scholarly journals Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers

2001 ◽  
Vol 178 (S41) ◽  
pp. s107-s119 ◽  
Author(s):  
Husseini K. Manji ◽  
Gregory J. Moore ◽  
Guang Chen
Keyword(s):  
Molecular Mechanisms ◽  
Chronic Administration ◽  
Binding Activity ◽  
Therapeutic Effects ◽  
Activator Protein 1 ◽  
Cellular Mechanisms ◽  
Neuroprotective Effects ◽  
Neuronal Communication ◽  
Dna Binding Activity ◽  
New Research

BackgroundNew research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication.AimTo elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilisers.MethodResults from integrated clinical and laboratory studies are reviewed.ResultsChronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein 1 family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2.ConclusionsThe results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilisers. Additionally, mood stabilisers may exert underappreciated neuroprotective effects.

Differential use of SCL/TAL-1 DNA-binding domain in developmental hematopoiesis

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1056-1067 ◽  
Author(s):  
Mira T. Kassouf ◽  
Hedia Chagraoui ◽  
Paresh Vyas ◽  
Catherine Porcher
Keyword(s):  
Dna Binding ◽  
Molecular Mechanisms ◽  
Binding Activity ◽  
Hematopoietic Stem ◽  
Helix Loop Helix ◽  
Experimental Systems ◽  
Dna Binding Activity ◽  
Independent Functions

Abstract Dissecting the molecular mechanisms used by developmental regulators is essential to understand tissue specification/differentiation. SCL/TAL-1 is a basic helix-loop-helix transcription factor absolutely critical for hematopoietic stem/progenitor cell specification and lineage maturation. Using in vitro and forced expression experimental systems, we previously suggested that SCL might have DNA-binding–independent functions. Here, to assess the requirements for SCL DNA-binding activity in vivo, we examined hematopoietic development in mice carrying a germline DNA-binding mutation. Remarkably, in contrast to complete absence of hematopoiesis and early lethality in scl-null embryos, specification of hematopoietic cells occurred in homozygous mutant embryos, indicating that direct DNA binding is dispensable for this process. Lethality was forestalled to later in development, although some mice survived to adulthood. Anemia was documented throughout development and in adulthood. Cellular and molecular studies showed requirements for SCL direct DNA binding in red cell maturation and indicated that scl expression is positively autoregulated in terminally differentiating erythroid cells. Thus, different mechanisms of SCL's action predominate depending on the developmental/cellular context: indirect DNA binding activities and/or sequestration of other nuclear regulators are sufficient in specification processes, whereas direct DNA binding functions with transcriptional autoregulation are critically required in terminal maturation processes.

Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension

2002 ◽  
Vol 103 (s2002) ◽  
pp. 25S-30S ◽  
Author(s):  
Rita C A TOSTES ◽  
Rhian M TOUYZ ◽  
Gang HE ◽  
Xin CHEN ◽  
Ernesto L. SCHIFFRIN
Keyword(s):  
Dna Binding ◽  
Renal Damage ◽  
Inflammatory Cell ◽  
Binding Activity ◽  
Inflammatory Cell Infiltration ◽  
Macrophage Infiltration ◽  
Activator Protein 1 ◽  
Endothelin 1 ◽  
Dna Binding Activity ◽  
Induced Hypertension

Aldosterone-induced hypertension is associated with renal damage that may be mediated by endothelin-1 (ET-1). We evaluated whether inflammatory cell infiltration and DNA-binding activity of the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) were increased in kidneys from aldosterone-infused rats. The role of ET-1 in these processes was evaluated by treating rats with the ETA-receptor blocker, BMS 182874. Rats were infused with aldosterone (0.75µg/h) via a mini-osmotic pump and were given 1% NaCl in the drinking water in the absence and presence of BMS 182874 or of the aldosterone receptor blocker, spironolactone. Renal sections were used to assess inflammatory cell infiltration, which was identified immunocytochemically using monoclonal antibodies against macrophages (ED1+). Electrophoretic mobility shift assays evaluated the DNA-binding activity of NF-κB and AP-1 in renal tissue. Systolic blood pressure (BP) was increased in the aldosterone-infused group compared with controls (123±6 versus 110±10mmHg, P<0.05). BMS 182874 and spironolactone significantly decreased BP (P<0.05). Macrophage infiltration was increased in the kidneys of aldosterone-infused rats compared with controls. Renal binding activity (arbitrary units) of AP-1, in contrast with that of NF-κB, increased in aldosterone-infused rats compared with control rats (AP-1, 4.2±0.3 versus 1.0±0.1, P<0.05; NF-κB, 1.6±0.5 versus 1.2±0.5). BMS 182874 and spironolactone decreased macrophage infiltration (by 70% and 50% respectively) and AP-1 binding activity (1.0±0.3 and 0.8±0.3 respectively). In conclusion, kidneys from aldosterone-infused rats exhibited macrophage infiltration and increased AP-1 DNA-binding activity. These processes were attenuated by BMS 182874. Our findings suggest that renal damage in aldosterone-dependent hypertension is associated with inflammatory processes that are mediated in part via ET-1.

Protective role of silibinin on matrix metalloproteinase-2 and activator protein-1 on LoVo cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15136-e15136
Author(s):  
C. Lin ◽  
Y. Chen
Keyword(s):  
Colon Cancer ◽  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Binding Activity ◽  
Matrix Metalloproteinase 2 ◽  
Lovo Cell ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
Lovo Cells

e15136 Background: Silibinin, a flavonoid and the major active component of milk thistle, has been as a safe diet supplement for several decades. It has been proved with anti-hepatotoxic properties and pleiotropic anticancer capabilities. Current study aimed to investigate the role of silibinin as potential therapeutic target of colon cancer through antiangiogenesis and its related molecular mechanisms with matrix metalloproteinase- 2 (MMP-2) and activator protein-1 (AP-1). Colon cancer cell line, LoVo cells, treated with a major prognostic factor, interleukin-6 (IL-6), was studied. Methods and Results: By western blot analysis, silibinin suppressed MMP- 2 protein expression in time- and concentration-dependent manners. Furthermore, the inhibitors of JNK/AP-1 binding activity abolished the expression of MMP-2 in IL-6-stimulated LoVo cells, but not PI3K pathways. We also demonstrated that silibinin inhibited IL-6- stimulated LoVo cell migration and further tumor angiogenesis, which similar to the effects from addition with AP-1 inhibitor. By EMSA, the binding activity of AP-1 in LoVo cells was also decreased with silibinin treatment. In addition, the imaging of confocal microscopy revealed that AP-1 presentation was attenuated on IL-6-stimulated LoVo cells plus silibinin treatment. Conclusions: Taken together, these data indicated that silibinin inhibits angiogenesis through the suppression of MMP-2 expression and AP-1 binding activity in colon cancer cells. It suggests a novel anti-metastatic application of silibinin in colon cancer chemoprevention. No significant financial relationships to disclose.

scholarly journals Proteomic changes induced by harmine in human brain organoids reveal signaling pathways related to neuroprotection

2021 ◽  
Author(s):  
Karina Karmirian ◽  
Lívia Goto-Silva ◽  
Juliana Minardi Nascimento ◽  
Marcelo N Costa ◽  
José Alexandre Salerno ◽  
...  
Keyword(s):  
Human Brain ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Therapeutic Potential ◽  
Antioxidant Activities ◽  
Cellular Mechanisms ◽  
Neuroprotective Effects ◽  
Vesicle Cycle ◽  
Neurotrophin Signaling

Harmine is a β-carboline found in Banisteriopsis caapi, a constituent of ayahuasca brew. Ayahuasca is consumed as a beverage in native Americans' sacred rituals and in religious ceremonies in Brazil. Throughout the years, the beneficial effects of ayahuasca to improve mental health and life quality have been reported, which propelled the investigation of its therapeutic potential to target neurological disorders such as depression and anxiety. Indeed, antidepressant effects of ayahuasca have been described, raising the question of which cellular mechanisms might underlie those effects. Previous animal studies describe potential neuroprotective mechanisms of harmine, including anti-inflammatory and antioxidant activities, and neurotrophin signaling activation. However, the cellular and molecular mechanisms modulated by harmine in human models remain less investigated. Here we analyzed the short-term changes in the proteome of human brain organoids treated with harmine using shotgun mass spectrometry. Harmine upregulates proteins related to synaptic vesicle cycle, cytoskeleton-dependent intracellular transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling pathway. In addition, protein expression levels of Akt and phosphorylated CREB were increased after 24 hour-treatment. Our results shed light on the potential mechanisms that may underlie harmine-induced neuroprotective effects.

scholarly journals Interleukin-7 Upregulates the Interleukin-2–Gene Expression in Activated Human T Lymphocytes at the Transcriptional Level by Enhancing the DNA Binding Activities of Both Nuclear Factor of Activated T Cells and Activator Protein-1

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2690-2700 ◽  
Author(s):  
Sonja I. Gringhuis ◽  
Lou F.M.H. de Leij ◽  
Emmy W. Verschuren ◽  
Peter Borger ◽  
Edo Vellenga
Keyword(s):  
T Lymphocytes ◽  
Dna Binding ◽  
Binding Activity ◽  
Transcriptional Level ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activated T Cells ◽  
Dna Binding Activity ◽  
Interleukin 7 ◽  
Activated T Lymphocytes

Abstract In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2–gene regulation in activated T lymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2 –gene regulation. T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor κB (NFκB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal. Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2–mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2–gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFκB and CD28RC, which was confirmed by transfection assays. We also show that the IL-7–induced enhancement of the AP-1–DNA binding activity is not cyclosporin A-sensitive. Since AP-1 is part of the NFAT complex, we conclude that the IL-7–signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.

Sign in / Sign up

Export Citation Format

Share Document