Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin deficiency at different ages on working and short-term recognition and spatial memory in rats. An age-related decline in memory function was tested using the Y-maze, the object recognition test, and the radial arm maze. The brain-derived neurotrophic factor (BDNF), TrkB receptor, the extracellular signal-regulated kinase (ERK)1/2 and pERK1/2 expression in the hippocampus was assessed by immunohistochemistry. The pCREB/CREB ratio in the frontal cortex (FC) and hippocampus was evaluated by ELISA. Young adult and middle-aged rats with pinealectomy had memory impairment whereas old melatonin-deficient rats were unaffected. Aging was associated with reduced expression of BDNF and its receptor throughout the hippocampus and reduced ratio of pCREB/CREB in the FC and hippocampus, whereas pinealectomy exacerbated this process in 3- and 14-month-old rats. The region-specific reduced expression of the ERK1/2 and pERK1/2 was observed in young adult rats with pinealectomy. However, in middle-aged rats, the expression of these signaling molecules was either downregulated or upregulated in different regions of the hippocampus. Our study provides insights into the molecular pathways involved in age-related memory changes associated with melatonin deficiency, highlighting the importance of the BDNF/ERK1/2/CREB pathway in the hippocampus and suggesting a critical period for intervention.

Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma primarily affecting children and young adults. This disease is more prevalent in children under 15, with two main types: embryonal Rhabdomyosarcoma (eRMS), which has a better prognosis, and alveolar Rhabdomyosarcoma (aRMS), which is more aggressive and associated with specific genetic alterations. The PI3K-Akt-mTOR pathway is often hyperactivated in RMS, contributing to cell proliferation, survival, and resistance to therapies. The presence of phosphorylated components of this pathway correlates with poor survival outcomes. Here, we discuss various therapeutic approaches targeting the PI3K-Akt-mTOR pathway. These include the use of specific inhibitors (e.g., PI3K inhibitors, Akt inhibitors) and combination therapies that may enhance treatment efficacy. Dietary supplements like curcumin and repurposed drugs such as chloroquine are also mentioned for their potential to induce apoptosis in RMS cells. We also emphasize the need for innovative strategies to improve survival rates, which have remained stagnant over the years. Targeting super-enhancers and transcription factors associated with RMS may provide new therapeutic avenues. Overall, this review underscores the critical role of the PI3K-Akt-mTOR pathway in RMS and the potential for targeted therapies to improve patient outcomes.

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.

Recent research underscores a crucial connection between circadian rhythm disruption and cancer promotion, highlighting an urgent need for attention.

Explore the molecular mechanisms by which modern lifestyle factors-such as artificial light exposure, shift work, and dietary patterns-affect cortisol/melatonin regulation and cancer risk.

Employing a narrative review approach, we synthesized findings from Scopus, Google Scholar, and PubMed to analyze lifestyle impacts on circadian health, focusing on cortisol and melatonin chronobiology as molecular markers. We included studies that documented quantitative changes in these markers due to modern lifestyle habits, excluding those lacking quantitative data or presenting inconclusive results. Subsequent sections focused solely on articles that quantified the effects of circadian disruption on adipogenesis and tumor microenvironment modifications.

This review shows how modern habits lead to molecular changes in cortisol and melatonin, creating adipose microenvironments that support cancer development. These disruptions facilitate immune evasion, chemotherapy resistance, and tumor growth, highlighting the critical roles of cortisol dysregulation and melatonin imbalance.

Through the presented findings, we establish a causal link between circadian rhythm dysregulation and the promotion of certain cancer types. By elucidating this relationship, the study emphasizes the importance of addressing lifestyle factors that contribute to circadian misalignment, suggesting that targeted interventions could play a crucial role in mitigating cancer risk and improving overall health outcomes.

Degenerative fundus disease encompasses a spectrum of ocular diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), which are major contributors to visual impairment and blindness worldwide. The development and implementation of effective strategies for managing and preventing the onset and progression of these diseases are crucial for preserving patients' visual acuity. Melatonin, a neurohormone primarily produced by the pineal gland, exhibits properties such as circadian rhythm modulation, antioxidant activity, anti-inflammatory effects, and neuroprotection within the ocular environment. Furthermore, melatonin has been shown to suppress neovascularization and reduce vascular leakage, both of which are critical in the pathogenesis of degenerative fundus lesions. Consequently, melatonin emerges as a promising therapeutic candidate for degenerative ocular diseases. This review provides a comprehensive overview of melatonin synthesis, its localization within ocular tissues, and its mechanisms of action, particularly in regulating melatonin production, thereby underscoring its potential as a therapeutic agent for degenerative fundus diseases.

Melatonin is a multifunctional hormone regulator that maintains homeostasis through circadian rhythms, and desynchronization of these rhythms can lead to gastrointestinal disorders and increase the risk of cancer. Preliminary clinical studies have shown that exogenous melatonin alleviates the harmful effects of anticancer therapy and improves quality of life, but the results are still inconclusive due to the heterogeneity of the studies. A personalized approach to testing clinical parameters and response to integrative treatment with nontoxic and bioavailable melatonin in patient-centered N-of-1 studies deserves greater attention. This clinical case of colon cancer analyzes and discusses the tumor pathology, the adverse effects of chemotherapy, and the dynamics of markers of inflammation (NLR, LMR, and PLR ratios), tumors (CEA, CA 19-9, and PSA), and hemostasis (D-dimer and activated partial thromboplastin time). The patient took melatonin during and after chemotherapy, nutrients (zinc, selenium, vitamin D, green tea, and taxifolin), and aspirin after chemotherapy. The patient's PSA levels decreased during CT combined with melatonin (19 mg/day), and melatonin normalized inflammatory markers and alleviated symptoms of polyneuropathy but did not help with thrombocytopenia. The results are analyzed and discussed in the context of the literature on oncostatic and systemic effects, alleviating therapy-mediated adverse effects, association with survival, and N-of-1 studies.

Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.

Melatonin, an endogenous neurohormone produced by the pineal gland, has received increased interest due to its potential anti-cancer properties. Apart from its well-known role in the sleep-wake cycle, extensive scientific evidence has shown its role in various physiological and pathological processes, such as inflammation. Additionally, melatonin has demonstrated promising potential as an anti-cancer agent as its function includes inhibition of tumorigenesis, induction of apoptosis, and regulation of anti-tumor immune response. Although a precise pathophysiological mechanism is yet to be established, several pathways related to the regulation of cell cycle progression, DNA repair mechanisms, and antioxidant activity have been implicated in the anti-neoplastic potential of melatonin. In the current manuscript, we focus on the potential anti-cancer properties of melatonin and its use in treating and managing pediatric osteosarcoma. This aggressive bone tumor primarily affects children and adolescents and is treated mainly by surgical and radio-oncological interventions, which has improved survival rates among affected individuals. Significant disadvantages to these interventions include disease recurrence, therapy-related toxicity, and severe/debilitating side effects that the patients have to endure, significantly affecting their quality of life. Melatonin has therapeutic effects when used for treating osteosarcoma, attributed to its ability to halt cancer cell proliferation and trigger apoptotic cell death, thereby enhancing chemotherapeutic efficacy. Furthermore, the antioxidative function of melatonin alleviates harmful side effects of chemotherapy-induced oxidative damage, aiding in decreasing therapeutic toxicities. The review concisely explains the many mechanisms by which melatonin targets osteosarcoma, as evidenced by significant results from several in vitro and animal models. Nevertheless, if further explored, human trials remain a challenge that could shed light and support its utility as an adjunctive therapeutic modality for treating osteosarcoma.

The history of studies of melatonin effects on cancer in mice is outlined, the main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over counter and thus needs no licensing for its applications in oncology.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.