{"id":13512,"date":"2024-05-10T10:58:16","date_gmt":"2024-05-10T08:58:16","guid":{"rendered":"https:\/\/semmelweis.hu\/pharmacology\/?page_id=13512"},"modified":"2024-10-11T19:40:00","modified_gmt":"2024-10-11T17:40:00","slug":"cardioprotection-research-group","status":"publish","type":"page","link":"https:\/\/semmelweis.hu\/pharmacology\/en\/research\/cardiovascular-and-metabolic-research-group\/cardioprotection-research-group\/","title":{"rendered":"Cardioprotection research group"},"content":{"rendered":"<p><iframe loading=\"lazy\" title=\"Cardiovascular And Metabolic Research Group\" width=\"753\" height=\"424\" src=\"https:\/\/www.youtube.com\/embed\/F89VrbDg4B4?feature=oembed\" frameborder=\"0\" allow=\"accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share\" referrerpolicy=\"strict-origin-when-cross-origin\" allowfullscreen><\/iframe><\/p>\n<div class=\"responsive-tabs\">\n<h2 class=\"tabtitle\">Projects<\/h2>\n<div class=\"tabcontent\">\n\n<p align=\"justify\"><strong><span lang=\"en-US\">Understanding Immunotherapy resistance and response of small cell lung cancer<\/span><\/strong><\/p>\n<p align=\"justify\"><span lang=\"en-US\">Project leaders: \u00c1gnes Pa\u00e1l, Anik\u00f3 G\u00f6rbe<\/span><\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12783 size-full\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/2.jpg\" alt=\"\" width=\"148\" height=\"222\" \/><\/td>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13292\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Gorbe-Aniko_SOTE_web004-683x1024.jpg\" alt=\"\" width=\"148\" height=\"222\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p align=\"justify\">\u00a0<\/p>\n<p style=\"text-align: justify\" align=\"justify\"><span lang=\"en-US\">Small cell lung cancer (SCLC) is one of the malignancies with the worst prognosis, for which there have been no significant advances in therapy over the last three decades. The first promising results have been with the use of immune checkpoint inhibitors (ICIs), but success is far below that seen in non-small cell lung cancer, where the use of ICIs has been a breakthrough in therapy. In SCLC, in some patients with extensive-stage disease, survival can be 1-2 months longer.<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12784 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/3-400x300.jpg\" alt=\"Microscopoical image of small round cells in small cell lung cancer\" width=\"400\" height=\"300\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/3-400x300.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/3.jpg 542w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/><\/p>\n<p style=\"text-align: center\" align=\"justify\"><span lang=\"en-US\">Microscopical image of small round cells in small cell lung cancer <\/span><\/p>\n<p align=\"justify\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12785 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-400x300.png\" alt=\"SCLC cells in culture\" width=\"400\" height=\"300\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-400x300.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-1024x768.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-768x576.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-1536x1152.png 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-753x565.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4.png 1600w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/><\/p>\n<p style=\"text-align: center\" align=\"justify\"><span lang=\"en-US\">SCLC cells in culture<\/span><\/p>\n<p style=\"text-align: justify\" align=\"justify\"><span lang=\"en-US\">These suggest that new approaches are needed to understand response and resistance of SCLC to Immunotherapy. Several research groups have identified molecular subtypes of SCLC, which partially correspond to each other. For example, weaker neuroendocrine marker expression is often associated with stronger immune infiltration (neuroendocrine-low, immune oasis tumors), which may suggest better Immunotherapy responsiveness in such tumors.<\/span><\/p>\n<p align=\"justify\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-large wp-image-12786\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-1024x503.png\" alt=\"A possible road to improved therapy: evolving subclassificiation of SCLC\" width=\"753\" height=\"370\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-1024x503.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-400x197.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-768x377.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-753x370.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5.png 1264w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p align=\"justify\">\u00a0<\/p>\n<p style=\"text-align: center\" align=\"justify\"><span lang=\"en-US\">A possible road to improved therapy: evolving subclassificiation of SCLC<\/span><\/p>\n<p align=\"justify\"><span lang=\"en-US\">Despite stronger immune infiltration, tumors do not always respond to ICIs, and local overexpression of immunosuppressive molecules has been detected. <\/span><\/p>\n<p align=\"justify\"><span lang=\"en-US\">We investigate the effects of silencing gene expression of one of these immunosuppressive molecules, annexin A1, in cell culture of neuroendocrine-low SCLC cell lines. We hypothesize that some features of the malignant phenotype may be affected by annexin A1 silencing, such as growth rate, epithelio-mesenchymal transition, metabolic shift, dominant transcription drivers and sensitivity to the classical chemotherapeutic agents, cisplatin and etoposide.<\/span><\/p>\n<p align=\"justify\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12787 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-300x400.png\" alt=\"\" width=\"300\" height=\"400\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-300x400.png 300w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-768x1024.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-1152x1536.png 1152w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-1536x2048.png 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-753x1004.png 753w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p align=\"justify\">\u00a0<\/p>\n<p style=\"text-align: center\" align=\"justify\"><span lang=\"en-US\">Fluorescent viability assay<\/span><\/p>\n<p style=\"text-align: justify\" align=\"justify\"><span lang=\"en-US\">We believe that studying the effects of annexin A1 silencing may help understand new aspects of small cell lung cancer that are relevant in therapy.<\/span><\/p>\n<p style=\"text-align: justify\" align=\"justify\"><span lang=\"en-US\">Learning opportunities:<\/span><\/p>\n<ul>\n<li style=\"text-align: justify\"><span lang=\"en-US\">culturing of small cell lung cancer cell lines<\/span><\/li>\n<li style=\"text-align: justify\"><span lang=\"en-US\">assessment of growth rate by cell counting and fluorescence viability assays<\/span><\/li>\n<li style=\"text-align: justify\"><span lang=\"en-US\">treatment of cells and chemosensitivity tests with fluorescence viability assays<\/span><\/li>\n<li style=\"text-align: justify\"><span lang=\"en-US\">western blot<\/span><\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13632 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-400x280.png\" alt=\"\" width=\"400\" height=\"280\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-400x280.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-1024x717.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-768x538.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-1536x1076.png 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-2048x1434.png 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/SCLC_sejtek_vmi_eng-753x527.png 753w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/><\/p>\n<p style=\"text-align: justify\" align=\"justify\"><span lang=\"en-US\">Related publications:<\/span><\/p>\n<ul>\n<li style=\"text-align: justify\">\n<p align=\"justify\">Dora, David et al. \u201cNeuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution.\u201d\u00a0<i>Molecular oncology<\/i>\u00a0vol. 14,9 (2020): 1947-1965. doi:10.1002\/1878-0261.12741<\/p>\n<\/li>\n<li style=\"text-align: justify\">\n<p align=\"justify\">Dora, David et al. \u201cCharacterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer.\u201d\u00a0<i>Biology<\/i>\u00a0vol. 10,6 502. 4 Jun. 2021, doi:10.3390\/biology10060502<\/p>\n<\/li>\n<li>\n<p style=\"text-align: justify\" align=\"justify\">Dora, David et al. \u201cProtein Expression of immune checkpoints STING and MHCII in small cell lung cancer.\u201d\u00a0<i>Cancer immunology, Immunotherapy : CII<\/i>\u00a0vol. 72,3 (2023): 561-578. doi:10.1007\/s00262-022-03270-w<\/p>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>Development of miRNAs as a new therapeutic tool in the treatment of cardiovascular diseases<\/strong><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-12849\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/1-3.png\" alt=\"\" width=\"310\" height=\"163\" \/><\/p>\n<p>Project supervisors: Prof. Dr. P\u00e9ter Ferdinandy Dr. Anik\u00f3 G\u00f6rbe<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-12850\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/2-3.png\" alt=\"\" width=\"221\" height=\"346\" \/><\/td>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-12851\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/3-3.png\" alt=\"\" width=\"231\" height=\"346\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-12852 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-4-393x400.png\" alt=\"\" width=\"393\" height=\"400\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-4-393x400.png 393w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/4-4.png 477w\" sizes=\"auto, (max-width: 393px) 100vw, 393px\" \/>Ischemic heart diseases and their pathological consequences belong to the leading causes of death worldwide. In the acute treatment of myocardial ischemia one of the most important tasks is the restoration of the tissue perfusion.<\/p>\n<p style=\"text-align: justify\">Unfortunately, reperfusion also causes further damage to the myocardium which is usually referred as reperfusion injury. In certain cases it is responsible for half of the total myocardial damage.<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify\">Despite that several small molecule drugs were found to decrease the infarct size in preclinical settings none of those were successfully translated to the human therapy. Therefore, it is necessary to find novel approaches and effective cardioprotective candidate molecules for future drug development.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12853 size-full\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-3.png\" alt=\"\" width=\"745\" height=\"439\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-3.png 745w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/5-3-400x236.png 400w\" sizes=\"auto, (max-width: 745px) 100vw, 745px\" \/><\/p>\n<p style=\"text-align: center\">Paolo Severino, Andrea D\u2019Amato et al., 2020, Int J Mol Sci., 10.3390\/ijms21218118<\/p>\n<p style=\"text-align: justify\">In the recent decades the potential application of oligonucleotide molecules such as miRNAs has emerged as an attractive and innovative approach in the treatment of various pathologies including cancers and even cardiovascular diseases.<\/p>\n<p style=\"text-align: justify\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-12854 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-3-336x400.png\" alt=\"\" width=\"336\" height=\"400\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-3-336x400.png 336w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/6-3.png 533w\" sizes=\"auto, (max-width: 336px) 100vw, 336px\" \/>It was identified that the dysregulation of miRNAs plays an important role in the pathomechanism myocardial infarction. MicroRNAs are short, ~18-25 nucleotide-long non-coding RNA sequences those negatively regulate gene expression at the post-transcriptional level either by inhibition of the translation or promotion of the target mRNA degradation. Even entire cellular pathways can be regulated by a single microRNA, therefore miRNAs have a great potential to become multi-target drugs for diseases with multifactorial origin. Two distinct types of the microRNA therapies are microRNA mimics and antagomiRs (Varga ZV et al., Am J Physiol Heart Circ Physiol, 10.1152\/ajpheart.00812.2013). MicroRNA mimics are double-stranded sequences, including \u201cguide\u201d strand, having the same sequence as its endogenous counterpart, and a not fully complementary passenger strand, which degrades after the detachment. AntagomiRs are essentially single-stranded antisense oligonucleotides with complementarity to an endogenous miRNA thereby blocking its function.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>1. Explorative pharmacokinetical profiling of miRNAs in murine models<\/strong><\/p>\n<p>Project leader and contact person: Dr. Andr\u00e1s Makkos, M\u00e1rta Szab\u00f3<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12855\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/7-1.png\" alt=\"\" width=\"223\" height=\"335\" \/><\/td>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13634\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/marta_szabo.jpg\" alt=\"\" width=\"223\" height=\"334\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-13635 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-400x208.png\" alt=\"\" width=\"400\" height=\"208\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-400x208.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-1024x532.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-768x399.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-1536x798.png 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles-753x391.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/06\/egeres_mirna_leveles.png 1573w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/>Although, the application of miRNAs are actively investigated in various indications, little is known about their pharmacokinetical properties and the differences in the characteristics between various miRNAs. Therefore, we aim to explore the pharmacokinetic profile of miRNA mimics and AntagomiRs in healthy animals.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13797 size-large\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan-1024x285.png\" alt=\"\" width=\"753\" height=\"210\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan-1024x285.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan-400x111.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan-768x214.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan-753x209.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvobe_3askep_1_pont_utan.png 1366w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>In vivo experimental methodologies (e.g., treatment with miRNAs, plasma\/tissue sampling)<\/li>\n<li>In vitro methods (e.g., western blot, RNA isolation, qRT-PCR)<\/li>\n<li>Histological methods (e.g., fixation, sectioning, staining methods, RNAscope)<\/li>\n<\/ul>\n<p>\n<strong>2. In vivo proof of concept studies of protectomiRs<\/strong><\/p>\n<p>Project leader and contact person: Dr. Andr\u00e1s Makkos, M\u00e1rta Szab\u00f3<\/p>\n<p>In these studies, we aim to explore and prove the cardioprotective effect of novel or previously identified protectomiRs (miRNAs) in murine model of myocardial infarction and heart failure. In addition, we also aim to characterize the tissue specific target gene expression profile changes both in the heart and various tissue types.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13798\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan.png\" alt=\"\" width=\"1472\" height=\"565\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan.png 1472w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan-400x154.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan-1024x393.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan-768x295.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_2es_pont_utan-753x289.png 753w\" sizes=\"auto, (max-width: 1472px) 100vw, 1472px\" \/><\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>In vivo experimental methodologies (treatment with miRNAs, plasma\/tissue sampling, murine models of myocardial infarction or heart failure)<\/li>\n<li>Histological methods (e.g. fixation, sectioning, staining methods, RNAscope)<\/li>\n<li>In vitro methodologies (e.g. western blot, RNA isolation, qRT-PCR)<\/li>\n<\/ul>\n<p><strong>3. Development of chemically modified miRNA mimics\/AntagomiRs<\/strong><\/p>\n<p>Project leader and contact person: Dr. Andr\u00e1s Makkos, M\u00e1rta Szab\u00f3<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-13799 size-full\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_3as_pont_1.png\" alt=\"\" width=\"221\" height=\"189\" \/>During the development of miRNA-based pharmacotherapies it is a crucial question to provide the proper bioavailability and tissue specificity meanwhile minimizing the potential toxicity of the medication. Accordingly, we are actively working on chemical modification-based improvement of our patented cardioprotective miRNA sequences in order to improve their pharmacokinetic properties and safety.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13800\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_3as_pont_2.png\" alt=\"\" width=\"415\" height=\"252\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_3as_pont_2.png 415w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_3as_pont_2-400x243.png 400w\" sizes=\"auto, (max-width: 415px) 100vw, 415px\" \/><\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>In vivo experimental methodologies (treatment with miRNAs, plasma\/tissue sampling)<\/li>\n<li>in silico modelling, preparative chemistry<\/li>\n<li>Cell culturing, cell culture-based experimental models (e.g. miRNA transfection, simulated-ischemia reperfusion model, viability assays, fluorescence signal measurement)<\/li>\n<li>Confocal microscopy imaging<\/li>\n<li>Histological methods (e.g. fixation, sectioning, staining methods, RNAscope)<\/li>\n<li>In vitro methodologies (e.g. western blot, RNA isolation, qRT-PCR)<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>4. Development of novel vehicle formulations with miRNA mimics\/AntagomiRs<\/strong><\/p>\n<p>Project leader and contact person: Dr. Andr\u00e1s Makkos<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-13802 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_1-400x314.jpg\" alt=\"\" width=\"400\" height=\"314\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_1-400x314.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_1.jpg 416w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/>As it was mentioned earlier the proper tissue specificity and plasma\/tissue half-life of the oligonucleotide-based therapies are challenging to provide. In addition to the chemical modifications the application of innovative vehicles could greatly improve the pharmacokinetic properties of cardioprotective miRNAs (e.g. tissue specifity, cellular uptake)<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: center\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13803\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben.png\" alt=\"\" width=\"1416\" height=\"701\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben.png 1416w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben-400x198.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben-1024x507.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben-768x380.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/mirvivo_4es_pont_egyben-753x373.png 753w\" sizes=\"auto, (max-width: 1416px) 100vw, 1416px\" \/><\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>Cell culturing, cell culture-based experimental models (e.g. miRNA transfection, simulated-ischemia reperfusion model, viability assays, fluorescence signal measurement)<\/li>\n<li>Confocal microscopy imaging<\/li>\n<li>In vivo experimental methodologies (treatment with oligonucleotides, plasma\/tissue sampling, murine models of myocardial infarction or heart failure)<\/li>\n<li>Histological methods (e.g. fixation, sectioning, staining methods, RNAscope)<\/li>\n<\/ul>\n<p>Publications:<\/p>\n<ul>\n<li>Makkos, A., \u00c1gg, B., Petrovich, B., Varga, Z. V., G\u00f6rbe, A., &amp; Ferdinandy, P. (2021). Systematic review and network analysis of microRNAs involved in cardioprotection against myocardial ischemia\/reperfusion injury and infarction: Involvement of redox signalling. Free radical biology &amp; medicine, 172, 237\u2013251. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2021.04.034<\/li>\n<li>Makkos, A., \u00c1gg, B., Varga, Z. V., Giricz, Z., Gy\u00f6ngy\u00f6si, M., Lukovic, D., Schulz, R., Bartekov\u00e1, M., G\u00f6rbe, A., &amp; Ferdinandy, P. (2021). Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs. International journal of molecular sciences, 22(17), 9539. https:\/\/doi.org\/10.3390\/ijms22179539<\/li>\n<li>Varga, Z. V., Zvara, A., Farag\u00f3, N., Kocsis, G. F., Pipicz, M., G\u00e1sp\u00e1r, R., Bencsik, P., G\u00f6rbe, A., Csonka, C., Pusk\u00e1s, L. G., Thum, T., Csont, T., &amp; Ferdinandy, P. (2014). MicroRNAs associated with ischemia-reperfusion injury and cardioprotection by ischemic pre- and postconditioning: protectomiRs. American journal of physiology. Heart and circulatory physiology, 307(2), H216\u2013H227. https:\/\/doi.org\/10.1152\/ajpheart.00812.2013<\/li>\n<li>Ferdinandy, P., Andreadou, I., Baxter, G. F., B\u00f8tker, H. E., Davidson, S. M., Dobrev, D., Gersh, B. J., Heusch, G., Lecour, S., Ruiz-Meana, M., Zuurbier, C. J., Hausenloy, D. J., &amp; Schulz, R. (2023). Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia\/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning. Pharmacological reviews, 75(1), 159\u2013216. https:\/\/doi.org\/10.1124\/pharmrev.121.000348<\/li>\n<li>On\u00f3di, Z., Visnovitz, T., Kiss, B., Hambalk\u00f3, S., Koncz, A., \u00c1gg, B., V\u00e1radi, B., T\u00f3th, V. \u00c9., Nagy, R. N., Gergely, T. G., Gerg\u0151, D., Makkos, A., Pelyhe, C., Varga, N., Re\u00e9, D., Ap\u00e1ti, \u00c1., Leszek, P., Kov\u00e1cs, T., Nagy, N., Ferdinandy, P., \u2026 Varga, Z. V. (2022). Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype. Journal of molecular and cellular cardiology, 165, 19\u201330. https:\/\/doi.org\/10.1016\/j.yjmcc.2021.12.007<\/li>\n<li>Schreckenberg, R., Klein, J., Kutsche, H. S., Schulz, R., G\u00f6m\u00f6ri, K., Bencsik, P., Benczik, B., \u00c1gg, B., S\u00e1ghy, \u00c9., Ferdinandy, P., &amp; Schl\u00fcter, K. D. (2020). Ischaemic post-conditioning in rats: Responder and non-responder differ in transcriptome of mitochondrial proteins. Journal of cellular and molecular medicine, 24(10), 5528\u20135541. https:\/\/doi.org\/10.1111\/jcmm.15209<\/li>\n<li>Tamargo, J., Agewall, S., Borghi, C., Ceconi, C., Cerbai, E., Dan, G. A., Ferdinandy, P., Grove, E. L., Rocca, B., Sulzgruber, P., Semb, A. G., Sossalla, S., Niessner, A., Kaski, J. C., &amp; Dobrev, D. (2023). New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022. European heart journal. Cardiovascular pharmacotherapy, 9(4), 353\u2013370. Advance online publication. https:\/\/doi.org\/10.1093\/ehjcvp\/pvad034<\/li>\n<li>Weber, B. Y., Brenner, G. B., Kiss, B., Gergely, T. G., Sayour, N. V., Tian, H., Makkos, A., G\u00f6rbe, A., Ferdinandy, P., &amp; Giricz, Z. (2022). Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia\/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo. Pharmaceuticals (Basel, Switzerland), 15(9), 1055. https:\/\/doi.org\/10.3390\/ph15091055<\/li>\n<li>S\u00e1ghy, \u00c9., V\u00f6r\u00f6s, I., \u00c1gg, B., Kiss, B., Koncsos, G., Varga, Z. V., G\u00f6rbe, A., Giricz, Z., Schulz, R., &amp; Ferdinandy, P. (2020). Cardiac miRNA Expression and their mRNA Targets in a Rat Model of Prediabetes. International journal of molecular sciences, 21(6), 2128. https:\/\/doi.org\/10.3390\/ijms21062128<\/li>\n<li>V\u00f6r\u00f6s, I., S\u00e1ghy, \u00c9., Poh\u00f3czky, K., Makkos, A., On\u00f3di, Z., Brenner, G. B., Baranyai, T., \u00c1gg, B., V\u00e1radi, B., Kem\u00e9ny, \u00c1., Leszek, P., G\u00f6rbe, A., Varga, Z. V., Giricz, Z., Schulz, R., Helyes, Z., &amp; Ferdinandy, P. (2021). Somatostatin and Its Receptors in Myocardial Ischemia\/Reperfusion Injury and Cardioprotection. Frontiers in pharmacology, 12, 663655. https:\/\/doi.org\/10.3389\/fphar.2021.663655<\/li>\n<li>Brenner, G. B., Makkos, A., Nagy, C. T., On\u00f3di, Z., Sayour, N. V., Gergely, T. G., Kiss, B., G\u00f6rbe, A., S\u00e1ghy, \u00c9., Z\u00e1dori, Z. S., L\u00e1z\u00e1r, B., Baranyai, T., Varga, R. S., Husti, Z., Varr\u00f3, A., T\u00f3thfalusi, L., Schulz, R., Baczk\u00f3, I., Giricz, Z., &amp; Ferdinandy, P. (2020). Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia\/Reperfusion. Cells, 9(3), 551. https:\/\/doi.org\/10.3390\/cells9030551<\/li>\n<li>Spannbauer, A., Traxler, D., Lukovic, D., Zlabinger, K., Winkler, J., Gugerell, A., Ferdinandy, P., Hausenloy, D. J., Pavo, N., Emmert, M. Y., Hoerstrup, S. P., Jakab, A., Gy\u00f6ngy\u00f6si, M., &amp; Riesenhuber, M. (2019). Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction. International journal of molecular sciences, 20(9), 2140. https:\/\/doi.org\/10.3390\/ijms20092140<\/li>\n<li>Sayour, N. V., Brenner, G. B., Makkos, A., Kiss, B., Kov\u00e1csh\u00e1zi, C., Gergely, T. G., Aukrust, S. G., Tian, H., Zenkl, V., G\u00f6m\u00f6ri, K., Szabados, T., Bencsik, P., Heinen, A., Schulz, R., Baxter, G. F., Zuurbier, C. J., Vok\u00f3, Z., Ferdinandy, P., &amp; Giricz, Z. (2023). Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study. Cardiovascular research, 119(6), 1336\u20131351. https:\/\/doi.org\/10.1093\/cvr\/cvad024<\/li>\n<li>Schreckenberg, R., Wolf, A., Szabados, T., G\u00f6m\u00f6ri, K., Szab\u00f3, I. A., \u00c1goston, G., Brenner, G., Bencsik, P., Ferdinandy, P., Schulz, R., &amp; Schl\u00fcter, K. D. (2022). Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo. International journal of molecular sciences, 23(12), 6512. https:\/\/doi.org\/10.3390\/ijms23126512<\/li>\n<\/ul>\n<p><strong>STUDIES ON THE HIDDEN CARDIOTOXIC OR CARDIOPROTECTIVE EFFECT OF PHARMACOLOGICAL COMPOUNDS<\/strong><\/p>\n<p style=\"text-align: justify\">The acute cessation of blood supply to the cardiac musculature during infarction leads to irreversible tissue damage and necrosis. These days the most efficient therapy to save the myocardium is the revascularization by either thrombolysis, percutaneous coronary intervention (PCI), or coronary bypass (CABG) surgery. However, the restoration of blood flow leads to further tissue damage. This phenomenon is termed ischemia\/reperfusion injury, which can manifest in 4 ways: an increase in the amount of infarcted tissues (see Figure 1), more pronounced microvascular obstruction, increased probability of arrhythmias, decreased cardiac contractility.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13805 size-large\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1-1024x430.png\" alt=\"\" width=\"753\" height=\"316\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1-1024x430.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1-400x168.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1-768x323.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1-753x316.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_1.png 1052w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p style=\"text-align: center\">Figure 1: A slice of rat heart undergone ischemia\/reperfusion and stained with Evan\u2019s blue and TTC. Pale area on the left slice represents infarcted tissue. The area of infarcted tissue is decreased by the application of a cardioprotective pharmacological agent.<\/p>\n<p>Licensed pharmacological tool for the treatment of ischemia\/reperfusion injury is not yet available despite the very intensive research in the field, however, there is a significant need for them to improve acute and long-term survival and\/or quality of life of patients with infarction. Therefore, we study the molecular aspects of cardiac ischemia\/reperfusion injury to identify novel pharmacological targets. Furthermore, we study the interaction between pharmacons used for other symptoms and the extent of ischemia\/reperfusion injury (hidden cardiotoxicity of drugs), and the effect of metabolic diseases on cardioprotective interventions and treatments.<\/p>\n<p><strong>1. Effect of pharmacological agents on ischemia\/reperfusion injury in small animal models: the significance of hidden cardiotoxicity<\/strong><\/p>\n<p>Project supervisors: Prof. Dr. P\u00e9ter Ferdinandy, Dr. Anik\u00f3 G\u00f6rbe Dr. Zolt\u00e1n Giricz,<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13291\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-scaled.jpg\" alt=\"\" width=\"210\" height=\"315\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-scaled.jpg 1707w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-267x400.jpg 267w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-683x1024.jpg 683w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-768x1152.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-1024x1536.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-1365x2048.jpg 1365w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-753x1130.jpg 753w\" sizes=\"auto, (max-width: 210px) 100vw, 210px\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13292\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Gorbe-Aniko_SOTE_web004.jpg\" alt=\"\" width=\"210\" height=\"315\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13806\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GZ.jpg\" alt=\"\" width=\"210\" height=\"315\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>Project leaders: Regina Nagy Bennet Weber Dr. Tam\u00e1s Gergely<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13811\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/NagyRegina.jpeg\" alt=\"\" width=\"190\" height=\"232\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13807\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/WeberBennet.jpg\" alt=\"\" width=\"210\" height=\"283\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-12909\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044.jpg\" alt=\"\" width=\"210\" height=\"315\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044.jpg 1365w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044-267x400.jpg 267w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044-683x1024.jpg 683w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044-768x1152.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044-1024x1536.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/12\/SOTE_web044-753x1130.jpg 753w\" sizes=\"auto, (max-width: 210px) 100vw, 210px\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p>Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market (see Figure 2). Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischemic tolerance and endogenous cardioprotective signaling pathways. Indeed, drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signaling due to ischemia\/reperfusion injury and\/or the presence of risk factors and\/or (ii) inhibition of cardioprotective survival signaling pathways, both of which may lead to ischemia-related cell death and\/or pro-arrhythmic effects. This led to a novel concept of \u2018hidden cardiotoxicity\u2019, defined as cardiotoxicity of a drug that manifests only in the diseased heart with e.g. ischemia\/reperfusion injury and\/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxicity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental in vivo and in vitro models of cardiac diseases (especially myocardial ischemia\/reperfusion and ischemic conditioning) in the presence and absence of major cardiovascular comorbidities and\/or cotreatments. (Ferdinandy et al, European heart journal, 2018)<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13813 size-full\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_2.jpg\" alt=\"\" width=\"942\" height=\"545\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_2.jpg 942w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_2-400x231.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_2-768x444.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_2-753x436.jpg 753w\" sizes=\"auto, (max-width: 942px) 100vw, 942px\" \/><\/p>\n<p style=\"text-align: center\">Figure 2: Cost of drug development during its phases. (Modified from: Ferdinandy et al. Eur Heart J, 2018)<\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>literature search methods,<\/li>\n<li>designing in vivo rat studies,<\/li>\n<li>animal handling, oral treatment of small animals,<\/li>\n<li>performing cardiac surgeries on rats,<\/li>\n<li>performing quantitative PCR and Western blots,<\/li>\n<li>data evaluation and presentation.<\/li>\n<\/ul>\n<p>\nOur major publications on the topic:<\/p>\n<p>Ferdinandy, P. et al. Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications. Eur Heart J, 2018. (link)<\/p>\n<p>Ferdinandy, P., et al. Interaction of risk factors, comorbidities, and comedications with ischemia\/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev, 2014. 66(4): p. 1142-74. (link)<\/p>\n<p>Brenner GB., et al. Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia\/Reperfusion. Cells. 2020 Feb 26;9(3):551. (link)<\/p>\n<p>Weber BY, et al. Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia\/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo. Pharmaceuticals (Basel). 2022 Aug 26;15(9):1055. (link)<\/p>\n<p>Gergely TG, et al. Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity. Int J Mol Sci. 2023 Jan 13;24(2):1585. (link)<\/p>\n<p><strong>2. Effect of pharmacological agents on ischemia\/reperfusion injury in in vitro cell culture models<\/strong><\/p>\n<p>Project supervisor: Dr. Anik\u00f3 G\u00f6rbe<\/p>\n<p>Project leaders: Bennet Weber, Regina Nagy, M\u00e1rta Szab\u00f3<\/p>\n<p>The hidden cardiotoxic effect of pharmacological compounds can be further tested in in vitro cell cultures. We have previously demonstrated the potential to investigate the safety of drug candidates in in vitro cell culture models in which simulation of ischemia\/reperfusion (I\/R) damage, and comorbidities can be achieved. Cardiac cell lines and primary isolated cardiac cells can be used for high throughput drug screening and their use is beneficial to assess the direct effects of drugs on cardiac cell types. In our project we test different agents that might show direct cardiotoxic effect on cardiac cells only in the presence of comorbidities like hypercholesterolemia or I\/R injury.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13814\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_csoportkep_1.png\" alt=\"\" width=\"556\" height=\"612\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_csoportkep_1.png 556w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_csoportkep_1-363x400.png 363w\" sizes=\"auto, (max-width: 556px) 100vw, 556px\" \/><\/p>\n<p style=\"text-align: center\">Figure 3: Cell maintenance practices in the cell culture laboratory.<\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>literature search methods,<\/li>\n<li>designing in vitro cell culture experiments,<\/li>\n<li>isolation of primary cardiac cells,<\/li>\n<li>maintaining cell cultures,<\/li>\n<li>treatment of cells with pharmacological compounds,<\/li>\n<li>performing viability assays,<\/li>\n<li>data evaluation and presentation.<\/li>\n<\/ul>\n<p>Our major publications on the topic:<\/p>\n<p>Brenner GB., et al. Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia\/Reperfusion. Cells. 2020 Feb 26;9(3):551. (link)<\/p>\n<p>Weber BY, et al. Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia\/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo. Pharmaceuticals (Basel). 2022 Aug 26;15(9):1055. (link)<\/p>\n<p><strong>3. Investigation of cardiac transcriptomic changes induced by pharmacological agents showing hidden cardiac effects<\/strong><\/p>\n<p>Project supervisor: Dr. Anik\u00f3 G\u00f6rbe<\/p>\n<p>Project leaders: Bennet Weber, Regina Nagy<\/p>\n<p style=\"text-align: justify\">Endogenous cardioprotective processes and molecules are well known in the reduction of myocardial ischemia \/ reperfusion (I\/R) damage, the effects of which are often lost during clinical translation, especially in the presence of comorbidities. In addition, many drugs may show myocardial side effects \/ hidden cardiotoxicity that have not been elucidated in current drug development practices. Changes in gene expression may also play a role in hidden cardiotoxicity, but these have not been fully explored and their research is a new aspect of safety pharmacology. In our project we aim to investigate the expression profile of myocardial microRNA and mRNA in rat treated with a drug with proven cardiotoxicity in an acute I\/R model may result in a number of differentially expressed target molecules. Based on the revealed expression profile changes, the mechanisms responsible for the side effects can be identified. The potential toxic or protective effects of selected microRNAs can be validated in an I\/R system in a human cardiomyocyte model. Molecular targets predicted in bioinformatics analysis can also be validated at transcript and protein levels.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13815 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_3-396x400.jpg\" alt=\"\" width=\"396\" height=\"400\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_3-396x400.jpg 396w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/hiddentox_3.jpg 701w\" sizes=\"auto, (max-width: 396px) 100vw, 396px\" \/><\/p>\n<p style=\"text-align: center\">Figure 4: Interaction network and cardiac miRNA target prediction analysis of downregulated miRNAs (green) and upregulated miRNAs (red) in a rat model of prediabetes.<\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>literature search methods,<\/li>\n<li>designing in vitro cell culture experiments,<\/li>\n<li>maintaining cell cultures,<\/li>\n<li>treatment of cells with pharmacological compounds,<\/li>\n<li>miRNA target search and validation by quantitative PCR and Western blots,<\/li>\n<li>data evaluation and presentation.<\/li>\n<\/ul>\n<p>Our major publications on the topic:<\/p>\n<p>S\u00e1ghy \u00c9, et al. Cardiac miRNA Expression and their mRNA Targets in a Rat Model of Prediabetes. Int J Mol Sci. 2020 Mar 20;21(6):2128. (link)<\/p>\n<p><strong>STUDIES ON THE METABOLIC COMORBIDITIES IN CARDIOVASCULAR DISEASES<\/strong><\/p>\n<p><strong>1. Effect of metabolic diseases on cardioprotective interventions and treatments against ischemia\/reperfusion injury<\/strong><\/p>\n<p>Project supervisors: Prof. Dr. Peter Ferdinandy, Dr. Anik\u00f3 G\u00f6rbe<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13291\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-267x400.jpg\" alt=\"\" width=\"210\" height=\"315\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-267x400.jpg 267w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-683x1024.jpg 683w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-768x1152.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-1024x1536.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-1365x2048.jpg 1365w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-753x1130.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Ferdinandy_Peter-scaled.jpg 1707w\" sizes=\"auto, (max-width: 210px) 100vw, 210px\" \/><\/td>\n<td style=\"width: 50%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13292\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/03\/Gorbe-Aniko_SOTE_web004.jpg\" alt=\"\" width=\"210\" height=\"315\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>Project leaders: Dr. Andr\u00e1s Makkos, Dr. Tam\u00e1s Gergely, Regina Nagy<\/p>\n<table style=\"border-collapse: collapse;width: 100%\">\n<tbody>\n<tr>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-12855\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2023\/11\/7-1.png\" alt=\"\" width=\"231\" height=\"347\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13809\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas.jpeg\" alt=\"\" width=\"210\" height=\"315\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas.jpeg 1365w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas-267x400.jpeg 267w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas-683x1024.jpeg 683w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas-768x1152.jpeg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas-1024x1536.jpeg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/GergelyTamas-753x1130.jpeg 753w\" sizes=\"auto, (max-width: 210px) 100vw, 210px\" \/><\/td>\n<td style=\"width: 33.3333%\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13811\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/NagyRegina.jpeg\" alt=\"\" width=\"190\" height=\"232\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p style=\"text-align: justify\">Metabolic derangements, such as obesity or diabetes, are major risk factors of cardiovascular diseases. The healthy heart can adapt to a certain level of ischemic injury (e.g., during a heart attack), but metabolic diseases, such as hypercholesterolemia, have a negative effect of this ischemia-tolerance of the heart, and may increase the extent of injury afflicted by ischemia\/reperfusion. The mechanism of the changes in the myocardium due to metabolic co-morbidities are not fully understood, more detailed information on them would enable the development of novel cardioprotective therapies, which would lead to a better prognosis of ischemic heart diseases. In our Department infarction is inflicted on anesthetized high fat diet-fed rats, as a model for hypercholesterolemia, in our state of the art small animal surgery facility (Figure 1) by a surgical procedure, where the left descending coronary artery is occluded by placing a suture around it for 30-45 min then released. During surgery, we monitor vital parameters (e.g., blood pressure, ECG, temperature, respiration; Figure 2). Our undergraduate researchers learn surgical techniques and are involved actively in our ongoing studies.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13818 size-large\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1-1024x575.jpg\" alt=\"\" width=\"753\" height=\"423\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1-1024x575.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1-400x225.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1-768x432.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1-753x423.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_1.jpg 1196w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p style=\"text-align: center\">Figure 1: Small animal surgery suits in the Department of Pharmacology<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-13817\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_2.jpg\" alt=\"\" width=\"510\" height=\"141\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_2.jpg 510w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_2-400x111.jpg 400w\" sizes=\"auto, (max-width: 510px) 100vw, 510px\" \/><\/p>\n<p style=\"text-align: center\">Figure 2: Vital parameters during in-vivo ischemia\/reperfusion surgery. From top: body temperature, blood pressure in a central artery, ECG.<\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>literature search methods,<\/li>\n<li>designing in vivo rat studies,<\/li>\n<li>working with metabolic disease models in rats,<\/li>\n<li>animal handling, oral treatment of small animals,<\/li>\n<li>performing cardiac surgeries on rats,<\/li>\n<li>performing quantitative PCR and Western blots,<\/li>\n<li>data evaluation and presentation.<\/li>\n<\/ul>\n<p>Our major publications on the topic:<\/p>\n<p>Andreadou I, Daiber A, Baxter GF, Brizzi MF, Di Lisa F, Kaludercic N, Lazou A, Varga ZV, Zuurbier CJ, Schulz R, Ferdinandy P. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling. Free Radic Biol Med. 2021 Apr;166:33-52.<\/p>\n<p>Andreadou I, Tsoumani M, Vilahur G, Ikonomidis I, Badimon L, Varga ZV, Ferdinandy P, Schulz R. PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation. Front Physiol. 2020 Nov 12;11:602497. doi: 10.3389\/fphys.2020.602497. PMID: 33262707; PMCID: PMC7688516.<\/p>\n<p>Andreadou I, Schulz R, Badimon L, Adameov\u00e1 A, Kleinbongard P, Lecour S, Nikolaou PE, Falc\u00e3o-Pires I, Vilahur G, Woudberg N, Heusch G, Ferdinandy P. Hyperlipidaemia and cardioprotection: Animal models for translational studies. Br J Pharmacol. 2020 Dec;177(23):5287-5311<\/p>\n<p>Andreadou I, Iliodromitis EK, Lazou A, G\u00f6rbe A, Giricz Z, Schulz R, Ferdinandy P. Effect of hypercholesterolemia on myocardial function, ischemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. Br J Pharmacol. 2017 Jun; 174 (12):1555-1569. (link)<\/p>\n<p>Pavo N, Lukovic D, Zlabinger K, Zimba A, Lorant D, Goliasch G, Winkler J, Pils D, Auer K, Jan Ankersmit H, Giricz Z, Baranyai T, S\u00e1rk\u00f6zy M, Jakab A, Garamv\u00f6lgyi R, Emmert MY, Hoerstrup SP, Hausenloy DJ, Ferdinandy P, Maurer G, Gy\u00f6ngy\u00f6si M. Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling. Sci Rep.2017 Mar 7;7:43958.. (link)<\/p>\n<p>Nagy CT, Koncsos G, Varga ZV, Baranyai T, Tuza S, Kassai F, Ernyey AJ, Gyerty\u00e1n I, Kir\u00e1ly K, Ol\u00e1h A, Radovits T, Merkely B, Bukosza N, Sz\u00e9n\u00e1si G, Hamar P, Math\u00e9 D, Szigeti K, Pelyhe C, Jelemensk\u00fd M, On\u00f3di Z, Helyes Z, Schulz R, Giricz Z, Ferdinandy. Selegiline reduces adiposity induced by high-fat, high-sucrose diet in male rats. Br J Pharmacol. 2018 Sep;175(18):3713-3726. (link)<\/p>\n<p>Koncsos G, Varga ZV, Baranyai T, Boengler K, Rohrbach S, Li L, Schl\u00fcter KD, Schreckenberg R, Radovits T, Ol\u00e1h A, M\u00e1ty\u00e1s C, Lux \u00c1, Al-Khrasani M, Koml\u00f3di T, Bukosza N, M\u00e1th\u00e9 D, Deres L, Bartekov\u00e1 M, Rajt\u00edk T, Adameov\u00e1 A, Szigeti K, Hamar P, Helyes Z, Tretter L, Pacher P, Merkely B, Giricz Z, Schulz R, Ferdinandy P. Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress. Am J Physiol Heart Circ Physiol. 2016 Oct 1;311(4):H927-H943. (link)<\/p>\n<p>Baranyai, T., et al., Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning. Cardiovasc Diabetol, 2015. 14: p. 151.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-13819 size-large aligncenter\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-1024x682.jpg\" alt=\"\" width=\"753\" height=\"502\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-1024x682.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3-203x135.jpg 203w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_3.jpg 1247w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p style=\"text-align: center\">Figure 3: Cardiac ultrasonography and cardiac pressure-volume analysis in the small animal surgery suits.<\/p>\n<p><strong>2. Effect of hypercholesterolemia on inflammasome activation in macrophages<\/strong><\/p>\n<p>Project supervisors: Dr. Anik\u00f3 G\u00f6rbe, Dr. Zolt\u00e1n Varga<\/p>\n<p>Project leader: Regina Nagy<\/p>\n<p>Hypercholesterolemia induces cholesterol accumulation in immune cells, like macrophages, which promotes inflammation through Toll-like receptor (TLR) signaling and inflammasome activation. Intracellular cholesterol accumulation and the consequent inflammatory response is probably beneficial in the response to infection, however, it worsens diseases in association with chronic inflammation, like atherosclerosis. Inflammation also plays a critical role in the genesis, progression, and manifestation of several cardiovascular diseases. Direct inhibition of inflammasomes, rather than proinflammatory cytokine suppression, can be an effective anti-inflammatory management. Thus, exploring the molecular mechanisms behind inflammasome activation can lead to the discovery of new potential drug targets in hypercholesterolemic cardiovascular comorbidities. In our project we aim to investigate the effect of in vitro hypercholesterolemic treatment on the inflammatory mechanisms of human monocytes\/macrophages.<\/p>\n<p>Learning opportunities:<\/p>\n<ul>\n<li>literature search methods,<\/li>\n<li>working with metabolic disease models in cell cultures,<\/li>\n<li>designing in vitro cell culture experiments,<\/li>\n<li>maintaining cell cultures,<\/li>\n<li>treatment of cells with pharmacological compounds,<\/li>\n<li>performing quantitative PCR and Western blots,<\/li>\n<li>data evaluation and presentation.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13822 size-medium\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_4-335x400.png\" alt=\"\" width=\"335\" height=\"400\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_4-335x400.png 335w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_4.png 509w\" sizes=\"auto, (max-width: 335px) 100vw, 335px\" \/><\/p>\n<p style=\"text-align: center\">Figure 4: The NLRP3 inflammasome complex.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-13821 size-medium aligncenter\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_5-400x174.png\" alt=\"\" width=\"400\" height=\"174\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_5-400x174.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_5.png 719w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/><\/p>\n<p style=\"text-align: center\">Figure 5: Fluorescent images of THP1-ASC-GFP monocytes following inflammasome stimulation by flagellin.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-13820 size-large\" src=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6-1024x249.png\" alt=\"\" width=\"753\" height=\"183\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6-1024x249.png 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6-400x97.png 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6-768x187.png 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6-753x183.png 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/07\/metab_6.png 1206w\" sizes=\"auto, (max-width: 753px) 100vw, 753px\" \/><\/p>\n<p style=\"text-align: center\">Figure 6: Fluorescent images of cholesterol uptake of THP1-ASC-GFP cells after treatment with different concentrations of hypercholesterolemic supplement.<\/p>\n\n<\/div><h2 class=\"tabtitle\">Members<\/h2>\n<div class=\"tabcontent\">\n\n<p><strong>Group Leader:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=11539\">Anik\u00f3 G\u00f6rbe<\/a>, MD, PhD<\/p>\n<p><strong>Researchers\/Postdocs:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=21659\">Orsolya Somogyi<\/a>, MSc<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=11976\">Andr\u00e1s Makkos<\/a>, MD, PhD<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=11975\">\u00c9va S\u00e1ghy<\/a>, MD, PhD<\/p>\n<p><strong>PhD Students:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=14236\">Regina Nagy<\/a>, MSc<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=20521\">M\u00e1rta Szab\u00f3<\/a>, MSc<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=21947\">Bennet Weber<\/a>, MD<\/p>\n<p><strong>Assistants:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=11044\">T\u00fcnde Petrovics<\/a>, MSc<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=14235\">L\u00e1szl\u00f3 Horv\u00e1th<\/a>, MSc, PhD<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=22985\">Orsolya Szalai<\/a>, MSc<br \/>\nReyad Ali<\/p>\n\n<\/div><h2 class=\"tabtitle\">Gallery<\/h2>\n<div class=\"tabcontent\">\n\n\r\n        [slb_exclude]\r\n        <div class=\"row galeria-wrapper mx-0 h-auto\">\r\n            <div class=\"col-9 pl-0 pr-2\">\r\n            <span class=\"gallery-item frame\">\r\n\t\t\t\t<div class=\"galeria-left-img\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-scaled.jpg\"><img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-scaled.jpg  \r\n                            alt=\"\" \r\n                            class=\"attachment-sote-gallery-big size-sote-gallery-big\" \r\n                            srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-2048x1365.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7351-203x135.jpg 203w\" ><\/a><\/div>\r\n            <\/span>\r\n\r\n            <\/div>\r\n\r\n\t\t\t<div class=\"col-3 pl-0 pr-0\">\r\n\t\t\t\t<div class=\"galeria-right-img d-flex justify-content-between flex-column h-100 w-100 px-0 mx-0 \">\r\n                <div class=\"galeria-box\">\r\n\t\t\t\t\t<h3 class=\"galeria-title\">Gal\u00e9ria<\/h3>\r\n\t\t\t\t\t<div class=\"galeria-subtitle\">\r\n\r\n\t\t\t\t\t\t<div class=\"galeria-page-counter\"><span>9<\/span>k\u00e9p<\/div>\r\n                    <\/div> <\/div>\r\n                    <span class=\"gallery-item frame d-none d-md-flex\">\r\n\t\t\t\t\t<div class=\"galeria-small-img mt-0\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-scaled.jpg\"><img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-scaled.jpg \r\n                                alt=\"\"  \r\n                                class=\"attachment-sote-gallery-small size-sote-gallery-small\" \r\n                                srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7434-203x135.jpg 203w\" ><\/a><\/div>\r\n                    <\/span>\r\n                    <span class=\"gallery-item frame d-none d-md-flex\">\r\n\t\t\t\t\t<div class=\"galeria-small-img mt-0\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-scaled.jpg\"><img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-scaled.jpg \r\n                                alt=\"\" \r\n                                class=\"attachment-sote-gallery-small size-sote-gallery-small\" \r\n                                srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7470-203x135.jpg 203w\" ><\/a><\/div>\r\n                    <\/span>\r\n\r\n                <\/div>\r\n\r\n            <\/div>\r\n\r\n            <span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7409-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7488-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7502-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7506-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-2048x1366.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7510-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-2048x1365.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL7275-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span>\r\n            <\/div>\r\n\r\n            [\/slb_exclude]\r\n\t\n<\/div><\/div>\n","protected":false},"excerpt":{"rendered":"<p>Understanding Immunotherapy resistance and response of small cell lung cancer Project leaders: \u00c1gnes Pa\u00e1l, Anik\u00f3 G\u00f6rbe \u00a0 Small cell lung cancer (SCLC) is one of the malignancies with the worst prognosis, for which there have been no significant advances in therapy over the last three decades. The first promising results have been with the use &hellip;<\/p>\n","protected":false},"author":102374,"featured_media":0,"parent":961,"menu_order":1,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"categories":[],"tags":[],"class_list":["post-13512","page","type-page","status-publish","hentry"],"acf":[],"_links":{"self":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/13512","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/users\/102374"}],"replies":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/comments?post=13512"}],"version-history":[{"count":10,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/13512\/revisions"}],"predecessor-version":[{"id":14190,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/13512\/revisions\/14190"}],"up":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/961"}],"wp:attachment":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/media?parent=13512"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/categories?post=13512"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/tags?post=13512"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}