TY - JOUR AU - Czuczi, Tamás AU - Murányi, József AU - Móra , István András AU - Gurbi, Bianka AU - Varga, Attila AU - Papp, Dávid AU - Schlosser, Gitta (Vácziné) AU - Csala, Miklós AU - Csámpai, Antal TI - Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 23 SN - 1661-6596 DO - 10.3390/ijms252313176 UR - https://m2.mtmt.hu/api/publication/35628010 ID - 35628010 AB - Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism, including colony formation as well as dose–response tests in HEK293T wild-type (WT) and HEK293T CLPP−/− cells. Following gradual structural fine-tuning based on high throughput screening, we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes N-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. We found that the compounds with IC50 values similar to those of ONC201 completely eradicated cancer cells at about 4 μM, while ONC201 treatment at even higher concentrations left 30–50% of viable cells behind. Both compounds exerted equal activity in WT and CLPP−/− HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives. By preserving tumor cytotoxicity, we aim to generate new drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window. LA - English DB - MTMT ER - TY - JOUR AU - Susán, Hanna AU - Orosz, Gabriella AU - Zámbó, Veronika AU - Csala, Miklós AU - Kereszturi, Éva TI - Severity Ranking of Missense and Frameshift Genetic Variants in SCD1 by In Silico and In Vitro Functional Analysis JF - NUTRIENTS J2 - NUTRIENTS VL - 16 PY - 2024 IS - 19 PG - 20 SN - 2072-6643 DO - 10.3390/nu16193259 UR - https://m2.mtmt.hu/api/publication/35422606 ID - 35422606 AB - Background: A considerable proportion of the symptoms associated with excessive dietary intake can be attributed to systemic imbalances in lipid metabolism. The prominent toxicity of saturated fatty acids has been repeatedly demonstrated and sheds light on the protective role of stearoyl-CoA desaturase-1 (SCD1), the key enzyme for fatty acid desaturation. SCD1 protein expression is regulated at the levels of transcription, translation, and degradation. However, the modulating effect of the variability of the human genome must also be taken into account. Therefore, we aimed to ascertain whether natural missense or frameshift mutations in SCD1 (p.H125P, p.M224L, p.A333T, p.R253AfsTer7) could influence the expression, degradation, or function of the enzyme. Methods: In silico and in vitro experiments were conducted to comprehensively evaluate the consequences associated with each genetic variation, with the objective of using the results to propose a risk or severity ranking of SCD1 variants. Results: As anticipated, the p.R253AfsTer7 variant was identified as the most deleterious in structural, functional, and quantitative terms. The p.H125P variant also reduced the desaturation capacity of the enzyme in accordance with the predicted structural alterations and augmented degradation resulting from folding complications. This was aggravated by increased mRNA instability and accompanied by mild endoplasmic reticulum stress induction. The p.A333T protein exhibited an intermediate phenotype, whereas p.M224L showed no deleterious effects and even increased the amount of SCD1. Conclusions: In conclusion, the large-scale identification of genetic variations needs to be supplemented with comprehensive functional characterization of these variations to facilitate adequate personalized prevention and treatment of lipid metabolism-related conditions. LA - English DB - MTMT ER - TY - JOUR AU - Gurbi, Bianka AU - Dános, Kornél AU - Birtalan, Ede AU - Krenács, Tibor AU - Kovács, Borbála AU - Tamás, László AU - Csala, Miklós AU - Varga, Attila TI - Potential Prognostic Role of Protein Kinase D Isoforms in Head and Neck Cancers JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 19 PG - 15 SN - 1661-6596 DO - 10.3390/ijms251910274 UR - https://m2.mtmt.hu/api/publication/35417664 ID - 35417664 N1 - Export Date: 24 November 2024 AB - Head and neck squamous cell carcinomas (HNSCC) are among the most common malignancies in men worldwide. Nevertheless, their clinical management is hampered by the limited availability of reliable predictive and prognostic biomarkers. Protein kinase D (PKD) isoforms contribute to major cellular processes. However, their potential role in HNSCC has not been studied systematically, which is the focus of this study. A total of 63 therapy-naive patients with squamous cell carcinoma were consecutively enrolled. Tissue microarray duplicate cores from each case were tested in situ for PKD1, PKD2, and PKD3 expression using immunohistochemistry, and the results were correlated with clinicopathological parameters. We found a high frequency of PKD1/PKD2 positive cases in oropharyngeal and PKD2 positive cases in laryngeal localizations. Only high PKD2 levels were statistically linked to elevated tumor grades, more advanced TNM (3–4) tumor stages, and p16INK4a expression, while elevated PKD3 levels were associated with favorable disease-specific survival. Both PKD2 and PKD3 have been proposed to promote tumor cell proliferation, migration/invasion, and angiogenesis. However, the role of PKD3 was elusive in some cancers. Our findings suggest that testing for PKD isotypes with immunohistochemistry may support the diagnostic estimation of tumor progression and prognosis in HNSCC with a potential therapeutic relevance. LA - English DB - MTMT ER - TY - JOUR AU - Csala, Miklós TI - Aktuális kutatási témák a lipidmetabolizmus területén JF - BIOKÉMIA: A MAGYAR BIOKÉMIAI EGYESÜLET FOLYÓIRATA J2 - BIOKÉMIA VL - 48 PY - 2024 IS - 2 SP - 8 EP - 17 PG - 10 SN - 0133-8455 UR - https://m2.mtmt.hu/api/publication/35078314 ID - 35078314 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Tibori, Kinga AU - Zámbó, Veronika AU - Orosz, Gabriella AU - Szelényi, Péter AU - Sarnyai, Farkas AU - Tamási, Viola AU - Rónai, Zsolt AU - Csala, Miklós AU - Kereszturi, Éva TI - Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 14 PY - 2024 IS - 1 PG - 14 SN - 2045-2322 DO - 10.1038/s41598-023-50700-5 UR - https://m2.mtmt.hu/api/publication/34473748 ID - 34473748 AB - Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed. Therefore, we aimed to investigate the impact of the two main TFAs, vaccenate and elaidate, and four common promoter polymorphisms (rs1054411, rs670213, rs2275657, rs2275656) on SCD1 expression in HEK293T and HepG2 cell cultures using luciferase reporter assay, qPCR and immunoblotting. We found that SCD1 protein and mRNA levels as well as SCD1 promoter activity are markedly elevated by elaidate, but not altered by vaccenate. The promoter polymorphisms did not affect the basal transcriptional activity of SCD1 . However, the minor allele of rs1054411 increased SCD1 expression in the presence of various FAs. Moreover, this variant was predicted in silico and verified in vitro to reduce the binding of ETS1 transcription factor to SCD1 promoter. Although we could not confirm an association with type 2 diabetes mellitus, the FA-dependent and ETS1-mediated effect of rs1054411 polymorphism deserves further investigation as it may modulate the development of lipid metabolism-related conditions. LA - English DB - MTMT ER - TY - CHAP AU - Csala, Miklós ED - Mandl, József ED - Csala, Miklós TI - Lipotoxicitás T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest SN - 9789632267821 PY - 2023 SP - 492 EP - 496 PG - 5 UR - https://m2.mtmt.hu/api/publication/34426442 ID - 34426442 LA - Hungarian DB - MTMT ER - TY - CHAP AU - Csala, Miklós ED - Mandl, József ED - Csala, Miklós TI - A rosszindulatú daganatok kialakulásának molekuláris alapjai T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest SN - 9789632267821 PY - 2023 SP - 421 EP - 445 PG - 25 UR - https://m2.mtmt.hu/api/publication/34426438 ID - 34426438 LA - Hungarian DB - MTMT ER - TY - CHAP AU - Csala, Miklós ED - Mandl, József ED - Csala, Miklós TI - Tejsavas acidózis és ketoacidózis - a pH-homeosztázis zavarai T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest SN - 9789632267821 PY - 2023 SP - 215 EP - 222 PG - 8 UR - https://m2.mtmt.hu/api/publication/34426434 ID - 34426434 LA - Hungarian DB - MTMT ER - TY - CHAP AU - Csala, Miklós ED - Mandl, József ED - Csala, Miklós TI - Az etanol anyagcseréjének patobiokémiája T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest SN - 9789632267821 PY - 2023 SP - 173 EP - 183 PG - 11 UR - https://m2.mtmt.hu/api/publication/34426431 ID - 34426431 LA - Hungarian DB - MTMT ER - TY - BOOK ED - Mandl, József ED - Csala, Miklós TI - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest PY - 2023 SN - 9789632267821 UR - https://m2.mtmt.hu/api/publication/34169550 ID - 34169550 LA - Hungarian DB - MTMT ER -