Maja Jazvinšćak Jembrek

The p53 protein is a pivotal tumor suppressor that is mutated in more than half of tumor cases in humans. In addition, its activity/function can be perturbed by various other mechanisms. Existence of two promoters in the TP53 gene and extensive splicing on N- and C-terminus, as well as alternative translation initiation, give rise to numerous p53 protein isoforms. Different p53 protein isoforms can form heterotetramers with canonical full-length p53 or compete in binding target genes’ promoters as tetramers which can result in modulation of p53 function. In this review we have gathered the most novel research on the p53 isoform network including the isoforms’ expression profiles and biological functions in the most frequent cancer types. The expression of p53 isoforms differs among tumor types and compared with normal tissues, thereby affecting biological processes associated with tumorigenesis, such as apoptosis, cell cycle regulation, migration, senescence, stemness, etc. We also discussed the potential of targeting p53 isoforms by direct mechanisms that can change the ratio between specific isoforms and thus modulate their activity or indirectly by targeting downstream pathways regulated by a specific isoform. More profound understanding of the p53 pathway regulation could contribute to improvement in current therapies.

NME/NDP kinases are enzymes primarily responsible for maintaining nucleotide balance in the cell. They arose early in evolution, during which they acquired additional biochemical and biological functions such as protein histidine kinase activity, DNA transcription and repair, and the binding and transfer of phospholipids. The human NME/NDPK family comprises 10 proteins divided into two groups. The well-documented Group I (NME1-4) is characterized by high sequence homology and a single active NDPK domain. In contrast, the remaining NME genes/proteins belong to the poorly understood and more heterogeneous Group II. They possess one or more NDPK domains and are divergent in their amino acid sequences. Except for NME6, they have been considered enzymatically inactive. In recent years, NME Group II proteins have attracted more interest from researchers, and new emerging evidence may change the established perspective.

Hyperthermia (HT) is a promising adjunct to conventional cancer therapies such as chemotherapy and radiotherapy (RT). It offers several advantages, including low toxicity to normal tissues, limited tumor resistance, and synergistic therapeutic effects. HT enhances treatment efficacy by inhibiting DNA repair mechanisms, increasing tumor membrane permeability for improved drug uptake, and improving oxygenation to reduce hypoxia-induced resistance. HT also promotes cancer cell death by inducing oxidative stress, leading to mitochondrial dysfunction, caspase activation, and PARP cleavage. It causes G2/M cell cycle arrest and damages tumor vasculature. Additionally, HT downregulates proangiogenic and invasive factors such as TGF-β1, VEGF, and MMP-2/9, contributing to reduced tumor progression. Combining HT with natural compounds like propolis and flavonoids further improves therapeutic outcomes. These natural agents are accessible, cost-effective, and exhibit multi-targeted anticancer activity. In synergy with HT, they enhance reactive oxygen species (ROS) generation, suppress heat shock proteins, modulate the tumor microenvironment (TME), and activate immune responses. They may also reduce the side effects of conventional therapies and support tissue regeneration. Overall, HT, especially in combination with natural compounds, offers a multifaceted and effective approach to cancer therapy.

Oxidative stress (OS) arises from a redox imbalance characterized by elevated levels of reactive oxygen species (ROS)

Ehrlich ascites tumor (EAT) is a rapidly growing, angiogenesis-dependent tumor characterized by high levels of vascular endothelial growth factor (VEGF). VEGF contributes to ascites formation, which supports tumor cell growth and the accumulation of tumor-associated macrophages (TAMs), primarily of the immunosuppressive M2 phenotype. M2 macrophages promote tumor progression by secreting angiogenic and immunomodulatory factors such as VEGF, matrix metalloproteinases (MMPs), and cyclooxygenase-2 (COX-2). This study investigated the effects of tannic acid (TA) on tumor growth and angiogenesis in EAT-bearing mice, focusing on TAM–tumor cell interactions. We evaluated ascites volume, cell counts, macrophage activity, peritoneal angiogenesis and blood vessel density, concentrations of VEGF, COX-2, and MMP-2/-9, blood biomarkers, and DNA damage using the comet assay. TA treatment significantly reduced tumor growth and angiogenesis by modulating TAM function. Specifically, TA inhibited VEGF, COX-2, and MMP-2/-9 expression, decreased M2 macrophage numbers, and enhanced the antitumor immune response, as shown by increased lymphocyte activation and favorable shifts in lymphocyte-to-monocyte (LMR) and neutrophil-to-lymphocyte (NLR) ratios. Additionally, TA induced DNA fragmentation in tumor and blood cells, indicating cytotoxicity and potential induction of apoptosis. These findings suggest that TA’s inhibition of TAMs may be a promising strategy for treating tumors and other angiogenesis-related conditions.

Aluminum (Al) is one of the most abundant metals on Earth and is well known as an environmental neurotoxic agent in the pathogenesis of Alzheimer’s disease. Aluminum toxicity is associated with oxidative stress, reduction of antioxidant enzymes, and disruption of the balance of cellular metals, such as iron (Fe), calcium (Ca), and copper (Cu), which causes structural and functional changes in the nervous tissue of the brain or peripheral nervous system. The intake of functional foods, rich in antioxidants, such as quercetin, may be beneficial in combating oxidative stress and neurodegenerative changes in the brain. The aim of this study was to provide deeper insight into the cellular and molecular neuroprotective effects of quercetin in regulating amyloid-beta (Aβ) accumulation, tau pathology, and neuroinflammation in the Al/D-galactose-induced rat model (Al/D-gal) of AD. The results showed that quercetin successfully modulated the impaired homeostatic and neuropathological consequences of aluminum chloride and D-galactose administration over 28 days: it directly protected neurons by regulating the level of oxidative stress and antioxidants, reduced Aβ aggregation by inhibiting the activity of acetylcholinesterase (AChE), increased the survival, growth, and differentiation of nerve cells by maintaining the level of brain-derived neurotrophic factor (BDNF), and regulated microglial immunoreactivity and neuroinflammation by reducing the level of proinflammatory cytokines. The multiple effects confirm that quercetin can be applied as an alternative non-pharmaceutical approach in reducing Al-induced neurotoxicity and maintaining adaptive homeostasis, which consequently affects the functioning of the central nervous system and the whole organism.

Oxidative stress (OS) refers to a metabolic imbalance caused by the excessive production of reactive oxygen species (ROS) and an insufficient antioxidant defense

Although commonly appreciated for their anti-oxidative and neuroprotective properties, flavonoids can also exhibit pro-oxidative activity, potentially reducing cell survival, particularly in the presence of metal ions. Disrupted copper homeostasis is a known contributor to neuronal dysfunction through oxidative stress induction. This study investigated the effects of myricitrin (1–20 μg/mL) on copper-induced toxicity (0.5 mM CuSO₄) in the neuroblastoma SH-SY5Y cell line. At non-toxic concentrations, myricitrin exacerbated copper’s toxic effects. The myricitrin-induced decrease in survival was accompanied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase activity, and a lower GSH/GSSG ratio. In combination with copper, myricitrin also activated caspase-3/7, promoted nuclear chromatin changes, and compromised membrane integrity. At the protein level, myricitrin upregulated p53 and PUMA expression. The toxic effects of myricitrin were alleviated by the p38 inhibitor SB203580, the intracellular calcium chelator BAPTA-AM, and the NMDA receptor blocker MK-801, highlighting the significant role of the ROS/p53/p38 axis in cell death and the critical involvement of calcium ions in apoptosis induction. The atomic force microscopy was used to assess the surface morphology and nanomechanical properties of SH-SY5Y cells, revealing changes following myricitrin treatment. This research highlights the toxic potential of myricitrin and emphasizes the need for caution when considering flavonoid supplementation in conditions with elevated copper levels.

Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial–mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients’ quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers.

Oxidative stress, characterized by increased production of reactive oxygen species (ROS) and disturbed redox homeostasis, is one of the key mechanisms underlying synaptic loss and neuronal death in various neurodegenerative diseases