Pubmed (TSA) du 31/05/26
1. Cordone V, Vallese A, Bianchi A, Guiotto A, Pecorelli A, Valacchi G. Impaired NF-κB/Nrf2 Crosstalk in Rett Syndrome. Faseb j. 2026; 40(10): e71929.
Rett syndrome (RTT), caused primarily by mutations in the X-linked MECP2 gene, is a neurodevelopmental disorder marked by systemic alterations, including mitochondrial dysfunction, chronic oxidative stress, and persistent subclinical inflammation. This OxInflammatory state suggests that disruption of redox-inflammatory regulatory pathways may contribute to disease pathophysiology. In this context, NF-κB and Nrf2 represent two important signaling regulators that operate in a coordinated crosstalk to balance inflammatory activation and antioxidant defense. In this study, we explored the functional status of NF-κB/Nrf2 crosstalk in primary dermal fibroblasts derived from RTT patients and healthy controls (CTR). Under basal conditions, RTT fibroblasts exhibited increased nuclear localization of NF-κB p65 and higher levels of acetylated NF-κB, indicating a constitutive inflammatory condition. In contrast, Nrf2 activation was not proportionally enhanced, suggesting an imbalance between inflammatory and antioxidant signaling. Following LPS stimulation, CTR fibroblasts displayed the expected coordinated activation of NF-κB and Nrf2 pathways, along with induction of downstream target genes. RTT fibroblasts, however, failed to activate either pathway and showed blunted transcriptional responses. These findings support the presence of a dysregulated signaling axis consistent with a chronic OxInflammatory state. Analysis of regulatory mechanisms revealed increased basal CBP/p300 levels in RTT cells without a compensatory increase in SIRT1, pointing toward altered acetylation dynamics that may favor persistent NF-κB activity. To mechanistically study the NF-κB/Nrf2 crosstalk, LPS-stimulated cells were treated with the Nrf2 activator sulforaphane (SFN), alone or combined with the NF-κB inhibitor BAY-117082. In RTT fibroblasts, these combined interventions significantly reduced pro-inflammatory cytokine expression and consistently enhanced HMOX1 transcription and HO-1 protein levels. Although nuclear localization changes were modest at the selected time point, downstream gene expression patterns indicated that coordinated modulation of inflammatory and antioxidant pathways can partially rebalance cellular responses. Taken together, our findings provide preliminary evidence that RTT exhibits a dysfunctional NF-κB/Nrf2 regulatory axis characterized by basal inflammatory activation and impaired antioxidant compensation. Modulation of NF-κB signaling, in combination with Nrf2 activation, may represent a promising strategy to counteract the persistent OxInflammatory milieu associated with RTT and warrants further investigation.
Lien vers le texte intégral (Open Access ou abonnement)
2. Yeung JT, Wan P, Chen W. Guanfacine as a Treatment Option for Persistent Mental Restlessness and Deliberate Self-harm Thoughts in a Patient with Attention-deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Borderline Personality Disorder, and Post-traumatic Stress Disorder: Case Report. Clin Psychopharmacol Neurosci. 2026; 24(2): 419-24.
Deliberate self-harm (DSH) in adolescents presents a significant clinical challenge, particularly when compounded by comorbidities such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), borderline personality disorder (BPD), and post-traumatic stress disorder (PTSD). We describe a case of a 16-year-old transgender Māori male with ADHD, ASD traits, BPD, and PTSD, who presented with persistent mental restlessness experienced as intrusive DSH ideation. He had limited benefit and intolerable side effects with atomoxetine but responded to guanfacine modified-release. Guanfacine modified-release (1 mg nocte) treatment coincided with a marked reduction in mental restlessness and intrusive DSH ideation. During the follow-up period, there was a decrease in acute healthcare utilisation. Then the patient self-ceased guanfacine, coinciding with a return of DSH ideation and behaviours. We hypothesise that the ADHD-related mental restlessness was associated with intrusive DSH ideation; amelioration of mental restlessness and self-harm ideation by guanfacine can be interpreted as the ‘dechallenge’ phase of a ‘challenge-dechallenge’ natural experiment. This case provides novel evidence for the potential therapeutic role of guanfacine in mitigating persistent self-harm thoughts, via modulation of mental restlessness and impulsivity. Our observation provides preliminary evidence of the potential benefit of guanfacine in treating DSH, in the context of patients with co-occurring cognitive rigidity, trauma exposure, and emotional dysregulation. This case aligns with emerging evidence for the efficacy of guanfacine for ASD and trauma-related disorders, but is the first – in the existing literature – for ADHD and trauma history in an adolescent with BPD and transgender intersectionality.
