Malwina Lisek

Calcium signaling is a fundamental regulator of cell physiology, controlling proliferation, differentiation, migration, metabolism, gene expression, and cell death. In cancer, these signaling pathways are extensively remodeled to generate spatially and temporally restricted Ca²⁺ signals that support malignant progression while avoiding calcium-induced cytotoxicity. PMCAs traditionally regarded as high-affinity calcium extrusion pumps, have recently emerged as multifunctional regulators of compartmentalized calcium signaling. In addition to maintaining low cytosolic Ca²⁺ concentrations, PMCA isoforms organize specialized signaling microdomains by interacting with receptors, ion channels, scaffold proteins, and downstream signaling molecules, thereby selectively modulating calcium-dependent pathways involved in tumor growth and metastasis. Accumulating evidence demonstrates that PMCA isoforms exert distinct, context-dependent functions in cancer. PMCA1 primarily contributes to basal calcium homeostasis but has also been implicated in tumor progression, angiogenesis, and regulation of the tumor immune microenvironment. PMCA2 promotes survival and oncogenic signaling in HER2-positive breast cancer through stabilization of receptor signaling complexes. PMCA3 has been linked mainly to endocrine tumors and selected malignancies, although mechanistic evidence remains limited. PMCA4 exhibits the greatest functional diversity, acting either as a tumor suppressor or a promoter depending on the cancer type by regulating localized calcium signaling, cell migration, invasion, differentiation, and interactions with oncogenic signaling networks. This review summarizes current advances in the structural biology, regulation, and signaling functions of PMCA isoforms, with particular emphasis on their emerging roles in cancer biology. We also discuss the potential of PMCAs as prognostic biomarkers and therapeutic targets, highlighting the importance of isoform-specific strategies for targeting calcium signaling in cancer.

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric condition with high global prevalence and significant personal and societal burdens. While traditionally focused on neuronal dysfunction, emerging research highlights a critical role for astrocytes—glial cells essential for maintaining brain homeostasis in the pathogenesis of depression. This review explores how chronic stress, a major risk factor for MDD, disrupts astrocyte function through multiple converging mechanisms. We detail the normal physiological roles of astrocytes in synaptic regulation, neurotransmitter cycling, metabolic support, and neurovascular integrity, and examine how these functions are compromised under chronic stress. Key molecular pathways implicated include glucocorticoid receptor (GR) signaling dysregulation, neuroinflammatory responses, glutamate excitotoxicity, oxidative stress, and epigenetic alterations. Evidence from histological and transcriptomic studies in both human postmortem tissue and rodent models reveals consistent changes in astrocyte-specific genes, such as GFAP, SLC1A2, SLC1A3, BDNF, and AQP4, supporting their involvement in depressive pathology. Finally, we discuss therapeutic strategies targeting astrocyte dysfunction—including EAAT2 upregulation, neuromodulation, anti-inflammatory approaches, GR modulation, and glial-focused epigenetic therapies. Understanding astrocyte pathology in the context of chronic stress not only refines our understanding of MDD but also opens novel avenues for treatment development.

Ischemic brain and retinal injuries trigger complex molecular cascades involving neuroinflammation, oxidative stress, and neuronal death. Among these mechanisms, epigenetic regulation has emerged as a critical modulator of the injury response. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) dynamically control gene expression by altering chromatin structure. HDACs often promote neuroinflammation and neuronal apoptosis through repression of neuroprotective and anti-inflammatory genes, while HATs generally enhance the transcription of genes involved in cell survival and repair. In ischemia, specific HDAC isoforms (e.g., HDAC1, HDAC2, HDAC3, and HDAC6) have been implicated in microglial activation, glial reactivity, and disruption of immune balance. Conversely, HATs such as CBP/p300 and Tip60 contribute to neuronal resilience and immune regulation. Understanding the dual and context-dependent roles of these epigenetic enzymes offers promising therapeutic avenues. Selective HDAC inhibitors or HAT activators may represent novel strategies to mitigate ischemic damage, support neuroprotection, and facilitate functional recovery.

Retinoblastoma, a pediatric ocular malignancy, presents significant challenges in comprehending its molecular underpinnings and targeted therapeutic approaches. The dysregulated activity of histone deacetylases (HDACs) has been associated with retinoblastoma pathogenesis, influencing critical cellular processes like cell cycle regulation or retinal ganglion cell apoptosis. Through their deacetylase activity, HDACs exert control over key tumor suppressors and oncogenes, influencing the delicate equilibrium between proliferation and cell death. Furthermore, the interplay between HDACs and the retinoblastoma protein pathway, a pivotal aspect of retinoblastoma etiology, reveals a complex network of interactions influencing the tumor microenvironment. The examination of HDAC inhibitors, encompassing both established and novel compounds, offers insights into potential approaches to restore acetylation balance and impede retinoblastoma progression. Moreover, the identification of specific HDAC isoforms exhibiting varying expression in retinoblastoma provides avenues for personalized therapeutic strategies, allowing for interventions tailored to individual patient profiles. This review focuses on the intricate interrelationship between HDACs and retinoblastoma, shedding light on epigenetic mechanisms that control tumor development and progression. The exploration of HDAC-targeted therapies underscores the potential for innovative treatment modalities in the pursuit of more efficacious and personalized management strategies for this disease.

The dysregulation of intracellular calcium levels is a critical factor in neurodegeneration, leading to the aberrant activation of calcium-dependent processes and, ultimately, cell death. Ca²⁺ signals vary in magnitude, duration, and the type of neuron affected. A moderate Ca²⁺ concentration can initiate certain cellular repair pathways and promote neuroregeneration. While the peripheral nervous system exhibits an intrinsic regenerative capability, the central nervous system has limited self-repair potential. There is evidence that significant variations exist in evoked calcium responses and axonal regeneration among neurons, and individual differences in regenerative capacity are apparent even within the same type of neurons. Furthermore, some studies have shown that neuronal activity could serve as a potent regulator of this process. The spatio-temporal patterns of calcium dynamics are intricately controlled by a variety of proteins, including channels, ion pumps, enzymes, and various calcium-binding proteins, each of which can exert either positive or negative effects on neural repair, depending on the cellular context. In this concise review, we focus on several calcium-associated proteins such as CaM kinase II, GAP-43, oncomodulin, caldendrin, calneuron, and NCS-1 in order to elaborate on their roles in the intrinsic mechanisms governing neuronal regeneration following traumatic damage processes.

The family of myocyte enhancer factor 2 (MEF2) transcription factors comprises four highly conserved members that play an important role in the nervous system. They appear in precisely defined time frames in the developing brain to turn on and turn off genes affecting growth, pruning and survival of neurons. MEF2s are known to dictate neuronal development, synaptic plasticity and restrict the number of synapses in the hippocampus, thus affecting learning and memory formation. In primary neurons, negative regulation of MEF2 activity by external stimuli or stress conditions is known to induce apoptosis, albeit the pro or antiapoptotic action of MEF2 depends on the neuronal maturation stage. By contrast, enhancement of MEF2 transcriptional activity protects neurons from apoptotic death both in vitro and in preclinical models of neurodegenerative diseases. A growing body of evidence places this transcription factor in the center of many neuropathologies associated with age-dependent neuronal dysfunctions or gradual but irreversible neuron loss. In this work, we discuss how the altered function of MEF2s during development and in adulthood affecting neuronal survival may be linked to neuropsychiatric disorders.

Vitamin C (ascorbic acid) is well known for its potent antioxidant properties, as it can neutralize ROS and free radicals, thereby protecting cellular elements from oxidative stress. It predominantly exists as an ascorbate anion and after oxidation to dehydroascorbic acid and further breakdown, is removed from the cells. In nervous tissue, a progressive decrease in vitamin C level or its prolonged deficiency have been associated with an increased risk of disturbances in neurotransmission, leading to dysregulation in brain function. Therefore, understanding the regulatory function of vitamin C in antioxidant defence and identification of its molecular targets deserves more attention. One of the key signalling ions is calcium and a transient rise in its concentration is crucial for all neuronal processes. Extracellular Ca²⁺ influx (through specific ion channels) or Ca²⁺ release from intracellular stores (endoplasmic reticulum, mitochondria) are precisely controlled. Ca²⁺ regulates the functioning of the CNS, including growth, development, myelin formation, synthesis of catecholamines, modulation of neurotransmission and antioxidant protection. A growing body of evidence indicates a unique role for vitamin C in these processes. In this short review, we focus on vitamin C in the regulation of calcium-involved pathways under physiological and stress conditions in the brain.