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1.
Dopaminergic neurons in the mammalian brain have received substantial attention in the past given their fundamental role in
several body functions and behaviours. The largest dopaminergic population is found in two nuclei of the ventral midbrain.
Cells of the substantia nigra pars compacta are involved in the control of voluntary movements and postural reflexes, and
their degeneration in the adult brain leads to Parkinson’s disease. Cells of the ventral tegmental area modulate rewarding
and cognitive behaviours, and their dysfunction is involved in the pathogenesis of addictive disorders and schizophrenia.
Because of their clinical relevance, the embryonic development and maintenance of the midbrain dopaminergic cell groups in
the adult have been intensively studied in recent years. In the present review, we provide an overview of the mechanisms and
factors involved in the development of dopaminergic neurons in the mammalian brain, with a special emphasis on the midbrain
dopaminergic population.
Received 17 August 2005; received after revision 28 September 2005; accepted 21 October 2005 相似文献
2.
Bernard C 《Cellular and molecular life sciences : CMLS》2005,62(11):1177-1181
Epilepsy mechanism chasers face one major difficulty. Since we don’t know how the normal brain works, we can’t start to understand how the diseased brain fails. Most of today’s hypotheses are based on what we think about ‘normal’ brain function, which may lead to misconceptions, as will be developed here. Furthermore, since there are many different types of epilepsies, some mechanisms may only be relevant to some epilepsies. Here, I shall focus on temporal lobe epilepsy (TLE) the most common form of partial epilepsy in adults. TLE is often drug resistant, as are 30–40% of all forms of epilepsies. The failure of drug-treatments most likely reflects our lack of knowledge of the underlying mechanisms.Received 10 January 2005; received after revision 3 March 2005; accepted 23 March 2005 相似文献
3.
Cholinomimetics produce seizures and brain damage in rats 总被引:9,自引:0,他引:9
Microinjections of the cholinergic agonists, carbachol and bethanechol, either into the amygdala or into the dorsal hippocampus produced sustained limbic seizures and brain damage in rats. Systemic administration of pilocarpine in rats resulted in a sequence of convulsive disorders and widespread brain damage as well. Scopolamine prevented the development of convulsive activity and brain damage produced by cholinomimetics. These results suggest that the excessive stimulation of cholinergic muscarinic receptors can lead to limbic seizures and brain damage. It is postulated that muscarinic cholinergic mechanisms are linked to the etiology of temporal lobe epilepsy and epileptic brain damage. 相似文献
4.
Salvatore Fusco Giovambattista Pani 《Cellular and molecular life sciences : CMLS》2013,70(17):3157-3170
Calorie restriction extends longevity and delays ageing in model organisms and mammals, opposing the onset and progression of an array of age-related diseases. These beneficial effects also extend to the maintenance of brain cognitive functions at later age and to the prevention, at least in rodents, of brain senescence and associated neurodegenerative disorders. In recent years, the molecular mechanisms underlying brain response to calorie restriction have begun to be elucidated, revealing the unanticipated role of a number of key nutrient sensors and nutrient-triggered signaling cascades in the translation of metabolic cues into cellular and molecular events that ultimately lead to increased cell resistance to stress, enhanced synaptic plasticity, and improved cognitive performance. Of note, the brain’s role in CR also includes the activation of nutrient-sensitive hypothalamic circuitries and the implementation of neuroendocrine responses that impact the entire organism. The present review addresses emerging molecular themes in brain response to dietary restriction, and the implications of this knowledge for the understanding and the prevention of brain disorders associated with ageing and metabolic disease. 相似文献
5.
6.
Albane le Maire William Bourguet Patrick Balaguer 《Cellular and molecular life sciences : CMLS》2010,67(8):1219-1237
Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine
system by interfering with hormone biosynthesis, metabolism, or action. The molecular mechanisms of EDCs involve different
pathways including interactions with nuclear hormone receptors (NHRs) which are primary targets of a large variety of environmental
contaminants. Here, based on the crystal structures currently available in the Protein Data Bank, we review recent studies
showing the many ways in which EDCs interact with NHRs and impact their signaling pathways. Like the estrogenic chemical diethylstilbestrol,
some EDCs mimic the natural hormones through conserved protein–ligand contacts, while others, such as organotins, employ radically
different binding mechanisms. Such structure-based knowledge, in addition to providing a better understanding of EDC activities,
can be used to predict the endocrine-disrupting potential of environmental pollutants and may have applications in drug discovery. 相似文献
7.
Popescu G 《Cellular and molecular life sciences : CMLS》2005,62(18):2100-2111
NMDA receptors (NRs) are key signaling proteins in the central nervous system and represent important targets for drug development in several neurologic disorders. They are critically involved with fundamental brain processes, and thus indiscriminate pharmacological suppression of NR currents has seen only modest therapeutic success so far. Targeting harmful NR receptor activities while sparing the receptor’s vital functions requires a better understanding of the complexity of NR activation reaction; of the range of mechanisms that modulate discrete receptor activities; and of the consequences of this modulation on specific receptor functions. A quantitative account of the NR activation pathway was recently proposed and validated. It describes the gating reaction as a sequential, multi-step process rather than a binary, on-off switch. Alongside isoform-specific modulators, state-specific modulators may represent sophisticated interventions with high potential for narrow, functional specifi city. Here I review physiologic mechanisms that control NR responses; the salient features of the NR activation reaction; and discuss the model’s validity and its implications for drug development and characterization.Submitted 25 May 2005; accepted 29 June 2005 相似文献
8.
Arianna Loregian Beatrice Mercorelli Giulio Nannetti Chiara Compagnin Giorgio Palù 《Cellular and molecular life sciences : CMLS》2014,71(19):3659-3683
Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection. 相似文献
9.
Glucocorticoids in T cell apoptosis and function 总被引:5,自引:0,他引:5
Glucocorticoids (GCs) are a class of steroid hormones which regulate a variety of essential biological functions. The profound
anti-inflammatory and immunosuppressive activity of synthetic GCs, combined with their power to induce lymphocyte apoptosis
place them among the most commonly prescribed drugs worldwide. Endogenous GCs also exert a wide range of immunomodulatory
activities, including the control of T cell homeostasis. Most, if not all of these effects are mediated through the glucocorticoid
receptor, a member of the nuclear receptor superfamily. However, the signaling pathways and their cell type specificity remain
poorly defined. In this review, we summarize our present knowledge on GC action, the mechanisms employed to induce apoptosis
and the currently discussed models of how they may participate in thymocyte development. Although our knowledge in this field
has substantially increased during recent years, we are still far from a comprehensive picture of the role that GCs play in
T lymphocytes.
Received 20 August 2005; received after revision 27 September 2005; accepted 10 October 2005 相似文献
10.
Joshi S Guleria RS Pan J Bayless KJ Davis GE Dipette D Singh US 《Cellular and molecular life sciences : CMLS》2006,63(23):2859-2870
Developmental exposure to ethanol impairs fetal brain development and causes fetal alcohol syndrome. Although the cerebellum
is one of the most alcohol-sensitive brain areas, signaling mechanisms underlying the deleterious effects of ethanol on developing
cerebellar granule neurons (CGNs) are largely unknown. Here we describe the effects of in vivo ethanol exposure on neurite formation in CGNs and on the activation of Rho GTPases (RhoA and Rac1), regulators of neurite
formation. Exposure of 7-day-old rat pups to ethanol for 3 h moderately increased blood alcohol concentration (BAC) (∼40 mM)
and inhibited neurite formation and Rac1 activation in CGNs. Longer exposure to ethanol for 5 h resulted in higher BAC (∼80 mM),
induced apoptosis, inhibited Rac1, and activated RhoA. Studies demonstrated a regulatory role of Rho GTPases in differentiation
of cerebellar neurons, and indicated that ethanol-associated impairment of Rho GTPase signaling might contribute to brain
defects observed in fetal alcohol syndrome.
Received 16 July 2006; received after revision 12 September 2006; accepted 13 October 2006 相似文献
11.
Pharmacological concepts tailored to status epilepticus, to epileptogenesis following acquired brain insults, and to ictogenesis
in established epilepsy vary considerably and should ideally be directed at those pathophysiological mechanisms that presumably
underly these conditions. Currently known important molecular targets include voltage-gated sodium and calcium channels, the
γ-aminobutyric acid (GABA) system and ionotropic glutamate receptors. Metabotropic glutamate receptors, potassium channels,
and neurotransmitters such as acetylcholine, glycine, and monoamines are beyond the scope of this review.
In status epilepticus, immediate failure of GABAergic inhibition occurs, and administration of benzodiazepines and barbiturates
displays the pharmacostrategic mainstay. In epileptogenesis within limbic structures, the most important underlying pathophysiological
mechanisms currently discussed are transient loss of inhibition and aberrant mossy fiber sprouting. Both processes may be
facilitated by N-methy-d-aspartat (NMDA) receptor regulation. NMDA antagonists may exhibit antiepileptogenic properties in experimental animals, but
reliable data in humans are lacking. In established epilepsy, voltage-gated ion channels and impairment of GABAergic functions
contribute to mechanisms facilitating ictogenesis. Blockade of sodium and calcium channels and enhancement of GABAergic inhibition
are currently the most important tools to prevent the occurrence of seizures.
Received 16 January 2007; received after revision 7 March 2007; accepted 17 April 2007 相似文献
12.
Kraemer N Issa L Hauck SC Mani S Ninnemann O Kaindl AM 《Cellular and molecular life sciences : CMLS》2011,68(10):1719-1736
Cyclin dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) has gained attention in the last years following
the discovery, in 2005, that recessive mutations cause primary autosomal recessive microcephaly. This disease is seen as an
isolated developmental defect of the brain, particularly of the cerebral cortex, and was thus historically also referred to
as microcephalia vera. Unraveling the pathomechanisms leading to this human disease is fascinating scientists because it can convey insight into
basic mechanisms of physiologic brain development (particularly of cortex formation). It also finds itself in the spotlight
because of its implication in trends in mammalian evolution with a massive increase in the size of the cerebral cortex in
primates. Here, we provide a timely overview of the current knowledge on the function of CDK5RAP2 and mechanisms that might
lead to disease in humans when the function of this protein is disturbed. 相似文献
13.
Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action 总被引:3,自引:0,他引:3
Montecucco C Gutiérrez JM Lomonte B 《Cellular and molecular life sciences : CMLS》2008,65(18):2897-2912
A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors
and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which
is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation
which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular
junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms
of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.
Received 05 March 2008; received after revision 08 April 2008; accepted 29 April 2008 相似文献
14.
Transmembrane ion channels play a crucial role in the existence of all living organisms. They partition the exterior from
the interior of the cell, maintain the proper ionic gradient across the cell membrane and facilitate signaling between cells.
To perform these functions, ion channels must be highly selective, allowing some types of ions to pass while blocking the
passage of others. Here we review a number of studies that have helped to elucidate the mechanisms by which ion channels discriminate
between ions of differing charge, focusing on four channel families as examples: gramicidin, ClC chloride, voltage-gated calcium
and potassium channels. The recent availability of high-resolution structural data has meant that the specific inter-atomic
interactions responsible for valence selectivity can be pinpointed. Not surprisingly, electrostatic considerations have been
shown to play an important role in ion specificity, although many details of the origins of this discrimination remain to
be determined.
Received 4 September 2005; received after revision 17 October 2005; accepted 2 November 2005 相似文献
15.
Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway 总被引:6,自引:0,他引:6
Enhanced cell migration is one of the underlying mechanisms in cancer invasion and metastasis. Therefore, inhibition of cell migration is considered to be an effective strategy for prevention of cancer metastasis. We found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), an active component from the rhizome of Rheum palmatum, significantly inhibited epidermal growth factor (EGF)- induced migration in various human cancer cell lines. In the search for the underlying molecular mechanisms, we demonstrated that phosphatidylinositol 3-kinase (PI3K) serves as the molecular target for emodin. In addition, emodin markedly suppressed EGF-induced activation of Cdc42 and Rac1 and the corresponding cytoskeleton changes. Moreover, emodin, but not LY294002, was able to block cell migration in cells transfected with constitutively active (CA)-Cdc42 and CA-Rac1 by interference with the formation of Cdc42/Rac1 and the p21-activated kinase complex. Taken together, data from this study suggest that emodin inhibits human cancer cell migration by suppressing the PI3K-Cdc42/Rac1 signaling pathway.Received 7 February 2005; received after revision 11 March 2005; accepted 18 March 2005 相似文献
16.
Moshnikova AB Afanasyev VN Proussakova OV Chernyshov S Gogvadze V Beletsky IP 《Cellular and molecular life sciences : CMLS》2006,63(2):229-234
Currently, chemical bifunctional cross-linkers are regarded as promising therapeutic agents capable of affecting cell metabolism.
Depending on the nature of the active groups and on the length of their mediating spacer, these cross-linkers have been shown
to influence mitochondrial functions, the cell cycle and cell death. The current study was aimed to assay cellular effects
of a cross-linker with ‘zero’-length spacer, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). When added to cultures
of transformed cells, EDC induced a G2/M blockade followed by cell death. Analysis of the molecular targets revealed that
alteration of the cell cycle was caused by EDC-induced interchain cross-linking within double-stranded DNA. Administration
of EDC to animals with experimental tumors increased their life span. The analysis of tumor cells from EDC-treated mice showed
up-regulation of p21/WAF1, disturbance of tumor cell cytokinesis and, hence, cell death. Thus, both in vitro and in vivo, EDC exhibits cytotoxic activity, which may be of potential therapeutic use.
Received 15 August 2005; received after revision 23 September 2005; accepted 15 November 2005 相似文献
17.
Raber J 《Cellular and molecular life sciences : CMLS》2007,64(6):735-741
Histamine might have an important role in brain development. However, most studies have focused on short-term effects of histamine receptor-mediated signaling on brain function in adulthood. Little is known about the potential long-term effects of histamine receptor-mediated signaling during development on brain function in adulthood. We hypothesize that increased postsynaptic histamine receptor-mediated signaling during development has detrimental effects on brain function in adulthood. Our data support this hypothesis. In the developing mouse brain, histamine H3 receptor blockade, which increases histamine release, has detrimental sex-dependent effects on object recognition, spatial learning in the water maze, and pre-pulse inhibition in adulthood. Our data also support the hypothesis that histamine mediates the detrimental long-term sex-dependent effects of methamphetamine exposure early in life on these brain functions in adulthood. Therefore, increased efforts are warranted to carefully evaluate the effects of drugs that directly or indirectly affect histamine receptor-mediated signaling during development on cognitive function later in life. 相似文献
18.
Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons 总被引:6,自引:1,他引:5
Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using
in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis
and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome,
we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational
exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis.
Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol
inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH
expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor,
and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated
Akt, GSK-3β, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3β and BAD protein expression.
The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly
impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in
the early postnatal period, which is critical for brain development.
Received 21 January 2002; received after revision 28 February 2002; accepted 25 March 2002 相似文献
19.
Meier S Bräuer AU Heimrich B Nitsch R Savaskan NE 《Cellular and molecular life sciences : CMLS》2004,61(9):1082-1094
Myelin is crucial for the stabilization of axonal projections in the developing and adult mammalian brain. However, myelin
components also act as a non-permissive and repellent substrate for outgrowing axons. Therefore, one major factor which accounts
for the lack of axonal regeneration in the mature brain is myelin. Here we report on the appearance of mature, fully myelinated
axons during hippocampal development and following entorhinal lesion with the myelin-specific marker Black Gold. Although
entorhinal axons enter the hippocampal formation at embryonic day 17, light and ultrastructural analysis revealed that mature
myelinated fibers in the hippocampus occur in the second postnatal week. During postnatal development, increasing numbers
of myelinated fibers appear and the distribution of myelinated fibers at postnatal day 25 was similar to that found in the
adult. After entorhinal cortex lesion, a specific anterograde denervation in the hippocampus takes place, accompanied by a
long-lasting loss of myelin. Quantitative analysis of myelin and myelin breakdown products at different time points after
lesion revealed a temporally close correlation to the degeneration and reorganization pha-ses in the hippocampus. In contrast,
electroconvulsive seizures resulted in brief demyelination and a faster recovery time course. In conclusion, we could show
that the appearance of mature axons in the hippocampus is temporally regulated during development. In the adult hippocampus,
demyelination was found after anterograde degeneration and also following seizures, suggesting that independent types of insult
lead to demyelination. Reappearing mature axons were found in the hippocampus following axonal sprouting. Therefore, our quantitative
analysis of mature axons and myelination effectively reflects the readjusted axonal density and possible electrophysiological
balance following lesion.
Received 22 December 2003; received after revision 11 February 2004; accepted 17 February 2004 相似文献
20.
Hedgehog signaling in pancreas development and disease 总被引:6,自引:0,他引:6
Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during
diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is
not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling
has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation
of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a
variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of
Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic
cancer.
Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005 相似文献