Bulgarian National Science Fund has granted within the framework of the Procedure for providing national co-funding for the participation of Bulgarian collectives in established actions under the European Cooperative Programme on Research and Technology COST (BG-175467353-2023-03) a project on

“Natural NRF2 activators modulating obesity mechanisms: molecular

pharmacology-based in vivo study (КП-06-КОСТ/4)”

 Project leader: Assoc. Prof. Liliya V. Mihaylova

Period: 23.05.2023-23.05.2025

Funding: 25 564 EUR

COST Action CA20121 BenBedPhar:Bench to Bedside transition for Pharmacological regulation of NRF2 in non communicable diseases Non-communicable diseases (NCDs) such as cancer, diabetes, cardiovascular, neurodegenerative, respiratory or immune diseases, account for 77% of all deaths in Europe and remain the most prevalent and without effective therapy. Networking among multidisciplinary teams that explore disease from a perspective of causative pathomechanisms rather than clinical symptoms is the most appropriate approach to overcome this problem. Such pathomechanisms imply the loss of homeostatic functions leading to the pathologic formation of reactive oxygen species, chronic inflammation, metabolic unbalance and proteinopathy. The transcription factor NRF2 is a master regulator of multiple cytoprotective responses and a key molecular link among many NCDs. It provides a unique strategy for drug development and repurposing that is now starting to be translated to the pharmacological and clinical arena. This Action will build a network of excellence for integrating and spreading the existing knowledge and providing innovative services, drugs and tools related to NRF2-pharmacology, with the final goal of boosting the translation to the European industry sector. To achieve this, the Action has already gathered a wide set of professionals from different disciplines (medical chemistry, pharmacology, clinical research, molecular biology, bioinformatics, etc.) and sectors (universities, research centres, hospitals, biobanks, biotech SMEs and pharma companies, etc.). The Action will expand among COST countries IPCs and NNCs, will actively involve SMEs and ECIs, and will respect gender balance.Thanks to COST tools the Action will boost the career of young researchers, wide participation (especially from ITC countries), and spread excellence.

The duration of BenBedphar is four years (19.10.2021-18.10.2025)
Reserach organizations from 33 coutries participate in BenBedPhar: https://benbedphar.org/management-committee/
CPSBB is represented by Dr. Liliya Mihaylova(Vasileva) as an MC member.
More information on the project you can find here: https://benbedphar.org/

Abstract

Excessive levels of oxidative stress and chronic low-grade inflammation are characteristic of the development of obesity and its associated pathologies. Cellular mechanisms of resistance against oxidative stress are controlled by the transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2). Pharmacological activation of NRF2 has been developed as a therapeutic approach for a number of non-communicable diseases, including obesity and diabetes. Accelerating the translation of the accumulated knowledge on modulating the activity of NRF2 “from bench to bedside” is the basis of the COST action 20121 “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar)”. The commitment to the BenBedPhar Management committee motivates the involvement of our team in the scientific tasks of CA20121.

In our department, an integrated approach between molecular pharmacology and ethnopharmacology has been adopted in order to identify plant secondary metabolites with anti-obesity activity. In this context, an in vivo model system of glucose-induced obesity was established in the nematode species Caenorhabditis elegans. This model organism allows an adequate assessment of obesity processes, as well as possessing a protein (skn-1) that is a functional analog of NRF. Within the framework of the proposed project, selected bioactive compounds – established NRF2 activators will be evaluated for their anti-obesity potential and the involvement of skn-1/NRF2 signaling in it. In addition, the most promising natural compounds will be included in a hybrid combination with orlistat and/or metformin to evaluate whether they enhance the effect of the anti-obesity drug compound.

In conclusion, the data obtained from our research will reveal the application potential of natural NRF2 activators against obesity and the molecular mechanism of their action, which could accelerate their subsequent clinical development.