Search Results (316)

Chemotherapy-associated cognitive impairment (CACI) is a common long-term complication of cancer treatment that predominantly affects attention, executive function, information processing, and working memory. Although considerable progress has been made in understanding its molecular basis, the relationship between chemotherapy-induced neurobiological alterations and the functional organization of working memory remains incompletely understood. This narrative review aims to integrate current evidence on the neuroanatomical organization of working memory, the molecular mechanisms underlying CACI, and neuroimaging findings in patients receiving chemotherapy. The review summarizes current knowledge regarding mitochondrial dysfunction, oxidative stress, neuroinflammation, blood–brain barrier disruption, purinergic signaling, and chemotherapy-specific mechanisms of central nervous system injury. Furthermore, the principal mechanisms by which commonly used chemotherapeutic agents reach or indirectly affect the brain are discussed. Clinical neuroimaging findings from selected malignancies are interpreted within the framework of the four-component model of working memory, including the visuospatial sketchpad, phonological loop, central executive, and episodic buffer. Current evidence indicates that chemotherapy induces structural and functional alterations involving the prefrontal cortex, parietal cortex, hippocampus, insula, anterior cingulate cortex, angular gyrus, and associated neural networks. These changes are accompanied by disturbances in executive control, visuospatial processing, verbal working memory, and multimodal information integration. However, considerable heterogeneity among available studies and the difficulty in distinguishing cancer-related from chemotherapy-induced cognitive impairment remain major limitations. By integrating molecular, neuroanatomical, and neuroimaging evidence, this review proposes a conceptual framework linking chemotherapy-induced brain alterations with dysfunction of specific working memory components. Future longitudinal studies combining multimodal neuroimaging, molecular biomarkers, and standardized neuropsychological assessment are needed to identify chemotherapy-specific patterns of cognitive dysfunction and support the development of personalized preventive and therapeutic strategies for cancer survivors. Full article

(1) Fibromyalgia syndrome (FMS) is a chronic pain disorder with a multifactorial pathogenesis involving neuroinflammation, oxidative stress, and immune dysfunction. This study aimed to evaluate serum biomarkers related to purinergic signaling, inflammasome activation, pyroptosis, and oxidative stress in patients with FMS. (2) Methods: A total of 93 patients with FMS and 93 age- and sex-matched healthy controls were enrolled. Serum levels of pannexin-1 (PANX1), purinergic receptor P2X7 (P2RX7), NLRP3, caspase-1 (CASP1), interleukin-1β (IL-1β), interleukin-18 (IL-18), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured using enzyme-linked immunosorbent assays (ELISA). (3) Results: Total antioxidant status (TAS) and total oxidant status (TOS) were determined. Patients with FMS exhibited significantly increased serum CASP1, GSDME, PANX1, P2RX7, and total oxidative stress (TOS) levels, whereas GSDMD, NLRP3, IL-18, and TAS levels were significantly decreased compared with controls (all p < 0.05). No significant differences were observed in IL-1β levels. Receiver operating characteristic analysis demonstrated exploratory discriminatory performance within this case–control cohort for CASP1 and TAS (AUC = 0.898), followed by TOS (AUC = 0.849) and P2RX7 (AUC = 0.757). (4) Conclusions: These findings indicate alterations in circulating biomarkers related to purinergic signaling, inflammasome-associated pathways, pyroptosis-related proteins, and oxidative stress in patients with FMS. These alterations may contribute to the pathophysiology of FMS and provide a foundation for future mechanistic studies investigating their potential as biomarkers and therapeutic targets. Full article

Nucleosides are extensively employed for the development of pharmaceuticals, chemotherapeutic agents, and bioregulators. Background/Objectives: The introduction of an additional chiral functionality into a carbohydrate or heterocyclic base fragment may increase the selectivity of interactions with nucleos(t)ide-metabolizing enzymes and receptors and, in some cases, lead to more specific physiological activities. Methods: An improvement of the selectivity of nucleoside-based drugs can be achieved either by the chemical modification of a carbohydrate or a base constituent or by a combination of these two approaches. Additionally, stereospecific enzymatic cleavage of nucleos(t)ide prodrugs containing biodegradable substituents can reduce cytotoxicity and enhance bioavailability. Results: A series of enantiomerically pure nucleosides modified at the ribose or heterocyclic base were obtained by chemical and enzymatic methods. Novel antiviral or anticancer active compounds, inhibiting viral or cellular enzymes or activating cellular nucleoside kinases have been found among chemically synthesized derivatives. Some exhibit strengthened “ligand–receptor” interaction, acting on receptors of the purinergic signaling system. During recent extensive structure–activity studies, several drugs and their prototypes have been proposed for the treatment of viral infections: the 2′C-fluoromethyl derivative of sofosbuvir (anti-SARS-CoV, preclinical), VV-261 (SFTSV, phase I clinical), balapiravir (dengue, phase I clinical), mericitabine (approved drug for HCV), and lumicitabine (approved drug for RSV and HMPV). Conclusions: Modern literature data within the scope of the present review suggest that direct modification of nucleosides with various chiral functionalities can be considered as an approach to increase their efficacy, specificity and selectivity. Full article

Gastric cancer is strongly associated with chronic inflammation and dysregulated immune signaling. Molecules involved in purinergic and innate immune pathways, including Toll-like receptor 3 (TLR3), P2Y purinoceptor 2 (P2RY2), and pannexin-1 (PANX1), may contribute to gastric cancer biology; however, their combined clinical relevance remains unknown. This study included 45 patients with gastric cancer and 45 healthy controls. The gene expression levels of TLR3, P2RY2, and PANX1 were analyzed using RT-PCR, and serum protein concentrations were measured using ELISA. Group comparisons, logistic regression, and ROC analyses were performed to evaluate the diagnostic performance. TCGA-STAD-based immune infiltration analyses were conducted using the TIMER platform, and prognostic significance was assessed using Kaplan–Meier survival analysis. Although alterations in gene expression were observed, none reached statistical significance. At the protein level, PANX1 was significantly elevated in patients with gastric cancer and was independently associated with disease status, whereas TLR3 and P2RY2 showed no significant circulating alterations. TIMER analysis demonstrated positive correlations between TLR3 and PANX1 expression and several immune cell populations, whereas P2RY2 expression showed predominantly negative correlations with immune cell infiltration. Kaplan–Meier analysis revealed that high PANX1 and TLR3 expression levels were associated with improved overall survival. ROC analyses indicated limited diagnostic accuracy for each marker. Collectively, our experimental findings provide evidence only for elevated circulating PANX1 in patients with gastric cancer. In contrast, the observations regarding TLR3 and P2RY2 were not statistically significant in our cohort and should therefore be considered exploratory and hypothesis-generating. Complementary bioinformatic analyses suggest that these molecules may participate in immune-related signaling pathways in gastric cancer; however, these observations require validation in independent tissue-based and larger prospective studies. Full article

Hypercaloric diet and obesity are strongly associated with cardiovascular dysfunction, diabetes and hypertension development mediated by sympathetic nervous system hyperactivity. In addition to the adrenergic system, purinergic signaling has emerged as a relevant modulator of cardiovascular physiopathology. However, its role in hypercaloric diet-induced cardiovascular dysfunction remains incompletely understood. In this study, we investigated the effects of a hypercaloric diet on metabolic parameters, atrial purinergic modulation and vascular reactivity. Rats fed the hypercaloric diet consumed a diet with ~31% greater caloric density than control animals that received a standard (3.5 kcal/g) pellet diet for 8 weeks. Metabolic and cardiovascular parameters were measured, and isolated right atria (RA), left atria (LA) and thoracic aortic vessels were used to evaluate function, contractility and vascular responsiveness. A hypercaloric diet significantly increased body weight and visceral adiposity, with elevated systolic blood pressure (SBP) and cardiac hypertrophy, associated with alterations in glucose levels and insulin sensitivity. In isolated atria, a hypercaloric diet increased basal contractile force in the LA. Also, ATP induced a biphasic response characterized by an initial negative inotropic effect (NIE) followed by a positive inotropic effect (PIE). A hypercaloric diet reduced ATP-mediated NIE and enhanced PIE in both atria, suggesting an altered balance between inhibitory-P1 and excitatory-P2 purinergic signaling. At the vascular level, a hypercaloric diet impaired adenosine-mediated relaxation and increased contraction, indicating vascular hyperreactivity. Collectively, these findings suggest that a hypercaloric diet induces cardiometabolic dysfunction associated with alterations in cardiovascular function linked to impaired P1/P2 purinergic regulation, contributing to obesity-associated cardiovascular remodeling and hypertension. Full article

Acute kidney injury (AKI) is characterized by a rapid decline or sudden loss of renal function over hours to days. Pathophysiological triggers such as renal ischemia–reperfusion (IR) injury and the accumulation of uremic toxins (UTs), notably indoxyl sulfate (IS), can initiate AKI and affect vascular beds distant from the ischemic site, like the aorta. In this context, purinergic signaling becomes relevant, since its components regulate vascular tone and inflammatory responses. This study aimed to evaluate the impact of AKI induced by IR with or without IS administration on purinergic signaling in the aorta of mice. Renal ischemia was induced by the occlusion of the left renal pedicle for 60 min, followed by reperfusion for 8 days (IR 8) or 15 days (IR 15). Some animals were also treated with saline solution or IS for 15 days. The IR15 group exhibited increased plasma IS concentrations and upregulated adenosine receptor gene expression. Furthermore, in the IR+IS group, there was increased expression of A1, A2a, NTPDase 1, and 2. This shift toward an adenosine-enriched signaling environment may represent a key mechanism linking renal injury to systemic vascular inflammation. Full article

Aflatoxin B₁ (AFB₁) and fumonisin B₁ (FB₁) are cereal-contaminating mycotoxins; co-exposure to these compounds is associated with hepatocellular carcinoma, although the underlying immunological mechanisms remain unclear. This study aimed to investigate the impact of AFB₁ and FB₁, individually and combined, on immune cell function, focusing on Th1-associated cytokines, cytotoxic capacity, oxidative stress involvement, and energy and purinergic metabolism. Rat splenocytes and intrahepatic leukocytes were exposed to AFB₁ (20 μM), FB₁ (10 μM), or a mixture of both (MIX), in the presence or absence of catalase. Cytokines and phenotypes were assessed by flow cytometry and ELISA, cytotoxicity by co-culture assays, and intra/extracellular adenine nucleotides and purines by HPLC. The MIX significantly impaired Th1-like differentiation and reduced IFNγ and TNFα production, FAS-L expression and cytolytic activity while increasing IL4 production, indicating a shift toward a Th2-like profile. These effects were prevented by catalase, supporting a key role for oxidative stress. Co-exposure disrupted intracellular energy balance, decreasing adenosine triphosphate (ATP) levels, ATP/ADP ratios, and total adenine nucleotide pools. It also enhanced purine degradation, extracellular ATP release and adenosine accumulation, suggesting altered purinergic signaling. Consequently, AFB₁-FB₁ co-exposure disrupts immune function through interconnected redox and metabolic mechanisms, promoting an immunosuppressive environment that may favor tumor progression. Full article

Gastric cancer remains a major cause of cancer-related mortality worldwide, highlighting the need for an improved understanding of its molecular mechanisms. Purinergic and glutamatergic signaling pathways, immune checkpoint molecules, and oxidative stress are thought to contribute to tumor biology; however, their combined evaluation in gastric cancer is limited. Methods: Gene expression levels of glutamate receptor ionotropic N-Methyl-D-aspartate 2A (GRIN2A), purinergic receptor P2X1 (P2RX1), and programmed death-ligand 1 (PD-L1/CD274) were analyzed using real-time PCR, while serum protein levels were determined by ELISA. Total antioxidant status (TAS) and total oxidant status (TOS) were also measured to assess systemic oxidative balance. Results: Gene expression analysis revealed an increased expression trend for P2RX1 in the gastric cancer group compared with healthy controls, whereas GRIN2A and CD274 (PD-L1) expression levels showed numerical decreases. Serum concentrations of GRIN2A and PD-L1, as well as TAS and TOS levels, were numerically higher in patients with gastric cancer; however, none of these differences reached statistical significance (p > 0.05). Likewise, serum P2RX1 levels did not differ significantly between groups. Receiver operating characteristic (ROC) analysis demonstrated area under the curve (AUC) values close to 0.5 for all evaluated parameters, indicating limited discriminatory and diagnostic performance. Conclusions: These findings suggest that these molecular markers may reflect disease-related biological alterations rather than serve as independent circulating diagnostic biomarkers in gastric cancer. Full article

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK–AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer’s disease, Parkinson’s disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation. Full article

Fibrosis is a common extracellular matrix pathology characterized by increased scarring, representing a critical checkpoint toward cirrhosis and hepatocellular carcinoma. Its onset involves coordinated interplay among hepatocytes, Kupffer, and hepatic stellate cells (HSCs). Extracellular ATP and its derivates act as crucial damage-associated molecular patterns when released by injured liver cells, binding to specific purinergic receptors (P2X, P2Y, and P1) to establish an autocrine–paracrine signaling loop. The hepatic fibrotic response underlies the activation of ATP receptors that generate second messengers and cationic conductance. In parallel, extracellular nucleotidases hydrolyze ATP towards less phosphorylated intermediates and adenosine. This review focuses on the role of P2X and P2Y receptors in liver injury. The P2X7 receptor regulates the NLRP3 inflammasome in Kupffer cells and HSCs, while the P2X4 receptor is upregulated in myofibroblasts, modulating migration and matrix synthesis. Among P2Y receptors, P2Y2 drives inflammation and steatosis but promotes HIF-1α-mediated DNA repair. The P2Y6 receptor promotes alcohol-induced injury but restrains metabolic-dysfunction-associated steatohepatitis. P2Y2 and P2Y4 receptors maintain biliary homeostasis in cholangiocytes, whereas the P2Y1 receptor preserves HSC quiescence by blocking YAP translocation. Finally, UDP-glucose–P2Y14 induces HSC activation. Targeting these specific purinergic receptors or ecto-nucleotidases represents a promising pharmacological frontier against hepatic fibrosis. Full article

Background: Bladder dysfunction is a complicated condition that substantially impairs quality of life for both men and women. Due to the adverse effects and limited efficacy of current therapies, new strategies must be rapidly developed. Female bladder dysfunction arises from multifaceted etiologies distinct from the predominantly male benign prostatic hyperplasia (BPH) that is the focus of existing drug development. In this study, we investigated the therapeutic potential of Quisqualis indica extract (QIE), a traditional medicinal herb that attenuates BPH-induced lower urinary symptoms (LUTS), to elucidate its underlying mechanisms in a female bladder dysfunction model. Methods and Results: A bladder dysfunction model was established by inducing partial bladder outlet obstruction (pBOO) in female Sprague Dawley rats, followed by the oral administration of QIE for 7 weeks. Voiding pattern analysis and cystometry were conducted to evaluate indicators such as voiding frequency, voiding volume, and intravesical pressure. Histological analysis of excised bladder tissue quantified smooth muscle hypertrophy and collagen deposition. Gene expression profiling of inflammatory cytokines and fibrosis-related markers within the bladder tissue was performed to assess tissue remodeling. Furthermore, pharmacological contraction studies examined the direct effects of QIE on detrusor muscle responsiveness to muscarinic and purinergic agonists. QIE administration significantly improved the elevated voiding pressure and abnormal inter-contraction intervals observed in the pBOO rats, restoring normal voiding patterns. Histological examination revealed a marked decrease in muscle hypertrophy and collagen deposition. Expression levels of pro-inflammatory cytokines (TNFα, IL-1β) and fibrosis-associated genes (TGF-β, α-SMA) were downregulated. Pharmacological contraction assays demonstrated that QIE attenuated the hypercontractile response of bladder smooth muscle to a muscarinic agonist, with concurrent reduced expression of muscarinic receptors (M₂, M₃) at the mRNA level. Conclusions:QIE ameliorates key aspects of bladder dysfunction, voiding abnormalities, inflammation, fibrosis, and hypercontractility by modulating muscarinic receptor signaling and fibrotic pathways. This study suggests that QIE warrants further investigation as a natural product-based therapeutic candidate for female bladder dysfunction. Full article

Little is known about how nicotinic signalling in human astrocytes may contribute to the functional neurotoxicity of compounds related to tobacco alkaloids and neonicotinoid pesticides. We generated a single-cell Ca²⁺-imaging assay in induced pluripotent stem cell (iPSC)-derived astrocytes, and profiled functional expressions of some neurotoxicologically relevant receptors. Responses to pharmacological tool compounds indicated the expression of nicotinic, muscarinic, purinergic, glutamatergic receptors and voltage-gated Na⁺/Ca²⁺ channels. Closer investigation of the nicotinic system, e.g., using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective positive allosteric modulator PNU-120596 and alpha7-preferring agonist (AR-R17779) demonstrated that Ca²⁺ signals elicited by nicotine and neonicotinoids are dominated by alpha7 nAChRs and depend on the downstream activation of L-type Ca²⁺ channels and tetrodotoxin-sensitive Na⁺ channels. Crosstalk of nAChR activation/desensitization was not observed for the inflammatory response elicited by TNF or for activation of glutamatergic or purinergic signalling. However, pre-stimulation of nAChR by neonicotinoids significantly blunted the response to the neurotransmitter acetylcholine. Comparative experiments in the human neuronal cultures (LUHMES cells) revealed similar potency ranges and pharmacological fingerprints for several neonicotinoids and their human-relevant metabolites descyanothiacloprid and desnitroimidacloprid. The pesticide metabolites showed a high potency, compared with their respective parent compounds. After this basic system characterization, the hitherto data-poor pesticides cycloxaprid and flupyradifurone were comparatively profiled in astrocytic and neuronal test systems. They showed the typical features of alpha7 nAChR agonists. The disruption of cholinergic signalling in astrocytes suggests that neonicotinoids affect not only neurons in human brains. Therefore, future neurotoxicity screening approaches may need to consider astrocyte toxicity. Full article

This research paper focused on the synthesis of 1-[2-hydroxy-3-(phenylcarbamoyloxy)propyl]-4-(R¹, R²-substituted phenyl)piperazin-1-ium chlorides (I)–(III), containing R¹, R² = H, Cl and/or OCH₃, and the evaluation of some of their physicochemical parameters. The in vitro biological investigation of these N-arylpiperazine (NAP) derivatives consisted in assessing their impact on purinergic P2X7-associated signaling, that is, the evaluation of antioxidant, anti-inflammatory and immunomodulatory characteristics. The ultraviolet type C (UVC) irradiation (λ = 254 nm, 0.954 kJ/m²) induced a pronounced stress response in human leukocytes without marked cytotoxicity while maintaining high cell viability (≥90%), as evidenced by increased interleukin (IL)-1β production (94%), elevated IL-1β mRNA expression, enhanced lipid peroxidation (66%), and increased intracellular adenosine 5′-triphosphate (ATP; 97%), respectively. Under basal conditions, these lipophilic NAPs, defined with logarithmic values of retention (capacity) factors corresponding to 100% water in isocratic elution RP-HPLC, i.e., k_w descriptors (varying from 2.3829 to 4.3689), and isocratic chromatographic hydrophobicity index (φ₀) parameters (ranging from 0.7578 to 0.8842), reduced IL-1β production (by 26–63%) and enhanced superoxide dismutase (SOD) activity (up to 64%) without inducing oxidative damage. Under UVC-induced stress, all evaluated compounds decreased lipid peroxidation (up to 45%) and significantly increased antioxidant enzyme activities, including SOD (up to 223%) as well as catalase (up to 145%). The observed effects were associated with changes in intracellular ATP levels and redox-related parameters. In the experiments described in this paper, intracellular ATP was measured so that no direct conclusions could be drawn regarding the extracellular ATP-dependent activation of purinergic receptors, including P2X7. Overall, the results demonstrated that variations within the structure of these NAPs significantly affected compounds’ biological activity, highlighting their potential for further optimization as cytoprotective and anti-inflammatory agents. Full article

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article