Systemic L-Buthionine -S-R-Sulfoximine Treatment Increases Plasma NGF and Upregulates L-cys/L-cys2 Transporter and γ-Glutamylcysteine Ligase mRNAs Through the NGF/TrkA/Akt/Nrf2 Pathway in the Striatum.

Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This response might be modulated by a peripheral increment of circulating nerve growth factor (NGF). NGF is an important activator of antioxidant pathways mediated by tropomyosin-related kinase receptor A (TrkA). Here, we report that peripheral administration of BSO increased plasma NGF levels. Additionally, BSO increased NGF levels and activated the NGF/TrkA/Akt pathway in striatal neurons. Moreover, the response in the striatum included an increased transcription of nrf2, gclm, lat1, eaac1, and xct, all of which are involved in antioxidant responses, and L-cys/L-cys2 and glutamate transporters. Using antibody against NGF confirmed that peripheral NGF activated the NGF/TrkA/Akt/Nrf2 pathway in the striatum and subsequently increased the transcription of gclm, nrf2, lat1, eaac1, and xct. These results provide evidence that the reduction of peripheral GSH pools increases peripheral NGF circulation that orchestrates a neuroprotective response in the CNS, at least in the striatum, through the NGF/TrkA/Akt/Nrf2 pathway.

Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione homeostasis via NGF/TrkA and mTOR signaling in the cerebellum.

Glutathione (GSH) is an essential component of intracellular antioxidant systems that plays a primordial role in the protection of cells against oxidative stress, maintaining redox homeostasis and xenobiotic detoxification. GSH synthesis in the brain is limited by the availability of cysteine and glutamate. Cystine, the disulfide form of cysteine is transported into endothelial cells of the blood-brain barrier (BBB) and astrocytes via the system xc-, which is composed of xCT and the heavy chain of 4F2 cell surface antigen (4F2hc). Cystine is reduced inside the cells and the L-type amino acid transporter 1 (LAT1) transports cysteine from the endothelial cells into the brain, cysteine is transported into the neurons through the excitatory amino acid transporter 3 (EAAT3), also known as excitatory amino acid carrier 1 (EAAC1). The mechanistic/mammalian target of rapamycin (mTOR) and neurotrophins can activate signaling pathways that modulate amino acid transporters for GSH synthesis. The present study found that systemic L-buthionine-S-R-sulfoximine (BSO) administration selectively altered GSH homeostasis and EAAT3 levels in the mice cerebellum. Intraperitoneal treatment of mice with 6 mmol/kg of BSO depleted GSH and GSSG in the liver at 2 h of treatment. The cerebellum, but not other brain regions, exhibited a redox response. The mTOR and the neuronal growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathways were activated and lead to an increase in the protein levels of the EAAT3 transporter, which was linked to an increase in the GSH/GSSG ratio and GSH concentration in the cerebellum at 0.5 and 2 h, respectively. Therefore, the cerebellum responds to peripheral GSH depletion via activation of the mTOR and NGF/TrkA pathways, which increase the transport of cysteine for GSH synthesis.

Boron and Coumaphos Residues in Hive Materials Following Treatments for the Control of Aethina tumida Murray.

In the search of alternatives for controlling Aethina tumida Murray, we recently proposed the BAA trap which uses boric acid and an attractant which mimics the process of fermentation caused by Kodamaea ohmeri in the hive. This yeast is excreted in the feces of A. tumida causing the fermentation of pollen and honey of infested hives and releasing compounds that function as aggregation pheromones to A. tumida. Since the boron is the toxic element in boric acid, the aim of this article is to assess the amount of boron residues in honey and beeswax from hives treated with the BAA trap. For this aim, the amount of bioaccumulated boron in products of untreated hives was first determined and then compared with the amount of boron of products from hives treated with the BAA trap in two distinct climatic and soil conditions. The study was conducted in the cities of Padilla, Tamaulipas, and Valladolid, Yucatan (Mexico) from August 2014 to March 2015. The quantity of boron in honey was significantly less in Yucatan than in Tamaulipas; this agrees with the boron deficiency among Luvisol and Leptosol soils found in Yucatan compared to the Vertisol soil found in Tamaulipas. In fact, the honey from Yucatan has lower boron levels than those reported in the literature. The BAA treatment was applied for four months, results show that the BAA trap does not have any residual effect in either honey or wax; i.e., there is no significant difference in boron content before and after treatment. On the other hand, the organophosphate pesticide coumaphos was found in 100% of wax samples and in 64% of honey samples collected from Yucatan. The concentration of coumaphos in honey ranges from 0.005 to 0.040 mg/kg, which are below Maximum Residue Limit (MRL) allowed in the European Union (0.1 mg/kg) but 7.14% of samples exceeded the MRL allowed in Canada (0.02 mg/kg).

The role of amino acid transporters in GSH synthesis in the blood-brain barrier and central nervous system.

Glutathione (GSH) plays a critical role in protecting cells from oxidative stress and xenobiotics, as well as maintaining the thiol redox state, most notably in the central nervous system (CNS). GSH concentration and synthesis are highly regulated within the CNS and are limited by availability of the sulfhydryl amino acid (AA) l-cys, which is mainly transported from the blood, through the blood-brain barrier (BBB), and into neurons. Several antiporter transport systems (e.g., x(c)(-), x(-)(AG), and L) with clearly different luminal and abluminal distribution, Na(+), and pH dependency have been described in brain endothelial cells (BEC) of the BBB, as well as in neurons, astrocytes, microglia and oligodendrocytes from different brain structures. The purpose of this review is to summarize information regarding the different AA transport systems for l-cys and its oxidized form l-cys(2) in the CNS, such as expression and activity in blood-brain barrier endothelial cells, astrocytes and neurons and environmental factors that modulate transport kinetics.