Metal complexes with dual anti-inflammatory activity

Diseases associated with chronic inflammation represent even today a significant medical problem. Elaborating of more effective strategies for treating these diseases, with less severe side effects, is one of the big challenges of the contemporary medicine. Simultaneous targeting of the intracellular signaling involving transcription factors NF-B and peroxisome proliferator-activated receptors (PPARs) could be a promising treatment approach of how to suppress inflammation. This project aims to identify novel potent anti-inflammatory substances based on lead compounds isolated from selected plants. The focus will be laid on prenylated phenolic compounds, derived mainly, but not exclusively, from medical plants Paulownia tomentosa and Morus alba. These substances will be isolated by different chromatographic techniques, and subsequently identified by analytical methods, especially mass spectrometry and nuclear magnetic resonance spectrometry. In order to increase their biological activity, prenylated phenolic compounds will be then used as starting material for coordination reactions with metal ions, such as copper(II), gold(I/III) and zinc(II). The newly synthesized metallocomplexes will be structurally characterized by a variety of appropriate analytic techniques, and will be tested on their biological activity in in vitro and in vivo assays. This testing will be performed in genetically-engineered human cell lines, allowing the assessment of NF-B- and PPAR- signaling. Selected candidate substances will be further tested in cultured human umbilical vein endothelial cells (HUVECs) on their potency to suppress the inflammatory response. Having confirmed their anti-inflammatory activity, selected substances will be analyzed regarding their suitability to prevent induction of cellular senescence during chronic inflammatory stimulation of HUVECs. In addition, these compounds will be tested regarding their ability to selectively eliminate HUVECs in the senescent state. The anti-inflammatory effects of selected substances in vivo will be tested in pre-clinical models of inflammation. This cooperative project will be accomplished by close interaction of the Austrian partner at the Medical University of Vienna, with Czech partners at the Regional Centre of Advanced Technologies and Materials in Olomouc and at the Faculty of Pharmacy of the Masaryk University in Brno. The novelty of the project lies in the targeted identification and structural improvement of novel substances with potent dual anti-inflammatory activity that belong to a generally well tolerated and biologically active class of plant compounds and therefore seem well suited to find therapeutic use in combating chronic inflammatory diseases, such as psoriasis, rheumatoid arthritis or inflammatory bowel disease.

This project investigated acute and chronic inflammatory processes in blood vessel cells (specifically, in endothelial cells, which line the inside of blood vessels). These cells play a crucial role in various inflammatory processes, as they bind immune cells, which then migrate into the tissue. In acute inflammation, this contributes to the immune response and is a physiological process. In chronic inflammation, however, it can contribute to the development of various diseases-especially atherosclerosis, which is essentially a chronic inflammation of the arteries. We were able to show that endothelial inflammatory activation accelerates atherosclerosis and that a change in the genetic program occurs even at normal cholesterol levels. This also leads to increased production of the SARS-CoV-2 virus receptor, which could explain why patients with chronic inflammatory conditions develop more severe cases of COVID-19. The inflammatory processes also reduce cell viability and increase dysfunctional disorders, which can then lead, for example, to cardiovascular complications. Furthermore, we were able to demonstrate that short- and long-term inflammatory activation of endothelial cells differ in terms of gene expression and that the observed changes are similar to those occurring during cellular senescence. This leads not only to the induction of immune defense and inflammatory genes but also of genes that alter the identity of the cells. In this context, we also observed reduced wound healing capacity in chronic inflammatory conditions and in cellular senescence. In collaboration with our Czech project partners, we were able to study the biological effects of various metal conjugates of natural substances and describe anti-inflammatory effects that could be explained by two important cellular signaling pathways.