Gutenberg Open Science

The Open Science Repository of Johannes Gutenberg University Mainz.

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Recent Submissions

ZeitschriftenaufsatzAccess status: Open Access ,
Lysine demethylase 6 (KDM6) : a promising therapeutic target in autoimmune disorders and cancer
(2025) Nastaranpour, Mahsa; Damara, Aman; Grabbe, Stephan; Shahneh, Fatemeh
Epigenetic dynamics, which influence gene expressions independent of DNA sequence alterations, play a pivotal role in regulating chromatin structure and transcription. Among these modifications, the dynamic methylation and demethylation of histone 3 lysine 27 (H3K27me2/3) by the Lysine Demethylase 6 (KDM6) subfamily are pivotal regulators of both physiological and pathological processes. In immune cells, KDM6A and KDM6B fine-tune the transcription of pro- and anti-inflammatory genes, influencing differentiation, polarization, and activation states in monocytes, macrophages, dendritic cells, T helper cells, and other key immune subsets. Dysregulated KDM6 activity underlies aberrant cytokine production, Th17 cell expansion, and imbalances in tissue repair responses, thus contributing to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Concurrently, KDM6A and KDM6B can act as either tumor suppressors or oncogenes in a context-dependent manner, mediating cellular proliferation, DNA damage repair pathways, and immune evasion in cancers ranging from hematologic malignancies to solid tumors of the bladder, breast, and brain. Recent efforts to exploit this duality include developing small-molecule inhibitors, notably GSK-J4, which block KDM6 demethylase activity and show promising therapeutic effects in models of chronic inflammation and cancer. Nonetheless, challenges such as incomplete target specificity, the interplay with other epigenetic mechanisms, and variations in tumor microenvironment emphasize the complexity of translating these findings into clinical practice. This review highlights the structural features, regulatory mechanisms, and disease associations of KDM6 demethylases, positioning them as compelling biomarkers and therapeutic targets at the intersection of autoimmunity and cancer.
ZeitschriftenaufsatzAccess status: Open Access ,
Assessing the helical stability of polyXYs at the boundaries of intrinsically disordered regions with MD simulations
(2025) Gonçalves-Kulik, Mariane; Baptista, Luis A.; Schmid, Friederike; Andrade-Navarro, Miguel A.
Intrinsically disordered regions (IDRs) of proteins lack a stable structure. Their high content of hydrophilic and charged residues prevents them from forming globular domains and contributes to their flexibility and accessibility. Naturally, regions with a reduced amino acid composition (low complexity regions; LCRs) are found within IDRs. Disorder and low complexity of protein sequences are linked to various biological functions, including phase separation, regulation, and molecular interactions, and mutations in these regions can contribute to several diseases, including cancer. Understanding these biological properties requires examining the structural properties of IDRs and the LCRs they contain, but their inherently dynamic nature requires specific approaches combining sequence analysis, structure predictions, and molecular dynamics (MD) simulations. Here, we leverage our previous work, where we identified that certain types of LCRs combining two residues (polyXY) are frequent within IDRs and confer them with a propensity to form helical conformations. We identified a significant accumulation of these polyXYs at the ends of IDRs, following alpha helices that begin outside the IDR and can extend through the polyXY into the IDR, particularly from the N-terminal end of the IDR. MD simulations support the dynamic nature of these helical conformations. Our results suggest a mechanism by which the evolutionary emergence of LCRs at IDR ends could provide proteins with flexible regions for fold-upon-binding.
ZeitschriftenaufsatzAccess status: Open Access ,
Revisiting the renin-angiotensin-aldosterone system in the eye : mechanistic insights and pharmacological targets
(2025) Buonfiglio, Francesco; Böhm, Elsa Wilma; Tang, Qi; Daiber, Andreas; Gericke, Adrian
The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in regulating blood pressure and fluid homeostasis through key effectors such as angiotensin II and aldosterone. These agents and their receptors have become crucial molecular targets in several cardiovascular and renal diseases. Over the past few decades, a growing body of evidence has revealed the presence of RAAS components in ocular structures, suggesting a tissue-specific RAAS within the eye. Building on this knowledge, studies have indicated that the ocular RAAS plays a significant role in the pathogenesis of various eye diseases. An impaired and overactivated RAAS contributes to the development of severe and widespread disorders affecting both the anterior and posterior segments of the eye. In this context, the current work aims to delve into the pivotal molecular pathways involving the RAAS, with an in-depth exploration of the ocular pathophysiology. It focuses on the relationship between overactivation of the RAAS and oxidative stress, as well as the exacerbation of neovascularization and inflammatory processes. The objective is to provide an updated and comprehensive understanding of the role of the RAAS in ophthalmological diseases, highlighting the therapeutic potential of RAAS modulators and discussing the controversies and challenges in this area of research.