Search Results (75)

Endocannabinoids are lipid mediators consisting of esters, amides and ethers of long-chain polyunsaturated fatty acids. In this work, attention was focused on N-arachidonoyl tyrosine (NA-Tyr) and N-arachidonoyl dopamine (NADA), the amides of arachidonic acid with tyrosine and dopamine, respectively. NADA is an endogenous ligand of both type 1 cannabinoid receptors and type 1 vanilloid channel receptors. NADA is considered an endogenous compound with capsaicin-like activity and is distributed in several brain areas. The metabolic fate of endocannabinoids involves numerous enzymatic activities, which are only partially characterized. In particular, the biological activity of these biomolecules is terminated by enzymes with hydrolytic or oxygenase/oxidase activity. As part of this problem, we studied the oxidation of NADA and NA-Tyr mediated by mushroom tyrosinase. Our experimental data show that tyrosinase can oxidize both NADA and NA-Tyr. The oxidation of these biomolecules was also carried out in the presence of cysteine, allowing us to observe the formation of endocannabinoid/endovanilloid adducts with cysteine. These results were derived from chromatographic analyses and mass spectral experiments. During the tyrosinase-mediated oxidation in the presence of cysteine, it was possible to observe the production of a melanin-like pigment. The spectral characteristics of this pigment are consistent with those of pheomelanin, the pigment that contributes to the structure of neuromelanin. While mushroom tyrosinase serves here as a convenient biomimetic model to investigate the oxidative susceptibility of NADA and NA-Tyr, extrapolating these in vitro findings to mammalian physiology requires caution. Nevertheless, considering the neuronal distribution of these precursors and the documented, albeit debated, presence of tyrosinase-like activity in the central nervous system (CNS), these results offer a chemical rationale to further investigate whether similar oxidative pathways occur in vivo and potentially contribute to neurodegenerative mechanisms. Full article

Background: D-amino acids are increasingly recognized as bioactive molecules with diverse physiological and pathological roles in humans, particularly in the gut, kidneys, and nervous system. Advances in analytical techniques have revealed their widespread presence in biological fluids, including plasma, urine, cerebrospinal fluid, amniotic fluid, and saliva, challenging the long-standing assumption that D-amino acids are absent or biologically insignificant in mammals. Scope: This review systematically summarizes the current knowledge on D-amino acid sources, distribution, metabolic regulation, and biological functions, with emphasis on their roles in human physiology and disease. Key findings: Accumulating evidence indicates that major D-amino acids, including D-serine, D-aspartate, and D-alanine, are derived from multiple sources such as diet, intestinal microbiota, and endogenous racemization processes. Rather than being passive metabolic byproducts, D-amino acids are now understood to participate in host–microbe interactions, neurotransmission, and renal physiology. Importantly, a consistent trend across studies is their dual and concentration-dependent nature, exhibiting beneficial effects under physiological conditions but potential cytotoxic effects at elevated levels. Conclusions and perspectives: Overall, D-amino acids represent multifunctional biomolecules with tightly regulated physiological roles and context-dependent pathological implications. However, major gaps remain in understanding their quantitative dynamics, tissue-specific regulation, and microbiota-dependent metabolism. Future studies addressing these mechanisms will be essential for establishing their clinical utility as biomarkers and for developing D-amino acid-based therapeutic and nutritional strategies. Full article

This narrative review aims to systematize the current knowledge on the dual role of reactive oxygen species and reactive nitrogen species in cancer processes, from their physiological function in redox signaling to their pathological impact in oxidative distress. The mechanisms of biomolecule damage, particularly DNA, and deregulation of signaling pathways induced by excessive ROS/RNS concentrations, which promote neoplastic transformation, are presented. The importance of diet and endogenous antioxidants in cancer prevention is also discussed, emphasizing the role of natural antioxidants in prevention and adjunctive therapy. In this context, oleanolic acid emerges as a promising compound with dual action modulating oxidative stress, capable of balancing cellular redox responses. We discuss the most important antioxidant mechanisms of oleanolic acid, the interconnection of oxidative stress with carcinogenesis-related pathways, anticancer mechanisms mediated by oxidative stress modulation, and structural modifications and modern application techniques that improve its bioavailability, as well as future perspectives on oleanolic acid research in the context of its antioxidant and anticancer activity. Overall, available experimental and preclinical data indicate that oleanolic acid, through pleiotropic modulation of oxidative stress and signaling networks, holds promise as an adjuvant agent in cancer prevention and therapy. Full article

Biomolecule-driven smart materials represent a paradigm shift in pharmacology, transitioning drug delivery from a passive process to an active, programmable, and highly specific intervention. These systems, constructed from or functionalized with biological macromolecules such as nucleic acids, peptides, proteins, and polysaccharides, are engineered to sense and respond to specific pathophysiological cues or external triggers. This review provides a comprehensive analysis of this rapidly evolving field. We first delineate the fundamental principles of stimuli-responsive actuation, categorizing systems based on their response to endogenous (pH, redox, enzymes, ROS) and exogenous (temperature, light, magnetic fields) triggers. We then conduct an in-depth survey of the primary biomolecular architectures, examining the unique design space offered by DNA nanotechnology, the functional versatility of peptides and proteins, and the biocompatibility of polysaccharides. Key therapeutic applications in oncology, inflammatory diseases, and gene therapy are discussed, highlighting how these intelligent systems are being designed to overcome critical biological barriers and enhance therapeutic efficacy. Finally, we address the formidable challenges—spanning biocompatibility, manufacturing scalability, and regulatory navigation—that constitute the “bench-to-bedside” chasm. We conclude by exploring future perspectives, including the development of multi-stimuli responsive, logic-gated systems and the transformative potential of artificial intelligence in designing the next generation of personalized nanomedicines. Full article

Lipids are structurally diverse biomolecules that play essential roles in cellular function, energy storage, and signaling. The human lipidome, a dynamic and complex subset of the metabolome, is shaped by both endogenous factors, such as genetics, sex, age, and metabolic health, and exogenous influences like lifestyle, diet, and microbiota. Among these, diet stands out as one of the most modifiable and impactful determinants, influencing lipid composition across plasma, serum, and lipoprotein fractions. While traditional lipid profiling provides limited insight, lipidomics enables comprehensive characterization of lipid species, revealing mechanistic links between lipid metabolism and diseases such as cardiovascular disease (CVD), metabolic syndrome (MetS), and inflammatory disorders. This review explores: (1) the relationship between lipid profiles and CVD risk, (2) the internal and external modulators of the lipidome, and (3) current evidence on how specific dietary patterns, including Mediterranean, Nordic, low glycemic, and vegetarian diets, and individual nutrients such as omega-3 fatty acids (FAs), plant sterols, and mycoprotein, influence lipidomic profiles. Advances in lipidomics highlight that dietary fat quality, food matrix, and eating patterns can significantly modulate lipid species such as triacylglycerols (TAGs), ceramides (Cers), and phospholipids, with implications for cardiometabolic health. Notably, distinct responses are observed across plasma High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) lipidomes, emphasizing the need for compartment-specific analyses. Understanding these diet-lipidome interactions offers promising avenues for precision nutrition and the development of lipid-based biomarkers for disease prevention and management. Full article

Hydrogen sulfide (H₂S), once regarded solely as a toxic gas, is now recognized as a vital endogenous signaling molecule with important roles in both health and disease. Growing evidence supports the developmental origins of health and disease (DOHaD) framework, in which early-life disturbances in H₂S signaling may drive the later development of cardiovascular–kidney–metabolic (CKM) syndrome—a condition that encompasses chronic kidney disease, obesity, diabetes, and cardiovascular disease. This review highlights the emerging importance of H₂S in CKM programming and the potential of H₂S-based interventions during gestation and lactation to prevent long-term adverse health outcomes in offspring. Findings from animal studies suggest that maternal supplementation with sulfur-containing amino acids, N-acetylcysteine, H₂S donors, and related sulfur-containing biomolecules can attenuate CKM-related risks in progeny. Despite these advances, several critical areas remain underexplored, including the role of gut microbiota-derived H₂S, the epigenetic mechanisms influenced by H₂S during development, and the clinical translation of preclinical findings. Targeting H₂S signaling offers a promising strategy for early-life prevention of CKM syndrome and may also hold broader potential for preventing other DOHaD-related chronic diseases. Full article

Tailored mesoporous silicate nanomaterials have attracted significant interest due to their exceptional surface properties, including high interfacial toughness, tunable thickness, customizable topology, optical transparency, and adjustable hydrophobicity. These characteristics enable them to exhibit a wide range of functional behaviors, such as antibacterial, anti-fouling, anti-fogging, lubricating, and abrasion-resistant properties, to name just a few. With recent advances in surface-modified nanosystems for bioengineering and biomedical applications, silica-based nanomaterials have emerged as promising candidates owing to their ease of surface functionalization, bioactivity, biocompatibility, biodegradability, and bioavailability. Consequently, they have been widely explored in various therapeutic contexts. This review provides a concise and concentrated summary of recent advances and applications of tailored mesoporous silicate nanomaterials in regenerative medicine and theranostics, with the primary focus being on how endogenous or exogenous triggers can be leveraged to achieve selective and precise delivery of various biomolecules and active therapeutics across diverse cellular environments, by harnessing the intrinsic properties of mesoporous silicate nanoparticles. This focus also guided the selection of specific examples provided to highlight their wide range of applications, with the report concluding with some perspectives and remaining challenges. Full article

Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (≥18 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF’s potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats. Full article

Cyanide (CN) is a potent, fast-acting toxicant that impacts endogenous biomolecules in the nervous system, including acid-sensing ion channels (ASICs), which play a vital role in various neurological and psychological conditions. Here, we demonstrate that CN rapidly potentiates ASIC currents in cultured mouse cortical neurons in a dose-dependent manner while causing a leftward shift in the pH dose–response curve. Notably, this potentiation was unaffected by a 30-min CN treatment or the presence of ATP in the recording pipette. Further investigations into the role of zinc revealed that TPEN, a high-affinity zinc chelator, did not enhance ASIC currents following CN pretreatment, nor did CN influence the potentiation of ASIC currents induced by TPEN. Low-affinity zinc blocked the potentiation of ASIC currents by CN. CN potentiated ASIC currents in cortical neurons from ASIC2 but not from ASIC1a knockout mice. In experiments with CHO cells expressing homomeric ASIC1a and heteromeric ASIC1a/2, CN potentiated ASIC1a currents but had no effect on homomeric ASIC1b, ASIC2a, or ASIC3 channels. Mutating lysine 133 (K133) to arginine (R) in the extracellular domain of ASIC1a abolished CN’s effect, suggesting that CN potentiates ASIC1a currents primarily via high-affinity zinc binding, with K133 being critical for this modulation. Full article

The amyloid hypothesis is the predominant model of Alzheimer’s disease (AD) pathogenesis, suggesting that amyloid beta (Aβ) peptide is the primary driver of neurotoxicity and a cascade of pathological events in the central nervous system. Aβ aggregation into oligomers and deposits triggers various processes, such as vascular damage, inflammation-induced astrocyte and microglia activation, disrupted neuronal ionic homeostasis, oxidative stress, abnormal kinase and phosphatase activity, tau phosphorylation, neurofibrillary tangle formation, cognitive dysfunction, synaptic loss, cell death, and, ultimately, dementia. Molecular dynamics (MD) is a powerful structure-based drug design (SBDD) approach that aids in understanding the properties, functions, and mechanisms of action or inhibition of biomolecules. As the only method capable of simulating atomic-level internal motions, MD provides unique insights that cannot be obtained through other techniques. Integrating experimental data with MD simulations allows for a more comprehensive understanding of biological processes and molecular interactions. This review summarizes and evaluates MD studies from the past decade on small molecules, including endogenous compounds and repurposed drugs, that inhibit amyloid beta. Furthermore, it outlines key considerations for future MD simulations of amyloid inhibitors, offering a potential framework for studies aimed at elucidating the mechanisms of amyloid beta inhibition by small molecules. Full article

Cell homing, a process that leverages the body’s natural ability to recruit cells and repair damaged tissues, presents a promising alternative to cell transplantation methods. Central to this approach is the recruitment of endogenous stem/progenitor cells—such as those from the apical papilla, bone marrow, and periapical tissues—facilitated by chemotactic biological cues. Moreover, biomaterial scaffolds embedded with signaling molecules create supportive environments, promoting cell migration, adhesion, and differentiation for the regeneration of the pulp–dentin complex. By analyzing in vivo animal studies using cell homing strategies, this review explores how biomolecules and scaffold materials enhance the recruitment of endogenous stem cells to the site of damaged dental pulp tissue, thereby promoting repair and regeneration. It also examines the key principles, recent advancements, and current limitations linked to cell homing-based regenerative endodontic therapy, highlighting the interplay of biomaterials, signaling molecules, and their broader clinical implications. Full article

Introduction/Objectives: Since the biological activities and toxicities of ‘foreign’ and/or excess levels of metal ions are predominantly determined by their precise molecular nature, here we have employed high-resolution ¹H NMR analysis to explore the ‘speciation’ of paramagnetic Ni(II) ions in human saliva, a potentially rich source of biomolecular Ni(II)-complexants/chelators. These studies are of relevance to the in vivo corrosion of nickel-containing metal alloy dental prostheses (NiC-MADPs) in addition to the dietary or adverse toxicological intake of Ni(II) ions by humans. Methods: Unstimulated whole-mouth human saliva samples were obtained from n = 12 pre-fasted (≥8 h) healthy participants, and clear whole-mouth salivary supernatants (WMSSs) were obtained from these via centrifugation. Microlitre aliquots of stock aqueous Ni(II) solutions were sequentially titrated into WMSS samples via micropipette. Any possible added concentration-dependent Ni(II)-mediated pH changes therein were experimentally controlled. ¹H NMR spectra were acquired on a JEOL JNM-ECZ600R/S1 spectrometer. Results: Univariate and multivariate (MV) metabolomics and MV clustering analyses were conducted in a sequential stepwise manner in order to follow the differential effects of increasing concentrations of added Ni(II). The results acquired showed that important Ni(II)-responsive biomolecules could be clustered into distinguishable patterns on the basis of added concentration-dependent responses of their resonance intensities and line widths. At low added concentrations (71 µmol/L), low-WMSS-level N-donor amino acids (especially histidine) and amines with relatively high stability constants for this paramagnetic metal ion were the most responsive (severe resonance broadenings were observed). However, at higher Ni(II) concentrations (140–670 µmol/L), weaker carboxylate O-donor ligands such as lactate, formate, succinate, and acetate were featured as major Ni(II) ligands, a consequence of their much higher WMSS concentrations, which were sufficient for them to compete for these higher Ni(II) availabilities. From these experiments, the metabolites most affected were found to be histidine ≈ methylamines > taurine ≈ lactate ≈ succinate > formate > acetate ≈ ethanol ≈ glycine ≈ N-acetylneuraminate, although they predominantly comprised carboxylato oxygen donor ligands/chelators at the higher added Ni(II) levels. Removal of the interfering effects arising from the differential biomolecular compositions of the WMSS samples collected from different participants and those from the effects exerted by a first-order interaction effect substantially enhanced the statistical significance of the differences observed between the added Ni(II) levels. The addition of EDTA to Ni(II)-treated WMSS samples successfully reversed these resonance modifications, an observation confirming the transfer of Ni(II) from the above endogenous complexants to this exogenous chelator to form the highly stable diamagnetic octahedral [Ni(II)-EDTA] complex (K_stab = 1.0 × 10¹⁹ M⁻¹). Conclusions: The results acquired demonstrated the value of linking advanced experimental design and multivariate metabolomics/statistical analysis techniques to ¹H NMR analysis for such speciation studies. These provided valuable molecular information regarding the identities of Ni(II) complexes in human saliva, which is relevant to trace metal ion speciation and toxicology, the in vivo corrosion of NiC-MADPs, and the molecular fate of ingested Ni(II) ions in this biofluid. The carcinogenic potential of these low-molecular-mass Ni(II) complexes is discussed. Full article

Oxidative stress is the result of the imbalance between reactive oxygen and nitrogen species (RONS), which are produced by several endogenous and exogenous processes, and antioxidant defenses consisting of exogenous and endogenous molecules that protect biological systems from free radical toxicity. Oxidative stress is a major factor in the aging process, contributing to the accumulation of cellular damage over time. Oxidative damage to cellular biomolecules, leads to DNA alterations, lipid peroxidation, protein oxidation, and mitochondrial dysfunction resulting in cellular senescence, immune system and tissue dysfunctions, and increased susceptibility to age-related pathologies, such as inflammatory disorders, cardiovascular and neurodegenerative diseases, diabetes, and cancer. Oxidative stress-driven DNA damage and mutations, or methylation and histone modification, which alter gene expression, are key determinants of tumor initiation, angiogenesis, metastasis, and therapy resistance. Accumulation of genetic and epigenetic damage, to which oxidative stress contributes, eventually leads to unrestrained cell proliferation, the inhibition of cell differentiation, and the evasion of cell death, providing favorable conditions for tumorigenesis. Colorectal, breast, lung, prostate, and skin cancers are the most frequent aging-associated malignancies, and oxidative stress is implicated in their pathogenesis and biological behavior. Our aim is to shed light on the molecular and cellular mechanisms that link oxidative stress, aging, and cancers, highlighting the impact of both RONS and antioxidants, provided by diet and exercise, on cellular senescence, immunity, and development of an antitumor response. The dual role of ROS as physiological regulators of cell signaling responsible for cell damage and diseases, as well as its use for anti-tumor therapeutic purposes, will also be discussed. Managing oxidative stress is crucial for promoting healthy aging and reducing the risk of age-related tumors. Full article

Recent advancements in aesthetic medicine offer innovative cosmetic solutions to enhance patient skin quality and appearance. Advanced treatment options enable practitioners to effectively address skin aging signs, pigmentation imbalance, and loss of elasticity in ambulatory and home-based care regimens. Exosomes (nanoscale cell-derived vesicles) transport a variety of biomolecules and are pivotal in physiological intercellular communication. Importantly, exosomes have recently emerged as key endogenous players in tissular regeneration. More broadly (from an active ingredient purity standpoint), exosomes, stem cell secretomes, and cell culture-conditioned media have been clinically proven to exert multifaceted beneficial topical effects (anti-inflammatory, antioxidant, anti-aging, skin rejuvenation). Therefore, human, animal, and plant-derived exosomes or other refined sub-cellular biological fractions are gaining substantial interest within the aesthetic and cosmetic industries. Notably, such approaches are thought to be among the most promising novel contenders for advanced, biologically inspired skin prejuvenation and rejuvenation care. The present narrative review summarizes the latest clinically oriented research on exosomes and cell culture-conditioned media, highlighting their mechanisms of action in various topical applications. Furthermore, it explores the innovation landscape and currently commercially available products on the global cosmetic market and discusses the potential future applications of advanced, biologically inspired ingredients in the medical aesthetic industry. Full article

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains. Full article