Posttranslational Nitration of Tyrosine Residues Modulates Glutamate Transmission and Contributes to N-Methyl-D-aspartate-Mediated Thermal Hyperalgesia

Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway—specifically NMDARs, glutamate transporter, and glutamine synthase (GS)—have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP5+ prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly

Cyclic Diarylheptanoids from Corylus avellana Green Leafy Covers: Determination of Their Absolute Configurations and Evaluation of Their Antioxidant and Antimicrobial Activities

The methanol extract of the leafy covers of Corylus avellana, source of the Italian PGI (protected geographical indication) product "Nocciola di Giffoni", afforded two new cyclic diarylheptanoids, giffonins T and U (2 and 3), along with two known cyclic diarylheptanoids, a quinic acid, flavonoid-, and citric acid derivatives. The structures of giffonins T and U were determined as highly hydroxylated cyclic diarylheptanoids by 1D and 2D NMR experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The absolute configurations of carpinontriol B (1) and giffonins T and U (2 and 3) were assigned by comparison of their experimental electronic circular dichroism curves with the TDDFT-predicted curves. The ability of the compounds to inhibit the lipid peroxidation induced by H2O2 and H2O2/Fe(2+) was determined by measuring the concentration of thiobarbituric acid reactive substances. Furthermore, the antimicrobial activity of the methanol extract of leafy covers of C. avellana and of the isolated compounds against the Gram-positive strains Bacillus cereus and Staphylococcus aureus and the Gram-negative strains Escherichia coli and Pseudomonas aeruginosa was evaluated. Carpinontriol B (1) and giffonin U (3) at 40 μg/disk caused the formation of zones of inhibition

The Use of Partial Least Squares–Path Modelling to Understand the Impact of Ambivalent Sexism on Violence-Justification among Adolescents

Gender violence is generally conceived as a phenomenon concerning only adults. Nonetheless, it is also perpetrated within teenagers’ relationships, as many empirical studies have shown. We therefore have focused our attention on a non-probabilistic sample consisting of 400 adolescents living in Naples (Italy), to study the association between sexism and the justification of violent attitudes. Generally, sexism is recognised as a discriminatory attitude towards people, based on their biological sex. However, it is conventional to talk about sexism as a prejudice against women. The Ambivalent Sexism Inventory (ASI) for adolescents was used to evaluate the two dimensions of ambivalent sexism, i.e., hostile sexism (HS) and benevolent sexism (BS). Moreover, the questionnaire regarding attitudes towards diversity and violence (CADV) was administered to assess participants’ attitudes towards violence. A Partial Least Square–Second Order Path Model reveals that girls’ ambivalent sexism is affected more by benevolent sexism than hostile sexism. On the contrary, among boys, hostile sexism has a higher impact. Finally, benevolent sexist girls justify domestic violence more than boys do

Inhibition of spinal oxidative stress by bergamot polyphenolic fraction attenuates the development of morphine induced tolerance and hyperalgesia in mice

Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy

Transient receptor potential melastatin-3 (TRPM3) mediates nociceptive-like responses in Hydra vulgaris

The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamicacid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom