No abstract

The clinical side effects associated with the inhibition of cyclooxygenase enzymes under pathologic conditions have recently raised concerns. A better understanding of neuroinflammatory mechanisms and neuronal survival requires knowledge of cyclooxygenase downstream pathways, especially PGE2 and its G-protein-coupled receptors. In this study, we postulate that EP1 receptor is one of the mechanisms that propagate neurotoxicity and could be a therapeutic target in brain injury. This hypothesis was tested by pretreating C57BL/6 wildtype mice with the EP1 receptor selective agonist ONO-DI-004 and the selective antagonist ONO-8713, followed by striatal unilateral NMDA injection. Results revealed that ONO-DI-004 increased NMDA-induced lesion volume up to 128.7 +/- 12.0%, while ONO-8713 significantly decreased lesion volume to 71.3 +/- 10.9%, as compared to the NMDA-control group. Neurotoxic EP1 receptor properties were also studied using C57BL/6 EP1 receptor knockout (EP1-/-) mice, which revealed a significant decrease to 74.5 +/- 8.2%, as compared to wildtype controls. The protective effect of the antagonist ONO-8713 was also tested in the EP1-/- mice, revealing no additional protection in these mice. Together, these results support the selectivity of ONO-8713 toward EP1 receptor and suggest the neurotoxic role of EP1 receptor. Furthermore, the EP1 receptor role in ischemic brain damage was investigated using a model of middle cerebral artery occlusion (MCAO) and reperfusion. The infarct volume was significantly reduced to 56.9 +/- 11.5% in EP1-/- mice, as compared to wildtype controls. This is the first study that demonstrates that EP1 receptor aggravates neurotoxicity and that modulation of this receptor can determine the outcomes in both excitotoxic and focal ischemic neuronal damage.

Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), are active prostaglandin metabolites exerting a variety of biological effects that may be important in the pathogenesis of neurological diseases. Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain specific deubiquitinating enzyme whose aberrant function has been linked to neurodegenerative disorders. We report that [15d-PGJ 2 ] detected by quadrapole mass spectrometry (MS) increases in rat brain after temporary focal ischemia, and that treatment with 15d-PGJ 2 induces accumulation of ubiquitinated proteins and exacerbates cell death in normoxic and hypoxic primary neurons. 15d-PGJ 2 covalently modifies UCH-L1 and inhibits its hydrolase activity. Pharmacologic inhibition of UCH-L1 exacerbates hypoxic neuronal death while transduction with a TAT-UCH-L1 fusion protein protects neurons from hypoxia. These studies indicate UCH-L1 function is important in hypoxic neuronal death and excessive production of CyPGs after stroke may exacerbate ischemic injury by modification and inhibition of UCH-L1.

This review summarizes the influences of pyrolysis conditions and feedstock types on biochar properties and how biochar properties in turn affect soil properties. Mechanistic evidence of biochar's potential for enhancing crop productivity, carbon sequestration, and nutrient use efficiency are also discussed. The review identifies the knowledge gaps, limitations, and future research directions for large‐scale use of biochar. Both pyrolytic parameters and feedstock types are considered to be the main factors controlling biochar properties such as nutrient content, recalcitrance, and pH. Biochar produced at low temperatures may improve nutrient availability and crop yield in acidic and alkaline soils, whereas high‐temperature biochar may enhance long‐term soil carbon sequestration. Biochar can also improve the efficiency of inorganic and organic fertilizers by enhancing microbial functions and reducing nutrient loss, thereby making nutrients more available to plants. Integration of biochar and chemical or organic fertilizers generally provides for better nutrient management and crop yield in most types of soils. Although biochar can improve degraded soils, it is not a panacea; as such, soil‐ and crop‐specific biochar are needed in order to ensure optimum crop yield and agricultural sustainability.