The role of biogenic amines in the modulation of monocytes in autoimmune neuroinflammation.

Multiple sclerosis (MS) is inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) with autoimmune mechanism of development. The study of the neuroimmune interactions is one of the most developing directions in the research of the pathogenesis of MS. The influence of biogenic amines on the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS was shown by the modulation of subsets of T-helper cells and B-cells, which plays a crucial role in the autoimmunity of the CNS. However, along with T- and B-cells the critical involvement of mononuclear phagocytes such as dendritic cells, macrophages, and monocytes in the development of neuroinflammation also was shown. It was demonstrated that the activation of microglial cells (resident macrophages of the CNS) could initiate the neuroinflammation in the EAE, suggesting their role at an early stage of the disease. In contrast, monocytes, which migrate from the periphery into the CNS through the blood-brain barrier, mediate the effector phase of the disease and cause neurological disability in EAE. In addition, the clinical efficacy of the therapy with depletion of the monocytes in EAE was shown, suggesting their crucial role in the autoimmunity of the CNS. Biogenic amines, such as epinephrine, norepinephrine, dopamine, and serotonin are direct mediators of the neuroimmune interaction and may affect the pathogenesis of EAE and MS by modulating the immune cell activity and cytokine production. The anti-inflammatory effect of targeting the biogenic amines receptors on the pathogenesis of EAE and MS by suppression of Th17- and Th1-cells, which are critical for the CNS autoimmunity, was shown. However, the latest data showed the potential ability of biogenic amines to affect the functions of the mononuclear phagocytes and their involvement in the modulation of neuroinflammation. This article reviews the literature data on the role of monocytes in the pathogenesis of EAE and MS. The data on the effect of targeting of biogenic amine receptors on the function of monocytes are presented.

TADF and X-ray Radioluminescence of New Cu(I) Halide Complexes: Different Halide Effects on These Processes.

A series of complexes [Cu2X2(Pic3PO)2] (X = Cl, Br, I) based on tris(pyridin-2-ylmethyl)phosphine oxide (Pic3PO) has been synthesized. At 298 K, these compounds exhibit thermally activated delayed fluorescence (TADF) of 1(M+X)LCT type with λmax varying from 485 to 545 nm, and quantum efficiency up to 54%. In the TADF process, the halide effect appears as the emission intensification and bathochromic shift of λmax in the following order X = I < Br < Cl. Upon X-ray irradiation, the title compounds emit radioluminescence, the emission bands of which have the same shape as those at TADF, thereby meaning a similar radiative excited state. By contrast to TADF, the halide effect in the radioluminescence is reversed: its intensity grows in the order X = Cl < Br < I, since heavier atoms absorb X-rays more efficiently. These findings essentially contribute to our knowledge about the halide effect in the photo- and radioluminescent Cu(I) halide emitters.

Comparative Study of Cytotoxic and Membranotropic Properties of Betulinic Acid-F16 Conjugate on Breast Adenocarcinoma Cells (MCF-7) and Primary Human Fibroblasts.

The present study evaluates the cytotoxicity of a previously synthesized conjugate of betulinic acid (BA) with the penetrating cation F16 on breast adenocarcinoma (MCF-7) and human fibroblast (HF) cell lines, and also shows the mechanism underlying its membranotropic action. It was confirmed that the conjugate exhibits higher cytotoxicity compared to native BA at low doses also blocking the proliferation of both cell lines and causing cell cycle arrest in the G0/G1 phase. We show that the conjugate indeed has a high potential for accumulation in mitochondria, being visualized in these organelles, which is most pronounced in cancer cells. The effect of the conjugate was observed to be accompanied by ROS hyperproduction in both cancerous and healthy cells, despite the lower base level of ROS in the latter. Along with this, using artificial liposomes, we determined that the conjugate is able to influence the phase state of lipid membranes, make them more fluid, and induce nonspecific permeabilization contributing to the overall cytotoxicity of the tested agent. We conclude that the studied BA-F16 conjugate does not have significant selective cytotoxicity, at least against the studied breast cancer cell line MCF-7.

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis.

A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3ß-hydroxy-C2-nicotinoylidene, 3ß-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose-response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI50 value of 0.0347 µM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic N-methyl-piperazinyl amide 29, which exhibited a broad-spectrum inhibition activity with GI50 < 1 µM against 33 tumor cell lines and <2 µM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound 29 could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G0/G1 phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound 29 is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.