Sex differences in children's cognitive functions and phthalates exposure: a meta-analysis.

BACKGROUND: Phthalates exposure might affect children's intelligence development. This study aimed to determine (1) whether sex and age affect cognitive function and (2) whether sex differences in cognitive performance are wider with higher phthalate concentrations. METHODS: Data were collected from PubMed (1998-2022), PROQUEST (1997-2022), and SpringerLink (1995-2022). The study followed the PRISMA process. The included articles were followed by PECO framework. The GRADE applied to assess the certainty of evidence. Of 2422 articles obtained, nine were selected using inclusion criteria. The random-effects model was used to estimate the pooled effects. RESULTS: Our meta-regression indicated a significant difference between sex differences with age at phthalate concentration assessment (ß = -0.25; 95% CI = -0.47, -0.03) and MEHP concentration (ß = -0.20; 95% CI = -0.37, -0.03). CONCLUSIONS: The limitation of the current article is it only provides information on intelligence level rather than other aspects of cognitive function. Thus, the sequelae of phthalate exposure on attention and executive function are still unclear. Our analysis shows significant difference between sex differences in cognitive function scores associated with age at phthalate concentration assessment. Girls might be more resilient in cognitive function at a younger age or during lower concentrations of phthalates metabolites. IMPACT: This is the first meta-analysis to evaluate the pooled estimates of sex differences in objective cognitive functions among children with phthalate exposure. The female might be a protective factor when exposed to toxic plasticizers while the concentration is low. This study captures the possible role of sex in cognitive functioning and plasticizer exposure through a meta-analysis of children's sex, cognitive scores, and plasticizer exposure.

Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells.

Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates' effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates' neuroprotection mechanism. Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.

Fenamates inhibit human sodium channel Nav1.7 and Nav1.8.

Fenamates are N-substituted anthranilic acid derivatives, clinically used as nonsteroidal anti-inflammatory drugs (NSAIDs) in fever, pain and inflammation treatments. Previous studies have shown that they are also modulators of diverse ion channels, exhibiting either activation or inhibitory effects. However, the effects of fenamates on sodium channel subtypes are still unknown. In this study, fenamates, including mefenamic acid, flufenamic acid and tolfenamic acid, were examined by whole-cell patch clamp techniques on the sodium channels hNav1.7 and hNav1.8, which are closely associated with pain. The results showed that the mefenamic acid, flufenamic acid, and tolfenamic acid inhibited the peak currents of hNav1.7 and hNav1.8 in CHO cells stably expressing hNav1.7 and hNav1.8. However, much lighter inhibition effects of hNav1.8 were registered in the experimental system. Furthermore, the mefenamic acid, flufenamic acid and tolfenamic acid significantly affected the inactivation processes of hNav1.7 and hNav1.8 with I-V curves left-shifted to hyperpolarized direction. These data indicate that the inhibition effects of Nav1.7 and Nav1.8 by mefenamic acid, flufenamic acid and tolfenamic acid might contribute to their analgesic activity in addition to their inhibition of cyclooxygenase. These findings provide a basis for further studies in the discovery of other potential targets for NSAIDs.