Molekuláris Sejt- és Immunbiológia Doktori Iskola

Állandó link (URI) ehhez a gyűjteményhez

https://hdl.handle.net/2437/31600

Általános Orvostudományi Kar

Molekuláris Sejt- és Immunbiológia Doktori Iskola
(vezető: Dr. Balogh István)

Orvostudományi doktori tanács

D183

tudományág:
- elméleti orvostudományok

Böngészés

Molekuláris Sejt- és Immunbiológia Doktori Iskola Szerző szerinti böngészés "Általános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet"

Megjelenítve 1 - 2 (Összesen 2)
  • Nincs kép
    TételSzabadon hozzáférhető
    Effects of polyphenols on P-glycoprotein (ABCB1) activity
    (12/12/2025) Singh, Kuljeet; Katalin, Goda; Molekuláris sejt- és immunbiológia doktori iskola; Általános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet
    ABCB1 is an active transporter physiologically expressed in pharmacologically important tissue barriers and frequently associated with the development of multidrug resistance in cancer cells. Dietary polyphenols involve a chemically related, but extremely diverse group of compounds abundant in plant derived food. Previous research demonstrated that several polyphenols are substrates or inhibitors of certain ABC transporters. Our experiments revealed that certain dietary polyphenols found in sour cherry and other red berries interact with human ABCB1as substrates or inhibitors. When applied alone, these polyphenols did not induce complete ABCB1 inhibition. However, combined treatments with low concentration of verapamil and various polyphenols such as QUR, naringenin or ellagic acid brought about a practically complete inhibition of ABCB1. Similarly, the combined application of QUR and C3S also induced a synergistic ABCB1 inhibitory effect, which could be exploited in chemotherapy protocols targeting multidrug-resistant tumors. To understand the molecular details of the interaction of C3S and QUR we carried out in silico ligand docking studies and MD simulations. These experiments revealed that C3S and QUR may bind simultaneously to the complex substrate-binding pocket of ABCB1. The most favourable binding poses were obtained when the bulkier C3S molecule bound to the central substrate binding site and the smaller QUR molecule occupied the “access tunnel”. Binding free energy calculations demonstrated that the simultaneous binding of two C3S or two QUR molecules to the complex substrate-binding pocket of ABCB1 is energetically less favourable compared to the C3S–QUR combination. The additive or synergistic transport inhibitory effects observed with polyphenol–verapamil combinations highlight a potential risk of drug–drug interactions on the level of ABCB1. These interactions necessitate more caution when consuming dietary polyphenols alongside chemotherapy regimens involving ABCB1 substrate or inhibitor drugs. Collectively, the integration of wet lab data and in silico studies enhances our understanding of the molecular mechanisms underlying ligand–ABCB1 interactions and pave the way for more efficient inhibition strategies of ABCB1 to overcome multidrug resistance.
  • Nincs kép
    TételSzabadon hozzáférhető
    Ruxolitinib-mediated Modulation and Dynamic Expression of P-glycoprotein in Human CD8+ T Cell Memory Subsets During Differentiation
    (20251017) Biwott, Kipchumba; Bacso, Zsolt; Kipchumba, Biwott; Molekuláris sejt- és immunbiológia doktori iskola; Általános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet
    The study investigated the interaction between ruxolitinib (RUX), an FDA-approved JAK1/2 inhibitor, and P-glycoprotein (Pgp/ABCB1/MDR1), an ATP-binding cassette transporter involved in drug resistance and immune regulation. Pgp exports xenobiotics and is expressed in immune cells, including T lymphocytes. While high Pgp expression is linked to poor responses in autoimmune diseases, it enhances the resilience of memory T cells, supporting immune recovery after chemotherapy. To evaluate this interaction, human primary T cells and NIH-3T3 MDR1 cells were used. RUX inhibited Pgp activity in a dose-dependent manner (at non-therapeutic levels), downregulated PD-1 and Pgp in activated T cells, activated basal Pgp ATPase activity, and interfered with verapamil-induced activation, suggesting functional modulation. Molecular analyses revealed that ABCB1 mRNA was high in unprimed T cells but declined with activation. RUX treatment upregulated ABCB1 in activated T cells, indicating its role as a transcriptional regulator. These findings may improve chemotherapy outcomes and aid in GVHD management. The effect of RUX on T-cell maturation showed a shift toward naive and central memory (Tcm) CD8+ T cells, with reduced effector and effector memory (Tem) subsets. This reprogramming may enhance therapeutic efficacy in myelofibrosis and immune disorders. Using an in vitro model, T cells were primed with JY antigen-presenting cells, and maturation was tracked over a month. RUX exposure promoted Pgp+ long-lived memory T cell maintenance and delayed effector differentiation. It also expanded CD127⁺ memory T cells, supporting long-term immune memory. In conclusion, this study demonstrates that RUX modulates Pgp function and T cell differentiation, with implications for autoimmune disease, transplantation, and cancer therapy. Targeting Pgp in memory T cells could improve the effectiveness of immunotherapies by enhancing memory cell survival and immune resilience.