Browsing by Author "Berzins, Kristaps"

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    Metformin Transport Rates Between Plasma and Red Blood Cells in Humans
    (2022-01) Kurlovics, Janis; Zake, Darta Maija; Zaharenko, Linda; Berzins, Kristaps; Klovins, Janis; Stalidzans, Egils
    Background: Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs). Objective: We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transport rate coefficient values based on metformin concentration time series in plasma and RBCs from in vivo studies. Methods: An ordinary differential equation (ODE) system with two compartments was used to describe diffusion-based passive transport between plasma and RBCs. Metformin concentration time series in plasma and RBCs of 35 individuals were used for metformin transport parametrization. Plasma concentration has been approximated by biexponential decline. Results: A single passive transport coefficient, k = 0.044 ± 0.014 (h–1), can be applied, describing the uptake and release transport rate versus the linear equation v = k × (Mpl − MRBC), where Mpl is the metformin concentration in plasma and MRBC is the metformin concentration in RBCs. Conclusions: Our research suggests that passive transport can explain metformin distribution dynamics between plasma and RBCs because transport speed is proportional to the metformin concentration difference and independent of the transport direction. Concentration difference-driven passive transport can explain the mechanism of faster metformin distribution to RBCs the first few hours after administration, and faster release and domination of the redistribution transport rate after metformin concentration in plasma becomes smaller than in RBCs.
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    OptEnvelope : A target point guided method for growth-coupled production using knockouts
    (2023-11) Motamedian, Ehsan; Berzins, Kristaps; Muiznieks, Reinis; Stalidzans, Egils
    Finding the best knockout strategy for coupling biomass growth and production of a target metabolite using a mathematic model of metabolism is a challenge in biotechnology. In this research, a three-step method named OptEnvelope is presented based on finding minimal set of active reactions for a target point in the feasible solution space (envelope) using a mixed-integer linear programming formula. The method initially finds the reduced desirable solution space envelope in the product versus biomass plot by removing all inactive reactions. Then, with reinsertion of the deleted reactions, OptEnvelope attempts to reduce the number of knockouts so that the desirable production envelope is preserved. Additionally, OptEnvelope searches for envelopes with higher minimum production rates or fewer knockouts by evaluating different target points within the desired solution space. It is possible to limit the maximal number of knockouts. The method was implemented on metabolic models of E. coli and S. cerevisiae to test the method benchmarking the capability of these industrial microbes for overproduction of acetate and glycerol under aerobic conditions and succinate and ethanol under anaerobic conditions. The results illustrate that OptEnvelope is capable to find multiple strong coupled envelopes located in the desired solution space because of its novel target point oriented strategy of envelope search. The results indicate that E. coli is more appropriate to produce acetate and succinate while S. cerevisiae is a better host for glycerol production. Gene deletions for some of the proposed reaction knockouts have been previously reported to increase the production of these metabolites in experiments. Both organisms are suitable for ethanol production, however, more knockouts for the adaptation of E. coli are required. OptEnvelope is available at https://github.com/lv-csbg/optEnvelope.