Biological Role of Labile, Diffusible Molecules

Csaba Szabo has joined the University of Fribourg in 2018. The research interest of Pr. Szabo and his group focuses on the biological and pathophysiological roles of various labile, diffusible small biological molecules. 

One class of these molecules is called free radicals. These species (for example superoxide, or nitric oxide) are produced in various cells during biological and pathophysiological processes and are involved in various processes ranging from cell death to inflammatory responses. Free radicals can induce cellular injury through damage to proteins, lipids or nucleic acids. One of the consequences of free radical mediated cellular injury involves the activation of an enzyme called poly(ADP-ribose) polymerase (PARP). Pr. Szabo has been working on the role of PARP in various pathophysiological processes (vascular injury, circulatory shock, inflammation) for many years, and is now involved in efforts seeking to repurpose clinically used (for cancer) PARP inhibitors for  the experimental therapy of various non-oncological diseases. 

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) represent a unique class of labile biological mediators called gasotransmitters. These molecules travel easily through cell membranes and mediate multiple processes in the vascular, immune and nervous system through acting on multiple interrelated receptors and effectors. For the last decade, Pr. Szabo has been active in the field of H₂S biology, where he studies the pathophysiology, pharmacology and experimental therapy of various diseases (vascular, metabolic, cancer) in the context of alterations in H₂S homeostasis.

Main lines of research

• Role of the 3-MST system in metabolic and vascular disease

  3-mercaptopyruvate sulfurtransferase (3-MST) is one of the enzymes involved in the production of H₂S. This enzyme, present in the mitochondria as well as in the cytosol, is involved in the regulation of bioenergetic and signaling processes. With the support of a Swiss National Foundation (SNF) grant, Pr. Szabo's group studies the involvement of the 3-MST system in the regulation of hepatocyte dysfunction, adipocyte differentiation and vascular dysfunction in the context of metabolic disease.

  C. Szabo, T. Panagaki, F. Augsburger, K. Zuhra, E. Randi, K. Ascencao

• Role of the CBS/H₂S system in Down Syndrome

  CBS is one of the enzymes involved in the production of H₂S. This enzyme is overexpressed in Down Syndrome and, according to the so-called "Kamoun Hypothesis", it produces excessive amounts of H₂S that may lead to cytotoxicity. With the support of a LeJenue Foundation (Paris) grant, Pr. Szabo's group studies the involvement of the CBS system in the regulation of mitochondrial function, cell proliferation and cell viability in various experimental models of Down Syndrom.

  C. Szabo, T. Panagaki, E. Randi, L. Pecze, L. Montes-Lozano, K. Ascencao

• Role of the CBS system in colonic carcinogenesis

  The key enzyme responsible for H₂S production in colon cancer cells is cystathionine beta synthase (CBS). Although the phenomenon itself that cancer cells produce increased amounts of H2S to support their various biological functions is now well accepted, there are still significant gaps in our knowledge, with respect to the mechanism(s) how CBS is upregulated and activated in colon cancer cells in the early stages of colonic polypogenesis/carcinogenesis. With the support of a Swiss Krebsliga grant, identification of these activation and upregulation mechanisms is the goal of the current project.

  C. Szabo, N. Dilek, F. Augsburger, K. Ascencao

• Role of the PARP in acute lung injury

  Poly(ADP-ribose) polymerase is a multifunctional enzyme regulating DNA repair and cellular bioenergetics in health and disease.  With the support of a Swiss National Foundation (SNF) grant, Pr. Szabo's group studies the involvement of PARP in the regulation of acute lung injury.

  C. Szabo, V. Martins, E. Randi