👤 Maja Milanovic

Major depressive disorder (MDD) continues to be a primary cause of disability globally, with a significant number of patients exhibiting resistance to standard pharmacological and psychotherapeutic interventions. In recent years, non-invasive brain stimulation techniques, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have emerged as promising therapies for treatment-resistant MDD. A comprehensive search was performed in PubMed, which included all studies published over the last ten years. Eligible studies encompassed both animal models and clinical investigations. This review provides a comparative overview of transcranial electrical stimulation modalities, with a focus on their mechanisms of action, clinical efficacy, and underlying neurobiological mechanisms. We pay particular attention to the role of the neurotrophin system, specifically brain-derived neurotrophic factor (BDNF), in mediating the treatment effects of transcranial stimulation. Recent findings indicate that neuromodulation could improve neuroplasticity by increasing BDNF levels and associated signaling pathways, which may help stabilize mood and enhance the improvement of individuals with MDD. A more profound understanding of these mechanisms could lead to more precise, biomarker-driven interventions. Further research is essential to elucidating the long-term effects of brain stimulation on neurotrophin levels and to creating more individualized treatment strategies. Show less

Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on healthy long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B cells in an IL-21-dependent in vitro PC differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased the cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody therapies by increasing CD38 expression on tumor cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared with that on healthy PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME. Show less

The formation of amyloid-ß peptides (Aß), that accumulate in Alzheimer's disease (AD) brains, involves proteolytic processing of the amyloid precursor protein (APP) firstly by ß-secretase (BACE1). Since BACE1 cleaves a plethora of other substrates, in this work we investigated whether the proteolysis and/or distribution of other BACE1 substrates, such as seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), is altered in AD. To test this we used 5xFAD mouse model brains that show an early accumulation of Aß plaques already at 2-months of age. Here we show for the first time that accumulation of BACE1 in peri-plaque regions and its enhanced levels in AD brains does not affect proteolysis of BACE1 substrates other than APP, such as Sez6 and Sez6L. We observed altered distribution of Sez6 and Sez6L in the area of Aß plaques in 5xFAD brains which is distinct to that of APP, BACE1 and/or LAMP1, suggesting different localization and/or function of these BACE1 substrates. While it is necessary to further elucidate the potential role that this may play in the course of AD, it is likely that Aß-targeted therapies may have beneficial effects against accumulation and/or altered distribution of BACE1 and its substrates, in addition to APP. Show less