Potenciális bioaktivitással rendelkező cinkona alapú organokatalizátorok vizsgálata: Study of cinchona-based organocatalysts with potential bioactivity

One of the major representatives of organocatalysts is the group of  cinchona alkaloids, which, in addition to their outstanding role in organic synthesis, also have diverse biological effects. An excellent example is quinine, a long-known and generally used antimalarial agent possessing anticancer activity as well, thus the study of bioactivity and anticancer toxicity of other organocatalysts may be a question of interest. Multidrug resistance (MDR) is the main reason for the failure of chemotherapy, owing to the process in which malignant tumor cells develop resistance towards the cytotoxic agents used during the treatment. One of the most significant mechanisms of MDR is the elevated expression of P-glycoprotein (Pgp, ABCB1, MDR1), a protein belonging to the family of ABC (ATP-binding cassette) transporters, which recognizes many chemotherapeutic compounds as its substrate. We aimed to synthesize amine, thiourea, and squaramide derivatives from quinine, which, based on previous results of our research group, are presumably able to eliminate multidrug-resistant cells overexpressing Pgp. The synthesized compounds were tested and evaluated on parental and MDR cancer cell lines. Chemotypes have been successfully characterized in terms of cytotoxicity and resistance. Kivonat Az organokatalizátorok egy jelentős képviselői a cinkona alkaloidok, amelyek kémiai szerepük mellett változatos biológiai hatással is rendelkeznek. Ennek kiváló példája a kinin, amely egy régóta ismert és alkalmazott maláriaellenes szer, rákellenes hatással is rendelkezik, így érdekes kérdésként vetődhet fel további organokatalizátorok bioaktivitásának, rákellenes toxicitásának vizsgálata. A rosszindulatú tumorok kezelése során alkalmazott kemoterápia gyakran azért vall kudarcot, mert a tumorsejtek rezisztenssé válnak az alkalmazott citotoxikus szerekre, kialakul a multidrog rezisztencia (MDR). Az MDR egyik legjelentősebb mechanizmusa az ABC (ATP-binding cassette) transzporterek családjába tartozó P-glikoprotein (Pgp, ABCB1, MDR1) fehérje fokozott expressziója, amely számos kemoterápiás vegyületet szubsztrátjaként ismer fel. Célunk a kininből kiindulva olyan amin, tiokarbamid és négyzetamid származékok szintézise volt, amelyek a kutatócsoportunk korábbi eredményei alapján feltételezhetően képesek eliminálni a Pgp-t túlexpresszáló multidrog rezisztens sejteket. A szintetizált vegyületek tesztelését parentális és MDR rákos sejtvonalakon végeztük. Citotoxicitás és rezisztencia terén is sikeresen jellemeztük a kemotípusokat

Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy

The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction’s echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory ( Il6, Tnf ), fibrosis ( Col1 ), and apoptosis markers ( Bax/Bcl2 ) relative to the CKD group. In summary, KP-13’s influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle

Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy

The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction’s echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13’s influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.Peer reviewe