International Journal of Molecular Sciences

Depression is a common, debilitating, and potentially life-threatening mental disorder affecting individuals across all age groups and populations. It represents one of the major challenges of contemporary medicine. It is estimated that more than 300 million people worldwide are affected, and patients with major depressive disorder (MDD) exhibit a significantly increased risk of suicide, underscoring the urgent need for effective and long-lasting therapeutic strategies. Growing evidence indicates that the pathophysiology of depression involves a complex interplay of genetic vulnerability, chronic stress, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity, collectively contributing to symptom heterogeneity and treatment resistance. In this review, we synthesize data derived from PubMed, Google Scholar, and ClinicalTrials.gov databases concerning pharmacological and non-pharmacological treatment strategies, with particular emphasis on their cellular and molecular mechanisms of action. We present currently used classes of antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), discussing their limitations in the context of contemporary pathophysiological models of depression. We then focus on emerging therapies targeting the glutamatergic, GABAergic, and dopaminergic systems, including ketamine, esketamine, (R)-ketamine, the dextromethorphan–bupropion combination (DMX–BUP), neurosteroids (zuranolone, brexanolone), as well as selective serotonin receptor modulators (gepirone ER) and dopaminergic modulators (cariprazine). The review is complemented by a discussion of non-pharmacological neuromodulatory approaches, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and photobiomodulation. Rather than providing another summary of clinical response indicators, this article integrates the molecular underpinnings of novel antidepressant agents and neuromodulation techniques with current concepts of depression pathophysiology, highlighting their relevance for the development of precise, mechanistically targeted, and multimodal treatment strategies.

Epithelial ovarian cancer is one of the most lethal gynecological malignancies worldwide. Its development strongly depends on several genetic and environmental factors, with metabolic components and cellular redox homeostasis alterations playing a significant a role in its development and disease progression. In this review, we summarize the contribution of mitochondrial and endoplasmic reticulum (ER) stress in the pathogenesis of epithelial ovarian cancer along with their role as potential biomarkers and therapeutic targets, including proteins of glucose metabolism, mitochondrial fission and fusion, mitophagy, membrane-associated ring-CH-type finger 5 (MARCH5), A-kinase anchoring proteins (AKAPs), proteins regulating mitochondrial Ca²⁺ homeostasis, mitochondrial unfolded protein response (UPRmt) proteins, activating transcription factors (ATFs), CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), ‘mitokines’, GRP75, and GRP78. Although many of these potential targets are in preclinical phase, they have a high potential to become valuable alternative or additive treatments for epithelial ovarian cancers.

Microgravity (µg)-generated three-dimensional (3D) multicellular aggregates can serve as models of tissue and disease development. They are relevant in the fields of cancer and in vitro metastasis or regenerative medicine (tissue engineering). Driven by the 3R concept—replacement, reduction, and refinement of animal testing—µg-exposure of human cells represents a new alternative method that avoids animal experiments entirely. New Approach Methodologies (NAMs) are used in biomedical research, pharmacology, toxicology, cancer research, radiotherapy, and translational regenerative medicine. Various types of human cells grow as 3D spheroids or organoids when exposed to µg-conditions provided by µg simulating instruments on Earth. Examples for such µg-simulators are the Rotating Wall Vessel, the Random Positioning Machine, and the 2D or 3D clinostat. This review summarizes the most recent literature focusing on µg-engineered tissues. We are discussing all reports examining different tumor cell types from breast, lung, thyroid, prostate, and gastrointestinal cancers. Moreover, we are focusing on µg-generated spheroids and organoids derived from healthy cells like chondrocytes, stem cells, bone cells, endothelial cells, and cardiovascular cells. The obtained data from NAMs and µg-experiments clearly imply that they can support translational medicine on Earth.