Biochimica et biophysica acta
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Biochim. Biophys. Acta · Nov 2010
Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome.
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is one of the few known genetic causes of autism. FXS results from the loss of Fmr1 gene function; thus, Fmr1 knockout mice provide a model to study impairments associated with FXS and autism and to test potential therapeutic interventions. The inhibitory serine phosphorylation of glycogen synthase kinase-3 (GSK3) is lower in brain regions of Fmr1 knockout mice than wild-type mice and the GSK3 inhibitor lithium rescues several behavioral impairments in Fmr1 knockout mice. ⋯ No alterations in peripheral immune function were identified in Fmr1 knockout mice. However, examination of glia, the immune cells of the brain, revealed reactive astrocytes in several brain regions of Fmr1 knockout mice and treatment with lithium reduced this in the striatum and cerebellum. These results provide further evidence of the involvement of dysregulated GSK3 in FXS, and demonstrate that lithium administration reduces macroorchidism and reactive astrocytes in Fmr1 knockout mice.
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Biochim. Biophys. Acta · Oct 2010
Monitoring mitochondrial electron fluxes using NAD(P)H-flavoprotein fluorometry reveals complex action of isoflurane on cardiomyocytes.
Mitochondrial bioenergetic studies mostly rely on isolated mitochondria thus excluding the regulatory role of other cellular compartments important for the overall mitochondrial function. In intact cardiomyocytes, we followed the dynamics of electron fluxes along specific sites of the electron transport chain (ETC) by simultaneous detection of NAD(P)H and flavoprotein (FP) fluorescence intensities using a laser-scanning confocal microscope. This method was used to delineate the effects of isoflurane, a volatile anesthetic and cardioprotective agent, on the ETC. ⋯ These effects are likely responsible for the reported mild stimulation of mitochondrial reactive oxygen species (ROS) production required for the cardioprotective effects of isoflurane. In conclusion, isoflurane exhibits complex effects on the ETC in intact cardiomyocytes, altering its electron fluxes, and thereby enhancing ROS production. The NAD(P)H-FP fluorometry is a useful method for exploring the effect of drugs on mitochondria and identifying their specific sites of action within the ETC of intact cardiomyocytes.
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Aurora kinase family of serine/threonine kinases are important regulators of mitosis that are frequently over expressed in human cancers and have been implicated in oncogenic transformation including development of chromosomal instability in cancer cells. In humans, among the three members of the kinase family, Aurora-A, -B and -C, only Aurora-A and -B are expressed at detectable levels in all somatic cells undergoing mitotic cell division and have been characterized in greater detail for their involvement in cellular pathways relevant to the development of cancer associated phenotypes. Aurora-A and -B are being investigated as potential targets for anticancer therapy. ⋯ Preclinical studies and early phase I and II clinical trials of multiple Aurora kinase inhibitors as targeted anticancer drugs have provided encouraging results. This article discusses functional involvement of Aurora kinase-A and -B in the regulation of cancer relevant cellular phenotypes together with findings on some of the better characterized Aurora kinase inhibitors in modulating the functional interactions of Aurora kinases. Future possibilities about developing next generation Aurora kinase inhibitors and their clinical utility as anticancer therapeutic drugs are also discussed.
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Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, and autoimmune diseases are examples of diseases that may cause neuropathic pain. Unfortunately no satisfactory treatment is yet available for this type of pain. ⋯ In recent years, most of the neuropathic pain models initially developed in the rat have been translated to mice in order to exploit the resource represented by genetically modified mice. Obviously the most useful animal models of pain would be ones in which the etiology of the pain would be endogenous and not induced by the experimenters: together with the classic models based on peripheral nerve ligation, in the last years other techniques are being developed that mimic more closely clinical pain syndromes, often by attempting to induce the disease associated to neuropathic pain. Although several variables must be taken into account when using animal models for mimicking clinical neuropathic pain, the huge number of models that are now reproducible and well characterized should help to reach important goals in the comprehension of mechanisms and to discover novel therapeutic target for this disease.
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Biochim. Biophys. Acta · Sep 2010
Mitochondrial respiration and membrane potential are regulated by the allosteric ATP-inhibition of cytochrome c oxidase.
This paper describes the problems of measuring the allosteric ATP-inhibition of cytochrome c oxidase (CcO) in isolated mitochondria. Only by using the ATP-regenerating system phosphoenolpyruvate and pyruvate kinase full ATP-inhibition of CcO could be demonstrated by kinetic measurements. The mechanism was proposed to keep the mitochondrial membrane potential (DeltaPsi(m)) in living cells and tissues at low values (100-140 mV), when the matrix ATP/ADP ratios are high. ⋯ With rat heart mitochondria, which lack these enzymes, no decrease of DeltaPsi(m) was found. From the data we conclude that high matrix ATP/ADP ratios keep DeltaPsi(m) at low values by the allosteric ATP-inhibition of CcO, thus preventing the generation of reactive oxygen species which could generate degenerative diseases. It is proposed that respiration in living eukaryotic organisms is normally controlled by the DeltaPsi(m)-independent "allosteric ATP-inhibition of CcO." Only when the allosteric ATP-inhibition is switched off under stress, respiration is regulated by "respiratory control," based on DeltaPsi(m) according to the Mitchell Theory.