3-磷酸甘油酸脱氢酶促进丝氨酸合成在肿瘤进展中的机制

丝氨酸生物合成途径活性的上调是许多癌症明显的共同特征。该途径的第一种限速酶3-磷酸甘油酸脱氢酶(PHGDH)在黑色素瘤、乳腺癌和肾癌等癌组织中高表达，对肿瘤细胞增殖、转移、侵袭有着重要作用。糖酵解中间产物3-磷酸甘油酸在PHGDH作用下，氧化为磷酸羟基丙酮酸并最终合成丝氨酸。丝氨酸转化为甘氨酸，然后在核苷酸、s-腺苷甲硫氨酸(SAM)和还原型谷胱甘肽(GSH)的合成中起着重要的作用。PHGDH 有望成为肿瘤治疗的新靶点。     

Antioxidant and anti-inflammatory activities of lycopene against 5-fluorouracil-induced cytotoxicity in Caco2 cells

5-fluorouracil (5FU) is widely used to treat colorectal cancer (CC) and its main mechanisms of anticancer action are through generation of ROS which often result in inflammation. Here, we test the effect of Lycopene against 5FU in Caco2 cell line. Caco2 cells were exposed to 3 µg/ml of 5FU alone or with 60, 90, 120 µg/ml of lycopene. This was followed by assessment of cytotoxicity, oxidative stress, and gene expression of inflammatory genes. Our findings showed that Lycopene and 5FU co-exposure induced dose-dependent cytotoxic effect without compromising the membrane integrity based on the LDH assay. Lycopene also significantly enhanced 5FU-induced SOD activity and GSH level compared to control for all mixture concentrations (p < 0.01). Lycopene alone and combination with 5FU-induced expression of IL-1β, TNF-α, and IL-6. Furthermore, IFN-γ expression was significantly enhanced by only mixture of lycopene (90 µg/ml) and 5FU (p < 0.05). In conclusion, Lycopene supplementation with 5FU therapy resulted in improvement in antioxidant parameters such as catalase and GSH levels giving the cell capacity to cope with 5FU-mediated oxidative stress. Lycopene also enhanced IFN-γ expression in the presence of 5FU, which may activate antitumor effects further enhancing the cancer killing effect of 5FU.     

Pérdida visual secundaria a intoxicación inhalatoria y cutánea por metanol y tolueno. A propósito de un caso

Methanol poisoning is often described in the literature, but not transdermal or inhalational poisoning. It usually involves variable multi-organ damage, among which visual, neurological, and gastrointestinal involvement, as well as the metabolic and electrolyte changes that can lead to death. Contact with toluene by occupational or intentional inhalation may also cause neurological abnormalities. This article describes the case of a female patient who was seen in the Emergency Department due to bilateral visual loss secondary to accidental poisoning (inhalation-transdermal) with a solvent containing methanol and toluene. She had a favourable outcome during admission after treatment with ethanol in perfusion and corticosteroids.     

DNA vaccine encoding the moonlighting protein Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) leads to partial protection in a mouse model of human filariasis

River blindness, caused by the filarial parasite Onchocerca volvulus, is a major socio-economic and public health problem in Sub-Saharan Africa. In January 2015, The Onchocerciasis Vaccine for Africa (TOVA) Initiative has been launched with the aim of providing new tools to complement mass drug administration (MDA) of ivermectin, thereby promoting elimination of onchocerciasis in Africa. In this context we here present Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) as a possible DNA vaccine candidate. We report that in a laboratory model for filariasis, immunization with Ov-GAPDH led to a significant reduction of adult worm load and microfilaraemia in BALB/c mice after challenge infection with the filarial parasite Litomosoides sigmodontis. Mice were either vaccinated with Ov-GAPDH.DNA plasmid (Ov-pGAPDH.DNA) alone or in combination with recombinantly expressed Ov-GAPDH protein (Ov-rGAPDH). During the following challenge infection of immunized and control mice with L. sigmodontis, those formulations which included the DNA plasmid, led to a significant reduction of adult worm loads (up to 57% median reduction) and microfilaraemia (up to 94% reduction) in immunized animals. In a further experiment, immunization with a mixture of four overlapping, synthetic Ov-GAPDH peptides (Ov-GAPDHpept), with alum as adjuvant, did not significantly reduce worm loads. Our results indicate that DNA vaccination with Ov-GAPDH has protective potential against filarial challenge infection in the mouse model. This suggests a transfer of the approach into the cattle Onchocerca ochengi model, where it is possible to investigate the effects of this vaccination in the context of a natural host–parasite relationship.     

Conditioned locomotion and place preference elicited by tactile cues paired exclusively with morphine in an open field

A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS–). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS–, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most active when all four quadrants were CS+ and least active when zero or one CS+ quadrant was present. Thus, once an animal approached and made contact with the CS+ it tended to maintain contact with this stimulus and to reduce its approach to and contact with other stimuli. The differentiating features of this version of the CPP technique, as well as the relationship between morphine-induced conditioned locomotion and CPP, are discussed.     

Effects of d-amphetamine injected into the nucleus accumbens on ethanol reinforced behavior

Rats, initiated to self-administer 10% (v/v) ethanol in an operant situation using the sucrose-fading procedure, received bilateral n. accumbens microinjections of d-amphetamine prior to operant sessions. Doses of 4 micrograms, 10 micrograms and 20 micrograms/brain were administered and some animals also received a 4 microgram/brain dose of LY171555. Three different effects were observed: increased, decreased and no change in total session responding. There was no clear relation between injection area in the n. accumbens and type of effect observed. For either an increase or decrease in total session responding, momentary response rates were decreased. Both d-amphetamine and LY171555 produced similar results. The data support the hypothesis that dopamine in the n. accumbens is involved with ethanol reinforced operant responding but in a complex manner.     

Repeated testing attenuates conditioned place preference with cocaine

Cocaine-treated rats acquired a preference for cocaine-associated contextual stimuli (CS) relative to saline-injected control rats. However, when animals were given repeated tests for conditioned place preference intermittent between conditioning trials, they displayed an attenuation in strength of conditioning. This attenuation was not due to pharmacologic tolerance (Experiment 1), but rather reflected a disruption in learning due to exposure to the CS alone (Experiment 2). Like other examples of classical conditioning, the strength of the conditioned response (CR) as assessed by the conditioned place preference model may be influenced by partial reinforcement.     

Soma size and oxidative enzyme activity in normal and chronically stimulated motoneurones of the Cat''s spinal cord

In normal adult cats we measured the density of staining for the activity of succinate dehydrogenase (SDH staining) in ventral horn cells of different sizes. The measurements were restricted to that part of the lumbar ventral horn (L6-L7) which is known to contain motoneurones of the peroneal nerve. A statistically significant tendency was found for the SDH staining to be denser in smaller than in larger neurones within the size range of a motoneurones (soma diameter greater than 40 microns). These results are consistent with recently published evidence for ventral horn cells of rats and qualitatively similar relationships between size and SDH staining have also been observed among skeletal muscle fibres (confirmed for mixed muscle of cat in present study). In hindlimb muscles, size as well as SDH staining are known to be markedly activity-dependent. We tested whether this is the case for peroneal motoneurones as well by analyzing the effects of chronic nerve stimulation on the properties of neurones within the appropriate region of the ventral horn. Prior to the final acute experiment, these cats had been subjected to a left-side dorsal rhizotomy and hemispinalization. By aid of a portable mini-stimulator, the left-side common peroneal nerve was activated by repetitive pulses during 50% of total time per day (intra-activity rate: 10, 20 or 40 Hz). After 8 weeks of such treatment, cell sizes as well as the densities of SDH staining showed hardly any differences between peroneal ventral horn cells of the experimental and control sides of the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)