Text Box: PBN

Text Box: GPCR





Text Box: 5HT 

Brain tumor


Neuropsychiatric disease




Text Box: Dvmat




Brain Res. 2006 Jan 5;1067(1):170-6. Epub 2005 Dec 15.

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Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008 Jul;33(7):606-11. Links

[Protein expression of Skp2 in osteosarcoma and its relation with prognosis.]

[Article in Chinese]

Liao QD, Zhong D, Chen Q, Zhu WF.

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China.

Objective To investigate the expression of Skp2 and its relation with P27 expression, clinic pathologic features, and prognostic indicator in osteosarcoma.Methods We collected osteosarcoma specimen from 52 patients (29 males and 23 females), who were all treated by radical resection of tumor. The expression of Skp2 and P27 was determined by SP immunohistochemistry. Forty-four patients were followed up for 4~84(mean=31.2)months, while the other 8 patients were lost. Twenty of them survived over 5 years and 24 died.Results In osteosarcoma, Skp2 highly expressed (mean value was 1.74). Expression intensity of Skp2 at the stage III was obviously higher than that of the stage II(IIa and IIb) (P<0.05). Skp2 expression was correlated with the relapse, metastasis, and 5-year survival in osteosarcoma(P<0.05), but not with different pathologic types, sex, or age(P>0.05). The expressions of skp2 and P27 were negative correlation in osteosarcoma(r=-0.907, P<0.05).Conclusion Skp2 plays an important role in the occurrence and development of osteocarcoma by causing the degradation of P27, and can be an important prognostic indicator in osteosarcoma.

PMID: 18667774 [PubMed - in process]



























Medial parabrachial nucleus neurons modulate d-fenfluramine-induced anorexia through 5HT2C receptors.

Trifunovic R, Reilly S.

Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, USA. radmila@uic.edu

We previously reported that lesions of the medial parabrachial nucleus (PBN) enhanced d-fenfluramine (DFEN)-induced anorexia; a finding that suggests these lesions may potentiate the release of serotonin (5HT) or increase the postsynaptic action of 5HT. In the present study, we used SB 206553 (a 5HT2B/2C receptor antagonist) or m-CPP (a 5HT2C/1B receptor agonist) in a standard behavioral procedure (deprivation-induced feeding) to further explore the role of the medial PBN in drug-induced anorexia. In Experiment 1, DFEN (0 or 1.0 mg/kg) was given alone or in combination with SB 206553 (2.0 or 5.0 mg/kg). In Experiment 2, we investigated the food-suppressive effects of m-CPP (0.5, 1.0 or 2.0 mg/kg). The results of Experiment 1 show that SB 206553, while having no influence on the performance of control subjects, attenuated (2.0 mg/kg) or abolished (5 mg/kg) the potentiating effect of the lesions on DFEN-induced anorexia. In Experiment 2, m-CPP induced a suppression of food intake in nonlesioned animals that was significantly potentiated in rats with medial PBN lesions. These results are consistent with the hypothesis that medial PBN neurons mediate anorexia through 5HT2C receptors.

PMID: 16343451 [PubMed - indexed for MEDLINE]

Biochemistry. 2005 Nov 8;44(44):14509-18.

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Expression of functional G protein-coupled receptors in photoreceptors of transgenic Xenopus laevis.

Zhang L, Salom D, He J, Okun A, Ballesteros J, Palczewski K, Li N.

Novasite Pharmaceuticals, Inc., San Diego, California 92121, USA.

G protein-coupled receptors (GPCRs) constitute the largest superfamily of transmembrane signaling proteins; however, the only known GPCR crystal structure is that of rhodopsin. This disparity reflects the difficulty in generating purified GPCR samples of sufficient quantity and quality. Rhodopsin, the light receptor of retinal rod neurons, is produced in large amounts of homogeneous quality in the vertebrate retina. We used transgenic Xenopus laevis to convert these retina rod cells into bioreactors to successfully produce 20 model GPCRs. The receptors accumulated in rod outer segments and were homogeneously glycosylated. Ligand and [(35)S]GTPgammaS binding assays of the 5HT(1A) and EDG(1) GPCRs confirmed that they were properly folded and functional. 5HT(1A)R was highly purified by taking advantage of the rhodopsin C-terminal immunoaffinity tag common to all GPCR constructs. We have also developed an automated system that can generate hundreds of transgenic tadpoles per day. This expression approach could be extended to other animal model systems and become a general method for the production of large numbers of GPCRs and other membrane proteins for pharmacological and structural studies.

PMID: 16262251 [PubMed - indexed for MEDLINE]

Mol Psychiatry. 2006 Jan;11(1):99-113.

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Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine.

Chang HY, Grygoruk A, Brooks ES, Ackerson LC, Maidment NT, Bainton RJ, Krantz DE.

Department of Psychiatry and Biobehavioral Sciences, Gonda (Goldschmied) Center for Genetic and Neuroscience Research, Geffen School of Medicine-UCLA, University of California at Los Angeles, 695 Charles Young Drive, Los Angeles, CA 90095-1761, USA.

Aminergic signaling pathways have been implicated in a variety of neuropsychiatric illnesses, but the mechanisms by which these pathways influence complex behavior remain obscure. Vesicular monoamine transporters (VMATs) have been shown to regulate the amount of monoamine neurotransmitter that is stored and released from synaptic vesicles in mammalian systems, and an increase in their expression has been observed in bipolar patients. The model organism Drosophila melanogaster provides a powerful, but underutilized genetic system for studying how dopamine (DA) and serotonin (5HT) may influence behavior. We show that a Drosophila isoform of VMAT (DVMAT-A) is expressed in both dopaminergic and serotonergic neurons in the adult Drosophila brain. Overexpression of DVMAT-A in these cells potentiates stereotypic grooming behaviors and locomotion and can be reversed by reserpine, which blocks DVMAT activity, and haloperidol, a DA receptor antagonist. We also observe a prolongation of courtship behavior, a decrease in successful mating and a decrease in fertility, suggesting a role for aminergic circuits in the modulation of sexual behaviors. Finally, we find that DMVAT-A overexpression decreases the fly's sensitivity to cocaine, suggesting that the synaptic machinery responsible for this behavior may be downregulated. DVMAT transgenes may be targeted to additional neuronal pathways using standard Drosophila techniques, and our results provide a novel paradigm to study the mechanisms by which monoamines regulate complex behaviors relevant to neuropsychiatric illness.

PMID: 16189511 [PubMed - indexed for MEDLINE]

Pain. 2005 Oct;117(3):292-303.

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Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.

Suzuki R, Rahman W, Rygh LJ, Webber M, Hunt SP, Dickenson AH.

Department of Pharmacology Medical Sciences Building, University College London, Gower Street, London WC1E 6BT, UK. ucklrsu@ucl.ac.uk

Not all neuropathic pain patients gain relief from current therapies that include the anticonvulsant, gabapentin, thought to modulate calcium channel function. We report a neural circuit that is permissive for the effectiveness of gabapentin. Substance P-saporin (SP-SAP) was used to selectively ablate superficial dorsal horn neurons expressing the neurokinin-1 receptor for substance P. These neurons project to the brain as shown by retrograde labelling and engage descending brainstem serotonergic influences that enhance spinal excitability via a facilitatory action on 5HT(3) receptors. We show the integrity of this pathway following nerve injury contributes to the behavioural allodynia, neuronal plasticity of deep dorsal horn neurons and the injury-specific actions of gabapentin. Thus SP-SAP attenuated the tactile and cold hypersensitivity and abnormal neuronal coding (including spontaneous activity, expansion of receptive field size) seen after spinal nerve ligation. Furthermore the powerful actions of gabapentin after neuropathy were blocked by either ablation of NK-1 expressing neurones or 5HT(3) receptor antagonism using ondansetron. Remarkably, 5HT(3) receptor activation provided a state-dependency (independent of that produced by neuropathy) allowing GBP to powerfully inhibit in normal uninjured animals. This circuit is therefore a crucial determinant of the abnormal neuronal and behavioural manifestations of neuropathy and importantly, the efficacy of gabapentin. As this spino-bulbo-spinal circuit contacts areas of the brain implicated in the affective components of pain, this loop may represent a route by which emotions can influence the degree of pain in a patient, as well as the effectiveness of the drug treatment. These hypotheses are testable in patients.

PMID: 16150546 [PubMed - indexed for MEDLINE]











Neuroscience. 2006;137(1):287-99. Epub 2005 Nov 10.

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Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors.

Gannon RL, Millan MJ.

Department of Biology, Idle Hour Boulevard, Dowling College, Oakdale, NY 11769, USA. gannonr@dowling.edu

Mammalian circadian activity rhythms are generated by pacemaker cells in the suprachiasmatic nucleus (SCN). As revealed by the actions of diverse agonists, serotonergic input from raphe nuclei generally inhibits photic signaling in the suprachiasmatic nucleus. In contrast, the serotonin (5HT)1A partial agonist, 4-(benzodioxan-5-yl)1-(indan2-yl)piperazine (S 15535), was found to enhance the phase-shifting influence of light on hamster circadian rhythms [Gannon, Neuroscience 119 (2003) 567]. Herein, we extend this observation in showing that S 15535 (5.0 mg/kg, i.p.) markedly (275%) enhanced the light-induced phase shift in circadian activity rhythms: further, this action was dose-dependently abolished by the highly-selective 5HT1A receptor antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-2-pyridinyl-cyclohexane-carboxamide maleate) (0.1-0.5 mg/kg, i.p.). WAY 100,635, which was inactive alone, shares the antagonist actions of S 15535 at postsynaptic 5HT1A sites, yet blocks its effects at their presynaptic counterparts. Thus, 5HT1A autoreceptor activation must be involved in this effect of S 15535 which contrasts with the opposite, inhibitory influence upon phase shifts of the "full" agonist, 8-OH-DPAT, which acts by stimulation of postsynaptic 5HT1A receptors [Rea et al., J Neurosci 14 (1994) 3635]. Despite the occurrence of 5HT2A and 5HT2C receptors in the (rat) suprachiasmatic nucleus, their influence on circadian rhythms is unknown since actions of selective ligands have never been evaluated. This issue was investigated with the most selective agents currently available. However, the 5HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.25 and 0.5 mg/kg), and the 5HT2C agonist, alphaS-6-chloro-5-fluoro-a-methyl-1H-indole-1-ethanamine fumarate (Ro-60-0175) (1.0 and 5.0 mg/kg), failed to affect light-induced phase shifts in hamsters. Moreover, even over broad dose-ranges, the 5HT2A antagonist, (+)-(2,3-dimethoxy-phenyl)-[1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl]methanol (MDL 100,907) (0.1-1.0 mg/kg), and the 5HT2C antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl carbamoyl]indoline (SB 242,084) (1.0-10.0 mg/kg), were likewise inactive. In view of evidence that 5HT2A and 5HT2C sites functionally interact with 5HT1A receptors, we also examined the influence of these agents upon the actions of S 15535, but no significant alteration was seen in its enhancement of rhythms. In conclusion, S 15535 elicits a striking enhancement of light-induced phase shifts in circadian rhythms by specifically recruiting 5HT1A autoreceptors, which leads to suppression of serotonergic input to the suprachiasmatic nucleus. Surprisingly, no evidence for a role of 5HT2A or 5HT2C sites was found, though comparable functional studies remain to be undertaken in rats. Indeed, the present work underlines the importance of comparative studies of circadian rhythms in various species, as well as the need for further study of potential interactions among 5HT receptor subtypes in their control.

















Gynecol Oncol. 2006 Apr 20; [Epub ahead of print]

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Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: An independent prognostic factor for tumor progression.

Jiang YP, Wu XH, Shi B, Wu WX, Yin GR.

Department of Obstetrics and Gynecology, the Second Hospital of Hebei Medical University, Shijiazhuang, China.

OBJECTIVES.: Chemokine CXCL12 and its unique receptor CXCR4 have been recently implicated in cancer metastasis. Our goal was to explore expression of CXCL12 and CXCR4 protein in normal ovarian surface epithelium, primary tumors and paired metastases of epithelial ovarian cancer as well as its association with clinicopathological features. We also wanted to test if expression of CXCR4 has prognostic value in epithelial ovarian cancer patients. METHOD.: Sections from 6 normal ovarian surface epithelium, 44 primary epithelial ovarian tumors and 30 paired metastatic tumors in omentum were evaluated for CXCL12 and CXCR4 expression using immunohistochemistry (IHC). RESULTS.: All samples of normal ovarian surface epithelium were negative for CXCL12 and CXCR4 protein. Ovarian cancer cells mainly showed cytoplasmic staining of CXCL12 and CXCR4. CXCL12 and CXCR4 staining were detected in 40/44 (91%) and 26/44 (59%) patients with primary epithelial ovarian tumors respectively. CXCR4 expression in primary tumors had no significant correlation with lymph nodes metastasis. However, if we combined CXCR4 expression in primary tumors with metastatic tumors, a significant correlation with lymph nodes metastasis was found (P = 0.018). The intensity of CXCL12 staining correlated with ascites (P = 0.014). The rate of CXCR4 expression in refractory and recurrent group (81% versus 28%, P = 0.0008) was significantly higher than that in no-recurrent group. After a median follow-up of 37 months, CXCR4 expression was found associated with an unfavorable prognosis with significantly reduced median disease progression-free survival and overall survival of 15 and 27 months (P = 0.0004, P = 0.017) respectively. Median time-to-event was not reached in patients with negative CXCR4 staining. In multivariate analysis, CXCR4 expression and residual tumor size emerged as independent prognostic factors in epithelial ovarian cancer patients. CONCLUSIONS.: This article provides the first evidence that CXCR4 expression could be an independent prognostic factor for epithelial ovarian cancer patients.

PMID: 16631235 [PubMed - as supplied by publisher]


: Neurochem Int. 2006 Apr 16; [Epub ahead of print]

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Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: Role of CXCR4 and SDF1 in glioma cell proliferation and migration.

Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, Ravetti JL, Zona G, Spaziante R, Corte G, Schettini G, Florio T.

Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.

Chemokines have been involved in cellular processes associated to malignant transformation such as proliferation, migration and angiogenesis. The expression of five CXC chemokine receptors and their main ligands was analysed by RT-PCR in 31 human astrocytic neoplasms. The mRNAs for all the receptors analysed were identified in a high percentage of tumours, while their ligands showed lower expression. CXCR4 and SDF1 were the most frequently mRNA identified (29/31 and 13/31 of the gliomas studied, respectively). Thus, we further analysed the cell localization of CXCR4 and SDF1 in immunohistochemistry experiments. We show a marked co-localization of CXCR4 and SDF1 in tumour cells, mainly evident in psudolpalisade and microcystic degeneration areas and in the vascular endothelium. In addition, hSDF1alpha induced a significant increase of DNA synthesis in primary human glioblastoma cell cultures and chemotaxis in a glioblastoma cell line. These results provide evidence of the expression of multiple CXC chemokines and their receptors in brain tumours and that in particular CXCR4 and SDF1 sustain proliferation and migration of glioma cells to promote malignant progression.

PMID: 16621164 [PubMed - as supplied by publisher]