@article{MTMT:35628010, title = {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}, url = {https://m2.mtmt.hu/api/publication/35628010}, author = {Czuczi, Tamás and Murányi, József and Móra , István András and Gurbi, Bianka and Varga, Attila and Papp, Dávid and Schlosser, Gitta (Vácziné) and Csala, Miklós and Csámpai, Antal}, doi = {10.3390/ijms252313176}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {25}, unique-id = {35628010}, issn = {1661-6596}, abstract = {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.}, year = {2024}, eissn = {1422-0067}, orcid-numbers = {Gurbi, Bianka/0000-0002-5635-6255; Papp, Dávid/0000-0002-2006-7777; Schlosser, Gitta (Vácziné)/0000-0002-7637-7133; Csala, Miklós/0000-0002-3829-4361; Csámpai, Antal/0000-0003-2107-7309} } @article{MTMT:35422606, title = {Severity Ranking of Missense and Frameshift Genetic Variants in SCD1 by In Silico and In Vitro Functional Analysis}, url = {https://m2.mtmt.hu/api/publication/35422606}, author = {Susán, Hanna and Orosz, Gabriella and Zámbó, Veronika and Csala, Miklós and Kereszturi, Éva}, doi = {10.3390/nu16193259}, journal-iso = {NUTRIENTS}, journal = {NUTRIENTS}, volume = {16}, unique-id = {35422606}, abstract = {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.}, year = {2024}, eissn = {2072-6643}, orcid-numbers = {Orosz, Gabriella/0000-0002-2030-287X; Csala, Miklós/0000-0002-3829-4361} } @article{MTMT:35417664, title = {Potential Prognostic Role of Protein Kinase D Isoforms in Head and Neck Cancers}, url = {https://m2.mtmt.hu/api/publication/35417664}, author = {Gurbi, Bianka and Dános, Kornél and Birtalan, Ede and Krenács, Tibor and Kovács, Borbála and Tamás, László and Csala, Miklós and Varga, Attila}, doi = {10.3390/ijms251910274}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {25}, unique-id = {35417664}, issn = {1661-6596}, abstract = {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.}, year = {2024}, eissn = {1422-0067}, orcid-numbers = {Gurbi, Bianka/0000-0002-5635-6255; Dános, Kornél/0000-0002-3829-8266; Birtalan, Ede/0000-0002-5699-3545; Krenács, Tibor/0000-0001-9164-065X; Kovács, Borbála/0000-0001-6864-6041; Tamás, László/0000-0003-3723-9149; Csala, Miklós/0000-0002-3829-4361} } @article{MTMT:35078314, title = {Aktuális kutatási témák a lipidmetabolizmus területén}, url = {https://m2.mtmt.hu/api/publication/35078314}, author = {Csala, Miklós}, journal-iso = {BIOKÉMIA}, journal = {BIOKÉMIA: A MAGYAR BIOKÉMIAI EGYESÜLET FOLYÓIRATA}, volume = {48}, unique-id = {35078314}, issn = {0133-8455}, year = {2024}, eissn = {2060-8152}, pages = {8-17}, orcid-numbers = {Csala, Miklós/0000-0002-3829-4361} } @article{MTMT:34473748, title = {Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression}, url = {https://m2.mtmt.hu/api/publication/34473748}, author = {Tibori, Kinga and Zámbó, Veronika and Orosz, Gabriella and Szelényi, Péter and Sarnyai, Farkas and Tamási, Viola and Rónai, Zsolt and Csala, Miklós and Kereszturi, Éva}, doi = {10.1038/s41598-023-50700-5}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {34473748}, abstract = {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.}, year = {2024}, eissn = {2045-2322}, orcid-numbers = {Tibori, Kinga/0000-0002-6808-4015; Orosz, Gabriella/0000-0002-2030-287X; Sarnyai, Farkas/0000-0002-5525-5508; Tamási, Viola/0000-0001-7419-5603; Rónai, Zsolt/0000-0002-0909-7932; Csala, Miklós/0000-0002-3829-4361} } @{MTMT:34426442, title = {Lipotoxicitás}, url = {https://m2.mtmt.hu/api/publication/34426442}, author = {Csala, Miklós}, booktitle = {Orvosi patobiokémia}, unique-id = {34426442}, year = {2023}, pages = {492-496}, orcid-numbers = {Csala, Miklós/0000-0002-3829-4361} } @{MTMT:34426438, title = {A rosszindulatú daganatok kialakulásának molekuláris alapjai}, url = {https://m2.mtmt.hu/api/publication/34426438}, author = {Csala, Miklós}, booktitle = {Orvosi patobiokémia}, unique-id = {34426438}, year = {2023}, pages = {421-445}, orcid-numbers = {Csala, Miklós/0000-0002-3829-4361} } @{MTMT:34426434, title = {Tejsavas acidózis és ketoacidózis - a pH-homeosztázis zavarai}, url = {https://m2.mtmt.hu/api/publication/34426434}, author = {Csala, Miklós}, booktitle = {Orvosi patobiokémia}, unique-id = {34426434}, year = {2023}, pages = {215-222}, orcid-numbers = {Csala, Miklós/0000-0002-3829-4361} } @{MTMT:34426431, title = {Az etanol anyagcseréjének patobiokémiája}, url = {https://m2.mtmt.hu/api/publication/34426431}, author = {Csala, Miklós}, booktitle = {Orvosi patobiokémia}, unique-id = {34426431}, year = {2023}, pages = {173-183}, orcid-numbers = {Csala, Miklós/0000-0002-3829-4361} } @book{MTMT:34169550, title = {Orvosi patobiokémia}, url = {https://m2.mtmt.hu/api/publication/34169550}, isbn = {9789632267821}, editor = {Mandl, József and Csala, Miklós}, publisher = {Medicina Kiadó Zrt.}, unique-id = {34169550}, year = {2023}, orcid-numbers = {Mandl, József/0000-0001-9172-7202; Csala, Miklós/0000-0002-3829-4361} }