Mood disorders are chronic, recurrent diseases characterized by changes in mood and emotions. The most common are major depressive disorder (MDD) and bipolar disorder (BD). Molecular biology studies have indicated an involvement of the immune system in the pathogenesis of mood disorders, and showed their correlation with altered levels of inflammatory markers and energy metabolism. Previous reports, including meta-analyses, also suggested the role of microglia activation in the M1 polarized macrophages, reflecting the pro-inflammatory phenotype. Lithium is an effective mood stabilizer used to treat both manic and depressive episodes in bipolar disorder, and as an augmentation of the antidepressant treatment of depression with a multidimensional mode of action. This review aims to summarize the molecular studies regarding inflammation, microglia activation and energy metabolism changes in mood disorders. We also aimed to outline the impact of lithium on these changes and discuss its immunomodulatory effect in mood disorders.

Despite lithium’s presence in modern psychiatry for three-quarters of a century, the mechanisms of its therapeutic action have not been fully elucidated. This article presents the evolution of the views on these mechanisms, and both the old and new findings are discussed. Among the old mechanisms, lithium’s effect on the purinergic system; electrolyte metabolism; membrane transport; and second messenger systems, namely, cyclic nucleotide and phosphatidylinositol (PI), glycogen synthase kinase-3beta (GSK-3β), brain-derived neurotrophic factor, and neurotransmitters, are discussed. The new data were obtained from in vitro studies, molecular biology, and genetic research. They showed the effects of lithium on the immune system, biological rhythms, telomere functions, and mitochondria. In this article, each lithium mechanism is considered in the light of its association with the pathogenesis of bipolar disorder or/and as a marker of the lithium response. Although not exhaustive, this review elucidates the multiple potential mechanisms of lithium action. It was also observed that many seemingly “old” mechanisms have experienced a resurgence in research conducted during the 21st century. Additionally, many studies converged on the previously postulated mechanisms of lithium inhibiting GSK-3β and PI.

Objective: In mood disorders chronic stress contributes to decreased glucocorticoid receptor signaling in the brain and resistance in the periphery. We hypothesized that aberrant glucocorticoid receptor function may result from genetic predisposition and that decreased GR signaling in the brain correlates with the expression of genes regulating GR complex formation. Methods: We performed the association analysis of 698 patients: 490 patients with bipolar disorder and 208 patients with major depressive disorder and 564 control subjects. We genotyped 11 variants using TaqMan assays. Gene expression in the brain tissue was done in male Wistar rats after chronic mild stress protocol. The SRSF5 serum concentration was performed using ELISA. Data were analyzed in Statistica and GraphPad. Results: We found an association of STIP1 and SRSF5 variants with major depressive disorder and BAG1 variant with bipolar disorder. Gene expression analysis in a rat model of depression confirmed significant changes in the expression of SRSF5, BAG1, and FKBP4 in the brain. For SRSF5, we observed significantly increased expression in the serum of depressed females and male rats exposed to chronic stress. Conclusions: Our results indicate the involvement of genes associated with GR function, SRSF5, BAG1, and FKBP4 with susceptibility to mood disorders.

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.

Knowledge of the tumor microenvironment is crucial for developing an effective strategy to treat cancer. Recently, anticancer therapies targeting macrophages have been intensively investigated. Increased understanding of the importance of the tumor microenvironment has led to the development of three‑dimensional (3D) in vitro tumor models. However, established techniques for studying tumor‑associated macrophages in vitro are limited. We have previously characterized a 3D breast cancer model consisting of breast cancer cells and fibroblasts cocultured on a silk scaffold. In the present study, the influence of this model on macrophage polarization was investigated. The expression of macrophage markers was studied using reverse transcription‑quantitative PCR and flow cytometry. The activity of nitric oxide synthase and arginase in macrophages was also measured. The presented model appeared to induce the polarization of macrophages towards an M2 phenotype. In this 3D tumor model, the in vivo behavior of macrophages could be reproduced. This model may be beneficial for the study of tumor biology and for screening drugs.