Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer’s disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer’s disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer’s disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions.

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC₅₀ > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H₂O₂-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

One of the pathological hallmarks of Alzheimer’s disease (AD) associated with its progression that contributes to β-amyloid (Aβ) generation is oxidative stress (OS). Clinical data suggest that melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aβ_1-42 model of AD, and combination of both pin and Aβ_1-42 model (pin+icvAβ_1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aβ_1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th–35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAβ_1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aβ_1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAβ_1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAβ_1-42 and pin+icvAβ_1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAβ_1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAβ_1-42-induced AD pathology.

The pineal gland regulates the aging process via the hormone melatonin. The present report aims to evaluate the effect of pinealectomy (pin) on behavioral and oxidative stress-induced alterations in cholesterol and sphingomyelin (SM) levels in young adult, mature and aging rats. Sham and pin rats aged 3, 14 and 18 months were tested in behavioral tests for motor activity, anxiety, and depression. The ELISA test explored oxidative stress parameters and SM in the hippocampus, while total cholesterol was measured in serum via a commercial autoanalyzer. Mature and aged sham rats showed low motor activity and increased anxiety compared to the youngest rats. Pinealectomy affected emotional responses, induced depressive-like behavior, and elevated cholesterol levels in the youngest rats. However, removal of the pineal gland enhanced oxidative stress by diminishing antioxidant capacity and increasing the MDA level, and decreased SM level in the hippocampus of 14-month-old rats. Our findings suggest that young adult rats are vulnerable to emotional disturbance and changes in cholesterol levels resulting from melatonin deficiency. In contrast, mature rats with pinealectomy are exposed to an oxidative stress-induced decrease in SM levels in the hippocampus.

(1) Background: The aim of the work is the evaluation of in vitro antiproliferative and pro-apoptotic activity of four benzimidazole derivatives containing colchicine-like and catechol-like moieties with methyl group substitution in the benzimidazole ring against highly invasive breast cancer cell line MDA-MB-231 and their related impairment of tubulin dynamics. (2) Methods: The antiproliferative activity was assessed with the MTT assay. Alterations in tubulin polymerization were evaluated with an in vitro tubulin polymerization assay and a docking analysis. (3) Results: All derivatives showed time-dependent cytotoxicity with IC₅₀ varying from 40 to 60 μM after 48 h and between 13 and 20 μM after 72 h. Immunofluorescent and DAPI staining revealed the pro-apoptotic potential of benzimidazole derivatives and their effect on tubulin dynamics in living cells. Compound 5d prevented tubulin aggregation and blocked mitosis, highlighting the importance of the methyl group and the colchicine-like fragment. (4) Conclusions: The benzimidazole derivatives demonstrated moderate cytotoxicity towards MDA-MB-231 by retarding the initial phase of tubulin polymerization. The derivative 5d containing a colchicine-like moiety and methyl group substitution in the benzimidazole ring showed potential as an antiproliferative agent and microtubule destabilizer by facilitating faster microtubule aggregation and disrupting cellular and nuclear integrity.

Betulinic acid (BA) is a natural pentacyclic triterpene with diverse biological activities. However, its low water solubility limits its pharmaceutical application. The conversion of pharmaceutically active molecules into ionic liquids (ILs) is a promising strategy to improve their physicochemical properties, stability, and/or potency. Here, we report the synthesis and characterization of 15 novel ILs containing a cation ethyl ester of a polar, non-polar, or charged amino acid [AAOEt] and an anion BA. Except for [ValOEt][BA], we observed preserved or up to 2-fold enhanced cytotoxicity toward hormone-dependent breast cancer cells MCF-7. The estimated IC50 (72 h) values within the series varied between 4.8 and 25.7 µM. We found that the most cytotoxic IL, [LysOEt][BA]₂, reduced clonogenic efficiency to 20% compared to that of BA. In addition, we evaluated the effect of a 72 h treatment with BA or [LysOEt][BA]₂, the most cytotoxic compound, on the thermodynamic behavior of MCF-7 cells. Based on our data, we suggest that the charged amino acid lysine included in the novel ILs provokes cytotoxicity by a mechanism involving alteration in membrane lipid organization, which could be accompanied by modulation of the visco–elastic properties of the cytoplasm.