Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
- MeSH
- bipolární porucha * farmakoterapie genetika MeSH
- celogenomová asociační studie MeSH
- fokální adheze MeSH
- fosfatidylinositol-3-kinasy genetika MeSH
- lidé MeSH
- lithium * farmakologie terapeutické užití MeSH
- multiomika MeSH
- protoonkogenní proteiny c-akt genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Periodontal disease is a significant burden for oral health, causing progressive and irreversible damage to the support structure of the tooth. This complex structure, the periodontium, is composed of interconnected soft and mineralised tissues, posing a challenge for regenerative approaches. Materials combining silicon and lithium are widely studied in periodontal regeneration, as they stimulate bone repair via silicic acid release while providing regenerative stimuli through lithium activation of the Wnt/β-catenin pathway. Yet, existing materials for combined lithium and silicon release have limited control over ion release amounts and kinetics. Porous silicon can provide controlled silicic acid release, inducing osteogenesis to support bone regeneration. Prelithiation, a strategy developed for battery technology, can introduce large, controllable amounts of lithium within porous silicon, but yields a highly reactive material, unsuitable for biomedicine. This work debuts a strategy to lithiate porous silicon nanowires (LipSiNs) which generates a biocompatible and bioresorbable material. LipSiNs incorporate lithium to between 1% and 40% of silicon content, releasing lithium and silicic acid in a tailorable fashion from days to weeks. LipSiNs combine osteogenic, cementogenic and Wnt/β-catenin stimuli to regenerate bone, cementum and periodontal ligament fibres in a murine periodontal defect.
- MeSH
- beta-katenin * MeSH
- křemík farmakologie MeSH
- kyselina křemičitá farmakologie MeSH
- lithium farmakologie MeSH
- myši MeSH
- nanodráty * MeSH
- poréznost MeSH
- zubní cement (tkáň) MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Lithium is an effective mood stabilizer, but the mechanism of its therapeutic action is not well understood. We investigated the effect of lithium on the circadian clock located in the ventricle barrier complex containing the choroid plexus (CP), a part of the glymphatic system that influences gross brain function via the production of cerebrospinal fluid. The mPer2Luc mice were injected with lithium chloride (LiCl) or vehicle, and their effects on the clock gene Nr1d1 in CP were detected by RT qPCR. CP organotypic explants were prepared to monitor bioluminescence rhythms in real time and examine the responses of the CP clock to LiCl and inhibitors of glycogen synthase kinase-3 (CHIR-99021) and protein kinase C (chelerythrine). LiCl affected Nr1d1 expression levels in CP in vivo and dose-dependently delayed the phase and prolonged the period of the CP clock in vitro. LiCl and CHIR-99021 had different effects on 1] CP clock parameters (amplitude, period, phase), 2] dexamethasone-induced phase shifts of the CP clock, and 3] dynamics of PER2 degradation and de novo accumulation. LiCl-induced phase delays were significantly reduced by chelerythrine, suggesting the involvement of PKC activity. The effects on the CP clock may be involved in the therapeutic effects of lithium and hypothetically improve brain function in psychiatric patients by aligning the function of the CP clock-related glymphatic system with the sleep-wake cycle. Importantly, our data argue for personalized timing of lithium treatment in BD patients.
- MeSH
- cirkadiánní hodiny * MeSH
- cirkadiánní proteiny Period genetika MeSH
- cirkadiánní rytmus genetika MeSH
- lithium farmakologie MeSH
- myši MeSH
- plexus chorioideus metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- amisulprid aplikace a dávkování farmakologie terapeutické užití MeSH
- antidepresiva * škodlivé účinky MeSH
- antipsychotika škodlivé účinky MeSH
- bolesti zad komplikace MeSH
- depresivní poruchy farmakoterapie komplikace MeSH
- krvácení chemicky indukované prevence a kontrola MeSH
- lidé středního věku MeSH
- lidé MeSH
- lithium * farmakokinetika farmakologie terapeutické užití MeSH
- nenasazení léčby MeSH
- perioperační péče metody MeSH
- poruchy osobnosti farmakoterapie komplikace MeSH
- pregabalin terapeutické užití MeSH
- venlafaxin hydrochlorid farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Lithium is regarded as a unique therapeutic agent for the management of bipolar disorder (BD). In efforts to explain the favourable effects of lithium in BD, a wide range of mechanisms was suggested. Among those, the effect of clinically relevant concentrations of lithium on the plasma membrane was extensively studied. However, the biophysical properties of brain membranes isolated from experimental animals exposed to acute, short-term and chronic lithium have not been performed to-date. In this study, we compared the biophysical parameters and level of lipid peroxidation in membranes isolated from forebrain cortex (FBC) of therapeutic lithium-treated and/or sleep-deprived rats. Lithium interaction with FBC membranes was characterized by appropriate fluorescent probes. DPH (1,6-diphenyl-1,3,5-hexatriene) and TMA-DPH (1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulphonate) were used for characterization of the hydrophobic lipid core and Laurdan (6-dodecanoyl-2-dimethylaminonaphthalene) for the membrane-water interface. Lipid peroxidation was determined by immunoblot analysis of 4-HNE-(4-hydroxynonenal)-protein adducts. The organization of polar head-group region of FBC membranes, measured by Laurdan generalized polarization, was substantially altered by sleep deprivation and augmented by lithium treatment. Hydrophobic membrane interior characterized by steady-state anisotropy of DPH and TMA-DPH fluorescence was unchanged. Chronic lithium had a protective effect against peroxidative damage of membrane lipids in FBC. In summary, lithium administration at a therapeutic level and/or sleep deprivation as an animal model of mania resulted in changes in rat FBC membrane properties.
- MeSH
- fluidita membrány účinky léků MeSH
- krysa rodu rattus MeSH
- lipidové dvojvrstvy metabolismus MeSH
- lithium farmakologie MeSH
- membránové lipidy metabolismus MeSH
- peroxidace lipidů účinky léků MeSH
- přední mozek účinky léků metabolismus MeSH
- spánková deprivace metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antidepresiva terapeutické užití MeSH
- bipolární porucha * farmakoterapie MeSH
- hodnocení léčiv MeSH
- lidé MeSH
- lithium * farmakologie terapeutické užití MeSH
- nežádoucí účinky léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodníky MeSH
- MeSH
- antidepresiva farmakologie terapeutické užití MeSH
- časná diagnóza MeSH
- glycin farmakologie terapeutické užití MeSH
- kognitivní remediace metody MeSH
- lidé MeSH
- lithium farmakologie terapeutické užití MeSH
- magnetická rezonanční tomografie metody MeSH
- nenasycené mastné kyseliny farmakologie terapeutické užití MeSH
- prodromální symptomy MeSH
- schizofrenie * diagnostické zobrazování farmakoterapie patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.
- MeSH
- bipolární porucha krev diagnóza farmakoterapie MeSH
- homeostáza telomer účinky léků fyziologie MeSH
- lidé MeSH
- lithium farmakologie terapeutické užití MeSH
- telomery účinky léků fyziologie MeSH
- výsledek terapie MeSH
- zkracování telomer účinky léků fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The effect of long-term exposure of live cells to lithium cations (Li) was studied in HEK293 cells cultivated in the presence of 1mM LiCl for 7 or 21days. The alteration of Na+/K+-ATPase level, protein composition and biophysical state of plasma membrane was determined with the aim to characterize the physiological state of Li-treated cells. METHODS: Na+/K+-ATPase level was determined by [3H]ouabain binding and immunoblot assays. Overall protein composition was determined by 2D electrophoresis followed by proteomic analysis by MALDI-TOF MS/MS and LFQ. Li interaction with plasma membrane was characterized by fluorescent probes DPH, TMA-DPH and Laurdan. RESULTS: Na+/K+-ATPase was increased in plasma membranes isolated from cells exposed to Li. Identification of Li-altered proteins by 2D electrophoresis, MALDI-TOF MS/MS and LFQ suggests a change of energy metabolism in mitochondria and cytosol and alteration of cell homeostasis of calcium. Measurement of Laurdan generalized polarization indicated a significant alteration of surface layer of isolated plasma membranes prepared from both types of Li-treated cells. CONCLUSIONS: Prolonged exposure of HEK293 cells to 1mM LiCl results in up-regulation of Na+/K+-ATPase expression, reorganization of overall cellular metabolism and alteration of the surface layer/polar head-group region of isolated plasma membranes. GENERAL SIGNIFICANCE: Our findings demonstrate adaptation of live HEK293 cell metabolism to prolonged exposure to therapeutic concentration of Li manifested as up-regulation of Na+/K+-ATPase expression, alteration of protein composition and change of the surface layer of plasma membrane.
- MeSH
- buněčná membrána účinky léků metabolismus MeSH
- buněčné linie MeSH
- cytosol účinky léků metabolismus MeSH
- energetický metabolismus účinky léků MeSH
- HEK293 buňky MeSH
- lidé MeSH
- lithium farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- ouabain farmakologie MeSH
- proteomika metody MeSH
- sodíko-draslíková ATPasa metabolismus MeSH
- upregulace účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
