Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl‑XL, bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment.

Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal transduction is hyperactive. The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons. Dopamine affects the phosphorylation of CREB via G protein-coupled receptors. Neurotrophins, such as brain derived growth factor (BDNF), are critical regulators during neurodevelopment and synaptic plasticity. The CREB is one of the major regulators of neurotrophin responses since phosphorylated CREB binds to a specific sequence in the promoter of BDNF and regulates its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the brain of individuals suffering from schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. The CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and the pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression, and biological functions in the brain and its interaction with dopamine signaling, neurotrophins, and susceptibility genes for schizophrenia. Animal models in which CREB function is modulated, by either overexpression of the protein or knocked down through gene deletion/mutation, implicating CREB in schizophrenia and antipsychotic drugs efficacy are also discussed. Targeting research and drug development on CREB could potentially accelerate the development of novel medications against schizophrenia.

We established a mouse model of cardiac dysfunction due to myocardial infarction (MI). For this we ligated the left anterior descending coronary artery in male C57BL/6J mice and assessed healing and left ventricular (LV) remodelling at 1, 2 and 4 days and 1, 2 and 4 weeks after MI. Echocardiography was performed at 1 and 2 weeks and 1, 2, 4 and 6 months after MI. We found that neutrophil infiltration of the infarct border was noticeable at 1-2 days. Marked macrophage infiltration occurred at day 4, while lymphocyte infiltration was apparent at 7-14 days. Massive proliferation of fibroblasts and collagen accumulation began by day 7-14, and scar formation was completed by day 21. LV diastolic dimension increased markedly at 2 weeks and remained at the same level thereafter. LV shortening fraction decreased significantly at 2 weeks and then slowly decreased. In non-infarcted areas of the LV, myocyte cross-sectional area and interstitial collagen fraction increased progressively, reaching a maximum at 4 months. This study provides important qualitative and quantitative information about the natural history of cardiac remodelling after MI in mice. Experimental Physiology (2002) 87.5, 547-555. 2385

Abstract-Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI). N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7Ϯ0.9 to 15.0Ϯ0.7 g/mg and in the reversal group from 22.6Ϯ2. , PϽ0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function. Key Words: rat Ⅲ myocardial infarction Ⅲ cardiac function Ⅲ collagen Ⅲ macrophages Ⅲ transforming growth factor-␤ N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. Ac-SDKP is released from its precursor thymosin-␤ 4 , which is present in most cells. 1 It inhibits pluripotent hematopoietic stem cell and hepatocyte proliferation by halting entry into the S phase of the cell cycle, maintaining cells in the G 0 /G 1 phase and thereby helping control their proliferation. [2][3][4] We have shown that in vitro Ac-SDKP inhibited cardiac fibroblast proliferation and collagen synthesis, 5 while in vivo it prevented collagen deposition in the left ventricle (LV) and kidneys in rats with aldosterone-salt hypertension and renovascular hypertension. 5,6 This decrease in collagen deposition was associated with a reduced number of proliferating cell nuclear antigen (PCNA)-positive cells, a marker of cell proliferation. These effects of Ac-SDKP occurred without changes in blood pressure or cardiomyocyte hypertrophy. Our studies suggest that one of the mechanisms by which Ac-SDKP prevents fibrosis is by inhibiting fibroblast proliferation and collagen synthesis. It is also known that inflammation plays a central role in the pathogenesis of interstitial and perivascular cardiac fibrosis in heart failure (HF) post-myocardial infarction (MI). Fibrosis is often co-localized with macrophages, which release cytokines such as transforming growth factor-␤ (TGF-␤) that play a crucial role in myocardial fibrosis. 7 There is evidence that Ac-SDKP inhibits TGF-␤ signal transduction through suppression of Smad2 phosphorylation. 8,9 However, it is not known whether it also inhibits the expression of TGF-␤.In the present study,...

Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126EC−/−), and miR-126 knockout control (miR-126fl/fl) mice were subjected to distal middle cerebral artery occlusion (dMCAo) (n = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126EC−/− mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126EC−/− (miR-126EC−/−EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126fl/fl (miR-126fl/fl-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126fl/fl-EC-Exo exhibited significantly decreased hypertrophy than with miR-126EC−/−EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice.