bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet-derived growth factor receptor-β, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma
Authors: Suzuki Shioto , Heldin Carl-Henrik , Heuchel Rainer Lothar 
Published: December 2007

Abstract

Background
Platelet-derived growth factor (PDGF)-BB and PDGF receptor (PDGFR)-β are mainly expressed in the developing vasculature, where PDGF-BB is produced by endothelial cells and PDGFR-β is expressed by mural cells, including pericytes. PDGF-BB is produced by most types of solid tumors, and PDGF receptor signaling participates in various processes, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. Furthermore, PDGF-BB-producing tumors are characterized by increased pericyte abundance and accelerated tumor growth. Thus, there is a growing interest in the development of tumor treatment strategies by blocking PDGF/PDGFR function. We have recently generated a mouse model carrying an activated PDGFR-β by replacing the highly conserved aspartic acid residue (D) 849 in the activating loop with asparagine (N). This allowed us to investigate, in an orthotopic tumor model, the role of increased stromal PDGFR-β signaling in tumor-stroma interactions.

Methods
B16 melanoma cells lacking PDGFR-β expression and either mock-transfected or engineered to express PDGF-BB, were injected alone or in combination with matrigel into mice carrying the activated PDGFR-β (D849N) and into wild type mice. The tumor growth rate was followed and the vessel status of tumors, i.e. total vessel area/tumor, average vessel surface and pericyte density of vessels, was analyzed after resection.

Results
Tumors grown in mice carrying an activated PDGFR-β were established earlier than those in wild-type mice. In this early phase, the total vessel area and the average vessel surface were higher in tumors grown in mice carrying the activated PDGFR-β (D849N) compared to wild-type mice, whereas we did not find a significant difference in the number of tumor vessels and the pericyte abundance around tumor vessels between wild type and mutant mice. At later phases of tumor progression, no significant difference in tumor growth rate was observed between wild type mice and mutant mice, although the pericyte coverage was higher around tumor vessels from mutant mice.

Conclusion
Our findings suggest that the activated PDGFR-β (D849N) in the host animal increased the total vessel area and the average vessel surface even in PDGF-negative tumors, resulting in a shorter lag phase during tumor establishment.
Delayed Functional Expression of Neuronal Chemokine Receptors Following Focal Nerve Demyelination in the Rat: A Mechanism for the Development of Chronic Sensitization of Peripheral Nociceptors
Authors: Bhangoo Sonia , Ren Dongjun , Miller Richard J , Henry Kenneth J , Lineswala Jayana , Hamdouchi Chafiq , Li Baolin , Monahan Patrick E , Chan David M , Ripsch Matthew S , White Fletcher A 
Published: December 2007

Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia. Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.
Comparative genomic analysis of the odorant-binding protein family in 12 Drosophila genomes: purifying selection and birth-and-death evolution
Authors: Vieira Filipe G , Sánchez-Gracia Alejandro , Rozas Julio 
Published: December 2007

Abstract
Background
Chemoreception is a widespread mechanism that is involved in critical biologic processes, including individual and social behavior. The insect peripheral olfactory system comprises three major multigene families: the olfactory receptor (Or), the gustatory receptor (Gr), and the odorant-binding protein (OBP) families. Members of the latter family establish the first contact with the odorants, and thus constitute the first step in the chemosensory transduction pathway.

Results
Comparative analysis of the OBP family in 12 Drosophila genomes allowed the identification of 595 genes that encode putative functional and nonfunctional members in extant species, with 43 gene gains and 28 gene losses (15 deletions and 13 pseudogenization events). The evolution of this family shows tandem gene duplication events, progressive divergence in DNA and amino acid sequence, and prevalence of pseudogenization events in external branches of the phylogenetic tree. We observed that the OBP arrangement in clusters is maintained across the Drosophila species and that purifying selection governs the evolution of the family; nevertheless, OBP genes differ in their functional constraints levels. Finally, we detect that the OBP repertoire evolves more rapidly in the specialist lineages of the Drosophila melanogaster group (D. sechellia and D. erecta) than in their closest generalists.

Conclusion
Overall, the evolution of the OBP multigene family is consistent with the birth-and-death model. We also found that members of this family exhibit different functional constraints, which is indicative of some functional divergence, and that they might be involved in some of the specialization processes that occurred through the diversification of the Drosophila genus.
The Brain as a Target for Inflammatory Processes and Neuroprotective Strategies
Authors: SKAPER STEPHEN D. 
Published: December 2007

AbstractThe importance of glial cell–propagated inflammation (i.e., neuroinflammation) disorders such as Alzheimer's disease (AD) was viewed previously as a bystander effect, or epiphenomenon, with inflammation occurring when damaged neurons elicit an activation response by glia. However, an accumulating body of evidence has challenged this earlier perspective and indicates a more active role of neuroinflammation in the pathophysiology of progressive neurodegenerative disorders such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This insight into pathophysiology evolved in concert with the appreciation that the brain is not as immunologically privileged as once thought. The central nervous system (CNS) has its own resident immune system, in which glial cells (microglia, astrocytes, and oligodendrocytes) not only serve supportive and nutritive roles for neurons but also engage from time to time in several “inflammatory” processes that defend the CNS from pathogens and help it to recover from stress and injury. These otherwise “normal” glial functions can sometimes result in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease. Excessive glial cell activation may thus constitute a viable target for the discovery of and development of neurodegenerative disease therapeutics. Suggestive clinical evidence in support of neuroinflammation as a drug discovery target for chronic neurodegenerative diseases, such as AD, comes from epidemiological and genetic linkage data. For example, long‐term use of nonsteroidal anti‐inflammatory drugs is correlated with a protective effect against AD, and certain polymorphisms in the genes for interleukin 1 and other proinflammatory mediator genes are associated with increased risk. In AD and Parkinson's disease, activated microglia and complement proteins have been identified in the brain regions most affected in these disorders. This report will briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, as well as their neuroprotective potential.
Inhibition of T‐type Calcium Current in the Reticular Thalamic Nucleus by a Novel Neuroactive Steroid
Authors: JOKSOVIC PAVLE M. , COVEY DOUGLAS F. , TODOROVIC SLOBODAN M. 
Published: December 2007

AbstractNeurons of the nucleus reticularis of the thalamus (nRT) serve as an important inhibitory gate that controls trafficking of thalamocortical sensory signals and states of sleep, arousal, and epilepsy. T‐type calcium channels in nRT play a crucial role in the subthreshold excitability of these neurons, but their modulation by neuroactive steroids has not been previously studied. Here we explored the effect of (3β,5β,17β)‐3‐hydroxyandrostane‐17‐carbonitrile (3β‐OH), a novel neuroactive steroid on T‐type currents recorded from nRT neurons in intact brain slices of young rats. We found in voltage‐clamp experiments that 3β‐OH potently and reversibly decreased T‐type Ca2+ current amplitude and stabilized inactive states of the channels. In current‐clamp experiments, 3β‐OH significantly decreased the frequency of action potential firing from negative membrane potentials and minimally changed passive membrane properties. Our results indicate that 5β‐reduced neuroactive steroids, through the mechanisms of inhibition of T‐type Ca2+ currents and diminished spike firing in nRT neurons, may be important agents in control of sensory information processing in physiological conditions and possibly pathological brain states associated with increased cellular excitability such as epilepsy and/or tissue ischemia/hypoxia.
Brain‐Derived Neurotrophic Factor Prevents Human Immunodeficiency Virus Type 1 Protein gp120 Neurotoxicity in the Rat Nigrostriatal System
Authors: MOCCHETTI ITALO , NOSHENY RACHEL L. , TANDA GIANLUIGI , REN KE , MEYER EDWIN M. 
Published: December 2007

AbstractHuman immunodeficiency virus type 1 (HIV‐1) causes neuronal degeneration and, at a late stage, creates HIV‐associated dementia (HAD) and other neurological abnormalities. Therefore, the need for neuroprotective agents is great. However, therapeutic agents that reduce HIV neurotoxicity are difficult to characterize and develop because rodents are not infected by HIV. This study was undertaken to develop an animal model of HIV neurotoxicity by using the HIV‐1 envelope glycoprotein 120 (gp120). Vehicle or gp120 was injected acutely in the striatum of adult rats. gp120 produced loss of nigrostriatal neurons, as shown both by histochemical analysis of brain sections for apoptosis and biochemical determination of dopamine. The neurotrophin brain‐derived neurotrophic factor (BDNF) delivered by a recombinant adeno‐associated viral vector prevented gp120 toxicity. This study's results support the notion that gp120 produces a widespread neurotoxicity similar to that observed in HIV‐positive individuals and that BDNF may be a suitable neuroprotective agent for HAD.
Neuroprotection at the Nanolevel—Part I
Authors: ANDREWS RUSSELL J. 
Published: December 2007

AbstractNanoneurosurgery demands a departure from the traditional “excise what you can see and touch” role of neurosurgeons. Moreover, there is a conceptual leap necessary for neuroscientists as well as neurosurgeons in developing and applying nanotechniques to neurosurgery at the nanolevel. After introducing the realm of nanotechnology and some unique properties of nanomaterials, I review several of the nanotechniques in development that are most likely to affect neuroprotection at the nanolevel. These techniques include quantum dot “nanobarcode” labeling of cellular and subcellular entities, as well as nanotechniques for following enzymatic reactions in real time. Nanoscaffolds offer mechanical enhancement of neurorepair; carbon nanotube electrode arrays can provide nanolevel electrical and chemical enhancement. Even traditional “cut and sew” surgery is being taken down to the micron, if not nano, level for single axon repair, and the technology can use capillaries to deliver therapeutics to virtually any portion of the nervous system with greater than pinpoint accuracy. In this report, I use these nanotechniques to introduce the multiplex nanodevices under development.
Neuroprotection at the Nanolevel—Part II
Authors: ANDREWS RUSSELL J. 
Published: December 2007

AbstractNanotechniques presented in this article's companion report are being multiplexed into nanodevices that promise to greatly advance our understanding and treatment of many nervous system disorders. Current neuromodulation techniques for deep brain stimulation have major drawbacks, such as large size (in comparison with ideal of small neuron group stimulation), lack of feedback monitoring of brain electrical activity, and high electrical current needs. Carbon nanotube nanoelectrode arrays address these drawbacks and offer the possibility of monitoring neurotransmitter levels at the synapse/neuronal level in real time. Such arrays can monitor and modulate electrochemical events occurring among neural networks, which should add greatly to our understanding of neuronal communication. A multiplex nanodevice for studying (and enhancing) axonal regeneration after spinal cord injury is also being developed. The nanotechniques described in the companion piece are combined in a micron‐sized neural growth tube lined with nanodevices through which the regenerating axon extends—allowing continuous monitoring and modulation of the axon's electrochemical environment plus directional guidance with a biodegradable nanoscaffold. Multifunction nanodevices provide opportunities for neuronal (and subneuronal) monitoring and modulation that will enhance neuroprotection and neurorepair far beyond the micro‐ and macrolevel techniques used heretofore.
Drug Delivery to the Spinal Cord Tagged with Nanowire Enhances Neuroprotective Efficacy and Functional Recovery following Trauma to the Rat Spinal Cord
Authors: SHARMA HARI SHANKER , ALI SYED F. , DONG W. , TIAN Z. RYAN , PATNAIK R. , PATNAIK S. , SHARMA ARUNA , BOMAN ARNE , LEK PER , SEIFERT ELISABETH , LUNDSTEDT TORBJÖRN 
Published: December 2007

AbstractThe possibility that drugs attached to innocuous nanowires enhance their delivery within the central nervous system (CNS) and thereby increase their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three compounds—AP173 (SCI‐1), AP713 (SCI‐2), and AP364 (SCI‐5) (Acure Pharma, Uppsala, Sweden)—were tagged with TiO2‐based nanowires using standard procedure. Normal compounds were used for comparison. SCI was produced by making a longitudinal incision into the right dorsal horn of the T10–T11 segments under Equithesin anesthesia. The compounds, either alone or tagged with nanowires, were applied topically within 5 to 10 min after SCI. In these rats, behavioral outcome, blood–spinal cord barrier (BSCB) permeability, edema formation, and cell injury were examined at 5 h after injury. Topical application of normal compounds in high quantity (10 μg in 20 μL) attenuated behavioral dysfunction (3 h after trauma), edema formation, and cell injury, as well as reducing BSCB permeability to Evans blue albumin and 131I. These beneficial effects are most pronounced with AP713 (SCI‐2) treatment. Interestingly, when these compounds were administered in identical conditions after tagging with nanowires, their beneficial effects on functional recovery and spinal cord pathology were further enhanced. However, topical administration of nanowires alone did not influence trauma‐induced spinal cord pathology or motor functions. Taken together, our results, probably for the first time, indicate that drug delivery and therapeutic efficacy are enhanced when the compounds are administered with nanowires.
Neuro‐ and Cardioprotective Effects of Blockade of Nitric Oxide Action by Administration of Methylene Blue
Authors: WIKLUND LARS , BASU SAMAR , MICLESCU ADRIANA , WIKLUND PER , RONQUIST GUNNAR , SHARMA HARI SHANKER 
Published: December 2007

AbstractMethylene blue (MB), generic name methylthioninium (C16H18ClN3 S · 3H2O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well‐known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia–reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S‐100β, as well as troponin I and creatine kinase isoenzyme MB, respectively.
Valproate and Acetyl‐l‐carnitine Prevent Methamphetamine‐Induced Behavioral Sensitization in Mice
Authors: COCCURELLO ROBERTO , CAPRIOLI ANTONIO , GHIRARDI ORLANDO , VIRMANI ASHRAF 
Published: December 2007

AbstractThis study deals with the possible inhibitory role played by acetyl‐l‐carnitine (ALC) against methamphetamine (METH)‐induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH‐mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH‐mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH‐induced sensitization. Another interesting observation was the significantly higher METH‐induced hyperactivity at day 15 (after a 7‐day drug‐free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH‐induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant‐mediated neurotoxicity. By demonstrating anin vivoaction against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior.
N‐Acetylcysteine Attenuates Arsenite‐Induced Oxidative Injury in Dorsal Root Ganglion Explants
Authors: CHAO P.L. , FAN S.F. , CHOU Y.H. , LIN ANYA M.Y. 
Published: December 2007

AbstractChronic exposure to arsenic causes health problems, including peripheral neuropathy. Oxidative stress is one of the mechanisms underlying arsenic‐induced neurotoxicity. For this report, we studied the protective effect of N‐acetylcysteine (NAC) on arsenic‐induced oxidative injury in dorsal root ganglion (DRG) explants. After 24‐h incubation, NAC concentration‐dependently attenuated arsenite‐induced depletion in glutathione (GSH) content and increases in the ratio of oxidized GSH/reduced GSH (GSSG/GSH ratio) in DRG explants. Furthermore, NAC inhibited arsenite‐induced elevation in the expression of stress proteins, such as heat shock protein 70 and heme oxygenase 1, as well as arsenite‐induced phosphorylation of p38 mitogen‐activated protein kinase. Incubation with NAC ameliorated arsenite‐induced apoptosis by abolishing both mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, NAC attenuated arsenite‐induced elevation in Bcl‐2 level and cytosolic cytochrome c, as well as arsenite‐induced reduction in procaspase‐3 levels. In the ER pathway, NAC suppressed arsenite‐induced increases in activating transcription factor 6 and C/EBP homologous protein in the nuclear fraction. Furthermore, arsenite‐induced reductions in procaspase‐12 and elevation in BIP and caspase‐12, an ER‐specific enzyme, were prevented after NAC incubation. Taken together, our results demonstrate that NAC is neuroprotective against arsenite‐induced oxidative injury in DRG explants. Furthermore, NAC inhibits arsenite‐induced toxicity by inhibiting ER and mitochondrion activation. Our data indicate that NAC is potentially therapeutic for arsenite‐induced peripheral neuropathy.