Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain.

Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy.

PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression.

Background And Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD.

Exploring protein conformations with limited proteolysis coupled to mass spectrometry.

Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models.

A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα.

Leveraging a self-cleaving peptide for tailored control in proximity labeling proteomics.

Protein-protein interactions play an important biological role in every aspect of cellular homeostasis and functioning. Proximity labeling mass spectrometry-based proteomics overcomes challenges typically associated with other methods and has quickly become the current state of the art in the field. Nevertheless, tight control of proximity-labeling enzymatic activity and expression levels is crucial to accurately identify protein interactors.

Glucocorticoid receptor signaling: intricacies and therapeutic opportunities.

The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits.

Selective Modulation of the Human Glucocorticoid Receptor Compromises GR Chromatin Occupancy and Recruitment of p300/CBP and the Mediator Complex.

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic.

Crosstalk between glucocorticoid and mineralocorticoid receptors boosts glucocorticoid-induced killing of multiple myeloma cells.

The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR action in myeloma. Here, we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that plays a role in improved myeloma cell killing.

The Biologist's Guide to the Glucocorticoid Receptor's Structure.

The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR's therapeutic potential, emphasizing the importance of resolving all of GR's context-specific action mechanisms.

The Zinc-Binding Group Effect: Lessons from Non-Hydroxamic Acid Vorinostat Analogs.

Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative disorders. In the past decade, HDAC inhibitors (HDACi) have emerged as relevant pharmaceuticals, with many efforts devoted to the development of new representatives. However, the growing safety concerns regarding the established hydroxamic acid-based HDAC inhibitors tend to drive current research more toward the design of inhibitors bearing alternative zinc-binding groups (ZBGs).

Compound A attenuates proinflammatory cytokine-induced endoplasmic reticulum stress in beta cells and displays beneficial therapeutic effects in a mouse model of autoimmune diabetes.

Type 1 diabetes (T1D) is characterized by an immune-mediated progressive destruction of the insulin-producing β-cells. Proinflammatory cytokines trigger endoplasmic reticulum (ER) stress and subsequent insulin secretory deficiency in cultured β-cells, mimicking the islet microenvironment in T1D. β-cells undergo physiologic ER stress due to the high rate of insulin production and secretion under stimulated conditions.

Novel assays monitoring direct glucocorticoid receptor protein activity exhibit high predictive power for ligand activity on endogenous gene targets.

Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs) that are able to separate anti-inflammatory effects via gene repression from metabolic effects via gene activation, have been unsuccessful so far.

Identification of mercaptoacetamide-based HDAC6 inhibitors a lean inhibitor strategy: screening, synthesis, and biological evaluation.

Non-selective inhibition of different histone deacetylase enzymes by hydroxamic acid-based drugs causes severe side effects when used as a (long-term) cancer treatment. In this work, we searched for a potent zinc-binding group able to replace the contested hydroxamic acid by employing a lean inhibitor strategy. This instructed the synthesis of a set of HDAC6-selective inhibitors containing the more desirable mercaptoacetamide moiety.

Hepatic glucocorticoid-induced transcriptional regulation is androgen-dependent after chronic but not acute glucocorticoid exposure.

Glucocorticoids exert their pleiotropic effects by activating the glucocorticoid receptor (GR), which is expressed throughout the body. GR-mediated transcription is regulated by a multitude of tissue- and cell type-specific mechanisms, including interactions with other transcription factors such as the androgen receptor (AR). We previously showed that the transcription of canonical glucocorticoid-responsive genes is dependent on active androgen signaling, but the extent of this glucocorticoid-androgen crosstalk warrants further investigation.

Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding.

The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GR) have previously helped to define the functions of GR monomers and dimers. Since GR retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GR mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR.

Reprogramming of glucocorticoid receptor function by hypoxia.

Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA-sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GR-responsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA-binding as measured by ChIP sequencing.

Approaches towards tissue-selective pharmacology of the mineralocorticoid receptor.

Mineralocorticoid receptor antagonists (MRAs) are highly effective therapies for cardiovascular and renal disease. However, the widespread clinical use of currently available MRAs in cardiorenal medicine is hampered by an increased risk of hyperkalaemia. The mineralocorticoid receptor (MR) is a nuclear receptor responsible for fluid and electrolyte homeostasis in epithelial tissues, whereas pathophysiological MR activation in nonepithelial tissues leads to undesirable pro-inflammatory and profibrotic effects.

How the glucocorticoid receptor contributes to platinum-based therapy resistance in solid cancer.

Synthetic glucocorticoids serve as co-medication against solid malignant tumors. However, glucocorticoid receptor activation may promote unsolicited cancer resistance to chemotherapy. The Kang team elucidated a glucocorticoid receptor-centred chemotherapy-resistance mechanism to cisplatin and characterized avenues towards a viable escape strategy.

ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation.

The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body's response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32 mice fail to increase their GC production in the absence of nutrients.

Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis.

Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor.

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and hematological cancers. Unfortunately, their use is associated with debilitating side effects, including hyperglycemia, osteoporosis, mood swings, and weight gain. Despite the continued efforts of pharma as well as academia, the search for so-called selective glucocorticoid receptor modulators (SEGRMs), compounds with strong anti-inflammatory or anti-cancer properties but a reduced number or level of side effects, has had limited success so far.

Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies.

Glucocorticoids are essential drugs in the treatment protocols of lymphoid malignancies. These steroidal hormones trigger apoptosis of the malignant cells by binding to the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily. Long term glucocorticoid treatment is limited by two major problems: the development of glucocorticoid-related side effects, which hampers patient quality of life, and the emergence of glucocorticoid resistance, which is a gradual process that is inevitable in many patients.