Carnitine-Induced Senescence in Glioblastoma Cells.

Carnitine-induced senescence in glioblastoma cells.

Filed under: Drug and Alcohol Rehabilitation

Exp Ther Med. 2012 Jul; 4(1): 21-25
Yamada S, Matsuda R, Nishimura F, Nakagawa I, Motoyama Y, Park YS, Nakamura M, Nakase H, Ouji Y, Yoshikawa M

Carnitine is essential for lipid metabolism in cells and is known to possess antioxidant properties. Previous reports have suggested that antioxidants are able to induce senescence in glioblastoma cells, consequently, in the present study, we investigated the effect of carnitine on glioblastoma cells. Under conditions of hyponutrition (undernutrition), the proliferation of glioblastoma cells was attenuated and the level of intracellular carnitine was increased. Glioblastoma cell proliferation was also attenuated in cultures that were supplemented with exogenous carnitine, where the induction of senescence was detected by senescence-associated ?-gal (SA-?-gal) staining. However, there was no evidence of the induction of apoptosis. These effects were not detected when cells were cultured with carnitine plus an inhibitor of p38 mitogen-activated protein kinase (MAPK). It, therefore, appears that carnitine has antioxidant actions in normal cells but induces senescence, which may be regarded as an opposite phenomenon, in glioblastoma cells. Senescence has been reported in cells exposed to temozolomide, which is a standard drug used for the treatment of glioblastoma. Carnitine could, therefore, represent an attractive alternative therapy for glioblastoma.
HubMed – drug


Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets.

Filed under: Drug and Alcohol Rehabilitation

Front Endocrinol (Lausanne). 2012; 3: 111
Ulven T

The deorphanization of the free fatty acid (FFA) receptors FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), GPR84, and GPR120 has made clear that the body is capable of recognizing and responding directly to nonesterified fatty acid of virtually any chain length. Colonic fermentation of dietary fiber produces high concentrations of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, a process which is important to health. The phylogenetically related 7-transmembrane (7TM) receptors free fatty acid receptor 2 (FFA2) and FFA3 are activated by these SCFAs, and several lines of evidence indicate that FFA2 and FFA3 mediate beneficial effects associated with a fiber-rich diet, and that they may be of interest as targets for treatment of inflammatory and metabolic diseases. FFA2 is highly expressed on immune cells, in particular neutrophils, and several studies suggest that the receptor plays a role in diseases involving a dysfunctional neutrophil response, such as inflammatory bowel disease (IBD). Both FFA2 and FFA3 have been implicated in metabolic diseases such as type 2 diabetes and in regulation of appetite. More research is however required to clarify the potential of the receptors as drug targets and establish if activation or inhibition would be the preferred mode of action. The availability of potent and selective receptor modulators is a prerequisite for these studies. The few modulators of FFA2 or FFA3 that have been published hitherto in the peer-reviewed literature in general have properties that make them less than ideal as such tools, but published patent applications indicate that better tool compounds might soon become available which should enable studies critical to validate the receptors as new drug targets.
HubMed – drug


Crosstalk and signaling switches in mitogen-activated protein kinase cascades.

Filed under: Drug and Alcohol Rehabilitation

Front Physiol. 2012; 3: 355
Fey D, Croucher DR, Kolch W, Kholodenko BN

Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation, and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength, and dynamics. This implies that signaling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT) signaling. Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonizes different MAPK responses resulting in pivotal cell fate decisions. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38, and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure of certain drugs to induce apoptosis.
HubMed – drug


Integrating experimentation and quantitative modeling to enhance discovery of Beta amyloid lowering therapeutics for Alzheimer’s disease.

Filed under: Drug and Alcohol Rehabilitation

Front Pharmacol. 2012; 3: 177
Lu Y

Drug discovery can benefit from a proactive-knowledge-attainment philosophy which strategically integrates experimentation and pharmacokinetic/pharmacodynamic (PK/PD) modeling. Our programs for Alzheimer’s disease (AD) illustrate such an approach. Compounds that inhibit the generation of brain beta amyloid (A?), especially A?42, are being pursued as potential disease-modifying therapeutics. Complexities in the PK/A? relationship for these compounds have been observed and the data require an advanced approach for analysis. We established a semimechanistic PK/PD model that can describe the PK/A? data by accounting for A? generation and clearance. The modeling characterizes the in vivo PD (i.e., A? lowering) properties of compounds and generates insights about the salient biological systems. The learning from the modeling enables us to establish a framework for predicting in vivo A? lowering from in vitro parameters.
HubMed – drug



Lifemusic gathering with Rod Paton – community through music – Lifemusic provides access to creative music making for people from all walks of life. It is based on the principle that everyone is musical. There are no wrong notes…every sound carries a meaning and in a Lifemusic session everyone is equal whatever their background, training or ability. Making music becomes an act of trust. Lifemusic promotes well-being, good relationships, a strong sense of self and well balanced communites. Recent projects include work with with children and families, busy professionals, neurodisability, international communities, older and younger people, music students, mental health and learning disabled adults. The Lifemusic method shares music-making with all, it encourages personal growth and bond forming with other people, within families and diverse community groups. Lifemusic offers access to music for those who may not otherwise be able to join in – including learning and physical disability, drug and alcohol rehabilitation and mental health environments. The immediate benefits of this easily-accessible music interaction are a sense of wellbeing and freedom from stress.


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