Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.

Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.

Lung- and liver-dominant phenotypes of Korean eight constitution medicine have different profiles of genotype associated with each organ function.

Eight Constitution Medicine (ECM), a ramification of traditional Korean medicine, has categorized people into eight constitutions. The main criteria of classification are inherited differences or predominance in the functions of organs, such as the liver or lung, diagnosed through ECM-specific pulse patterns. This study investigated the association between single nucleotide polymorphism (SNP) genotypes and ECM phenotypes and explored candidate genetic makeups responsible for each constitution using a genome-wide association study (GWAS). Sixty-three healthy volunteers, who were either categorized as the Hepatonia (HEP, n = 32) or Pulmotonia (PUL, n = 31) constitution, were enrolled. HEP and PUL are two contrasting ECM types representing the dominant liver and lung phenotypes, respectively. SNPs were analyzed from the oral mucosa DNA using a commercially available microarray chip that can identify 820,000 SNPs. We conducted GWAS using logistic regression analysis and additive mode genotypes and constructed phylogenetic trees using the SNPhylo program with 8 SNPs specific for the liver phenotype and 15 SNPs for the lung phenotype. Although genome-wide significant SNPs were not found, the phylogenetic tree showed a clear difference between the two constitutions. This is the first observation suggesting genetic involvement in the ECM and can be extended to all ECM constitutions.

The Responsiveness of Bee Venom Phospholipase A2 on Regulatory T Cells Correlates with the CD11c+CD206+Population in Human Peripheral Blood Mononuclear Cells.

Bee venom phospholipase A2 (bvPLA2) has been reported to have therapeutic effects such as neuroprotection, anti-inflammation, anti-nociception, anti-cancer properties, caused by increasing regulatory T cells (Tregs). The mechanism of Tregs modulation by bvPLA2 has been demonstrated by binding with the mannose receptor, CD206 in experimental models of several diseases. However, it remains unknown whether this mechanism can also be applied in human blood. In this study, we collected peripheral blood samples from healthy donors and analyzed the percentages of monocyte-derived dendritic cells with CD206 (CD206+ DCs) before expansion, the proportion of Tregs, and the subpopulations after expansion treated with bvPLA2 or PBS using flow cytometry and the correlations among them. The percentage of Tregs tended to be higher in the bvPLA2 group than in the control group. There were significant positive correlations between the CD206 population in hPBMC and the proportions of Tregs treated with bvPLA2, especially in the Treg fold change comparing the increase ratio of Tregs in bvPLA2 and in PBS. These findings indicate that bvPLA2 increased the proportion of Tregs in healthy human peripheral blood and the number of CD206+ DCs could be a predictor of the bvPLA2 response of different individuals.

A Molecular Basis for the Inhibition of Transient Receptor Potential Vanilloid Type 1 by Gomisin A.

Transient receptor potential (TRP) channel has critical actions as conditional sensors in primary afferent neurons. We studied the regulatory action of gomisin A on TRPV1 channel current in this report. Schisandra chinensis contains bioactive compounds such as the gomisin derivatives and their related compounds. Coapplication with gomisin A inhibited the capsaicin-mediated inward peak current. This inhibitory effect of gomisin A on capsaicin-induced inward current showed concentration-dependence and was reversible. The half maximal inhibitory concentration of gomisin A was 62.7 ± 8.4 µM. In addition, this inhibition occurred in a noncompetition regulation mode and voltage insensitive manner. Furthermore, molecular docking studies of gomisin A on TRPV1 showed that it interacted predominantly with residues at cavities in the segments 1 and 2 of each subunit. Four potential binding sites for this ligand in the extracellular region at sensor domain of TRPV1 channel were identified. Point mutagenesis studies were undertaken, and gomisin A potency decreased for both the Y453A and N467A mutants. The double mutation of Y453 and N467 significantly attenuated inhibitory effects by gomisin A. In summary, this study revealed the molecular basis for the interaction between TRPV1 and gomisin A and provides a novel potent interaction ligand.

Fear of acupuncture enhances sympathetic activation to acupuncture stimulation.

BACKGROUND: Acupuncture treatment frequently evokes both pain and fear, causing patients to be hesitant about undergoing the procedure. This study investigated individual differences in autonomic response to acupuncture stimulation and its relationship to fear of the procedure. METHODS: Twenty-seven participants filled out the acupuncture fear scale (AFS) questionnaire and underwent acupuncture stimulation at the LI4 acupuncture point. Autonomic responses were measured by recording the skin conductance response (SCR) throughout acupuncture stimulation. Pearson correlation analysis was performed between the self-reported AFS scores and changes in SCR. RESULTS: After acupuncture stimulation, SCR significantly increased and there were greater individual differences in enhanced sympathetic activations to acupuncture stimulation. Changes in SCR correlated with scores for the painful sensation domain of the AFS. CONCLUSIONS: Our results indicate that fear of acupuncture-induced pain is associated with physiological arousal when people receive acupuncture stimulation. Fear of pain is the dominant factor in acupuncture-related fear and it should be considered in practice and in research.