Мақола

Ferula sesquiterpenes, ferutinin, galbanic acid and karatavic acid, suppress thymocyte volume regulation and proliferation by blocking the volume-sensitive anion channel

Ravshan Z. SabirovInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan; Department of Biophysics, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]S. I. RustamovaInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]Gulnoza A. ToshtemirovaInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]Nargiza A. TsiferovaInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan; Center for Advanced Technologies, Tashkent 100174, Uzbekistan. Electronic address: [email protected]Sirojbek A KhojiboevInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]Diyor D. FayzievInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan; Department of Biophysics, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]Utkir K InogamovInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan; Tashkent Scientific Research Institute for Vaccines and Serums, Tashkent 100084, Uzbekistan. Electronic address: [email protected]Ranokhon Sh. KurbannazarovaInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan; Department of Biophysics, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]В. Н. СыровInstitute of Chemistry of Plant Substances, Academy of Sciences of Uzbekistan, Tashkent 100170, Uzbekistan. Electronic address: [email protected]Petr G. MerzlyakInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan. Electronic address: [email protected]

Biomedicine & Pharmacotherapyjournal2025en

ABI

Аннотация

BACKGROUND: T cell development and maturation requires efficient cell volume regulation (CVR) system. Although the molecular basis of CVR is being rapidly elucidated, pharmacology of its key components remains poorly developed. Biopharmaceuticals specifically targeting CVR and its central player, the volume-sensitive outwardly rectifying anion channel (VSOR/VRAC), are necessary to uncover relationships between the channel, CVR and cell proliferation and survival. METHODS: The effects of three Ferula sesquiterpenes, ferutinin, galbanic acid and karatavic acid on the regulatory volume decrease (RVD) of freshly isolated thymocytes by light transmittance, on proliferation of primary cultured thymocytes by cell counting and on the VSOR/VRAC by patch-clamp were evaluated. RESULTS: Ferutinin, galbanic acid and karatavic acid exerted a profound inhibitory effect on RVD of thymocytes, leading to proliferation arrest. All three sesquiterpenes blocked VSOR/VRAC in a voltage-independent "cork-in-bottle" manner with half-maximal efficiencies comparable to those for RVD. Hill coefficients of 2.0-3.3 imply that positively cooperated binding of 2-3 molecules of the Ferula sesquiterpenes to VSOR/VRAC is required to suppress cell proliferation via inhibition of CVR. The Ferula sesquiterpenes were not apoptogenic, but induced necrotic cell death, which was pronounced for ferutinin and less manifested for galbanic and karatavic acids. VSOR/VRAC and RVD inhibition did not correlate with necrotic cell death induction. CONCLUSION: The VSOR/VRAC channel blockage by Ferula sesquiterpenes was found to impair the CVR machinery of thymocytes, resulting in suppression of cell proliferation. The necrotic cell death is not a direct consequence of VSOR/VRAC and RVD inhibition, likely involving other cellular pathways.

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Мавзулар

Plant chemical constituents analysis Ion Transport and Channel Regulation Bioactive natural compounds

Идентификаторлар

DOI: 10.1016/j.biopha.2025.117875

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