Author: Mereu, Maddalena ; Munro, Caitlin A ; Amos, Mary Ellen ; Indarte, Martín ; Goldstein, Ruben I ; Katz, Jonathan L ; Tanda, Gianluigi ; Jorvig, Jessica E ; Surratt, Christopher K ; Dallman, Elizabeth ; Leak, Rehana K ; Madura, Jeffry D ; Nielsen, Cienna L ; Talbot, Jeffery N ; Geffert, Laura M ; Choi, Hailey ; Wolters, Nicholas E

Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecule library for high DAT affinity drug-like compounds. One hit, coded "MI-4", inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21day, 10mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10mg/kg, bid) in the novelty-induced hypophagia test, which requires chronic treatment to produce antidepressant-like effects. MI-4 (10mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social avoidance test following 10days of social defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold.

01 Nov 1988·Applied and Environmental MicrobiologyQ2 · BIOLOGY

Production of d -Aminoacylase from Alcaligenes denitrificans subsp. xylosoxydans MI-4

Q2 · BIOLOGY

Article

Author: Moriguchi, Mitsuaki ; Ideta, Kohtaro

A bacterial strain that produces d -aminoacylase was isolated from soil and identified as Alcaligenes denitrificans subsp. xylosoxydans MI-4. l -Aminoacylase activity in this strain was only 1 to 2% of d -aminoacylase activity. d -Aminoacylase was inducibly produced. N -Acetyl- dl -leucine was the best inducer, and the d -isomer had the ability to induce the enzyme. Enzymatic resolution of N -acetyl- dl -methionine with the crude enzyme was carried out, and the d / l ratio in the resolved methionine was approximately 100/7, suggesting that resolution with crude enzymes may become possible by removing small amounts of the contaminated l -form with l -amino acid oxidase.

International Journal of Molecular MedicineQ3 · MEDICINE

Effects of GM-CSF and M-CSF on tumor progression of lung cancer: Roles of MEK1/ERK and AKT/PKB pathways

Q3 · MEDICINE

Article

Author: Uemura, Yoshiki ; Kubota, Tetsuya ; Saito, Tsuyako ; Bandobashi, Kentaro ; Kobayashi, Makoto ; Taguchi, Hirokuni ; Nakata, Hideshi

Several studies have demonstrated that colony-stimulating factors (CSFs) are closely associated with tumor progression, metastasis and invasion through autocrine or paracrine mechanism in lung cancer. However, biologic roles of CSFs are still unknown. Elucidating the biologic roles of CSFs and the regulatory mechanisms of tumor-specific behavior by CSFs raises the possibility of having a new therapeutic approach for lung cancer. We previously established two adenocarcinoma cell lines, A924 and A964 and a large cell carcinoma cell line MI-4. MI-4 and A924 constitutively produced an abundant dose of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). We examined the effects of GM-CSF and M-CSF on tumor growth, death, and invasion in CSF-producing (A924 and MI-4) and non-producing lung cancer cells (A549 and A964). These cell lines demonstrated both GM-CSF and M-CSF receptor mRNA expression. In our study, GM-CSF seemed to have advantage for tumor proliferation and invasion in lung cancer cells. M-CSF seemed to have advantage for tumor invasion, but not proliferation. The tumor-specific phenotypes (proliferation, invasion and survival) up-regulated by GM-CSF and M-CSF were mediated through MEK/ERK and PI3k/Akt pathways. However, when MEK/ERK was activated by transfection of active form of MEK1 cDNA, the tumor-specific behavior was promoted in CSF-non-producing cells, whereas inhibited in CSF-producing cells though MEK/ERK activation increased constitutive GM-CSF production. MEK/ERK signaling regulated differently tumor-specific behavior between CSF-producing cells and CSF-non-producing cells.

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