than more complex organisms [2]. The yeast Saccharomyces cerevisiae is a model eukaryotic microorganism with a short generation time and very simple growth requirements. The molecular biology and genetics of this organism are well established. Mutants can be easily constructed and are commercially available, and plasmids and promoters for gene expression are well developed [3]. As such, Saccharomyces cerevisiae has been used extensively as a model organism for the study of mammalian diseases and pathways and for evaluation of toxic compounds [4], such as genotoxic and cytotoxic agents.Yeast cell colony growth can be monitored on agar plates containing dilutions of toxic agents to establish cytotoxicity/ cytostaticity of a compound [5]. Many toxic compounds introduce DNA damage and cause formation of bulky lesions that block DNA replication and/or RNA transcription, leading to cell cycle arrest and the inability of the cells to form colonies [6]. Current colony counting techniques and methods used to measure the size of yeast colonies have drawbacks that include: (i) inadequate sensitivity to determine the effect of low doses of cytotoxic/cytostatic compounds; (ii) high expense due to...