Search Results (1,079)

Ergogenic aids have long attracted scientific interest for their potential to enhance neuromuscular performance, with caffeine being among the most extensively studied. While traditionally attributed to peripheral actions on skeletal muscle, accumulating evidence indicates that, at physiological doses, caffeine’s ergogenic effects are predominantly mediated by antagonism of central adenosine receptors. This antagonism leads to increased arousal, reduced inhibitory neuromodulation, enhanced corticospinal excitability, and altered motor unit recruitment and firing behavior. Importantly, the concentrations required to elicit direct effects on excitation–contraction coupling via ryanodine receptors exceed those compatible with human safety, rendering such mechanisms unlikely in vivo. This narrative review synthesizes contemporary neurophysiological evidence to propose that caffeine acts primarily by “tuning” motor system gain through central neurotransmitter modulation, rather than by directly augmenting muscle contractile properties. Additionally, we highlight unresolved questions regarding persistent inward currents, sex-dependent neuromodulatory influences—including the potential role of estrogen in regulating adenosine receptor expression—and the implications of repeated caffeine use during training for neural adaptation and motor control. Finally, we outline key methodological and conceptual directions for future research aimed at refining our understanding of caffeine’s neuromuscular effects in both acute and chronic contexts. Full article

Plastic pollution is acknowledged as a serious problem for ecosystems. Among these plastics, polystyrene nanoplastics (PS-NPs) are emerging environmental pollutants, and their biological effects on hepatotoxicity are the least explored. Therefore, the present work examined the effect of PS-NPs on the hepatic transcription of the antioxidant genes Hmox1 and Sod3 in mice (n = 6, treatment (PS-NPs) vs. vehicle group (Veh)), mediated by RORγ and epigenetic modifications. The results show that PS-NP mice had significantly reduced body weight; increased activity of adenosine triphosphate (ATP), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH), and Complexes I, III, and V in the liver; and increased Alanine Transaminase (ALT), Aspartate Transaminase (ASP), Alkaline Phosphatase (ALP), malondialdehyde (MDA) and reactive oxygen species (ROS) compared to the Veh group. Furthermore, PS-NPs resulted in considerably lower relative mRNA expression of Hmox1, Sod3, and RORγ in the liver than the Veh group. Likewise, when compared to Veh, PS-NPs significantly reduced the enrichment of RORγ, as well as the occupancies of the key components of the transcriptional activation pathway (P300, SRC1, Pol II, Ser5-Pol II, and Ser2-Pol II) at the loci of Hmox1 and Sod3. In comparison to Veh, PS-NPs showed downregulated occupancies of the histone active marks H3K9ac and H3K18ac, while H3K4me3 and H3K27me3 were higher at the target loci of Hmox1 and Sod3. In conclusion, the present study highlights that PS-NPs induce oxidative stress by modifying Hmox1 and Sod3 in mice’s livers through histone changes and nuclear receptor RORγ modulation. Full article

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a multifactorial liver disease in which mitochondrial dysfunction, oxidative stress, and inflammation play key roles in driving the progression toward metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Dysfunctional mitochondria generate excess reactive oxygen species (ROS), impair antioxidant defenses, activate pro-inflammatory pathways and hepatic stellate cells, and perpetuate liver injury. Mitochondrial Complex I is a major ROS source, particularly under conditions of dysregulated energy metabolism. Since Complex I inhibition by metformin was shown to reduce ROS and activate the adenosine monophosphate-activated protein kinase (AMPK), this study aimed to evaluate whether a novel Complex I Modulator (CIM, BI4500) could attenuate oxidative stress, inflammation, and consequently reduce lipid accumulation and fibrosis in a methionine- and choline-deficient diet (MCD)-fed rat model of MASH. Methods: Rats were fed an MCD or an isocaloric control diet for six weeks. From week four, animals received daily oral treatment with CIM (10 mg/kg) or vehicle (Natrosol). At the endpoint, liver tissue was collected for histological, biochemical, and molecular analyses. Lipid droplet area, inflammatory infiltration, and collagen deposition were evaluated on tissue sections; total lipid content and oxidative stress markers were assessed in homogenates and isolated mitochondria. Molecular pathways related to oxidative stress, lipid metabolism, and fibrosis were assessed at protein and mRNA levels. Results: CIM treatment significantly reduced oxidative stress (ROS, lipid peroxidation, nitrogen species), promoting AMPK activation and metabolic reprogramming. This included increased expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its target genes, and decreased sterol regulatory element binding protein-1c (SREBP-1c)-driven lipogenesis. These changes halted fibrosis progression, as confirmed by Picro-Sirius Red staining and fibrosis markers. Conclusions: these findings indicate that Complex I modulation may represent a promising strategy to counteract MASLD progression toward MASH. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRAB_Ado). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco/ER Ca²⁺-ATPase (SERCA) machinery, which is essential for maintaining ER Ca²⁺ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca²⁺-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca²⁺ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways. Full article

Background/Objectives: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways. Methods: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming. Results: All CAR T cells exhibited activation of NF-κB–centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes. Conclusions: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism. Full article

Aging reduces the tissue regenerative capacity, promotes chronic inflammation, and contributes to neurodegenerative diseases, including age-related macular degeneration (AMD). AMD is a leading cause of vision loss in older adults and manifests as dry (atrophic) or wet (neovascular) disease. Although dry AMD is more prevalent, neovascular AMD (nAMD) causes the most severe vision impairment and remains a major public health burden. Oxidative stress-mediated inflammation and dysfunction of retinal pigment epithelium (RPE) cells and choriocapillaris drive early AMD. Neovascular AMD is marked by pathologic choroidal neovascularization (CNV), driven largely by dysregulated VEGF signaling. Anti-VEGF therapies are the current standard of care for nAMD but require frequent intravitreal injections, carry procedure-related risks, and are ineffective in a substantial subset of patients, underscoring the need for new therapeutic approaches. Caffeine, a widely consumed and well-tolerated adenosine receptor antagonist, has emerging relevance in vascular regulation and inflammatory signaling. Extracellular ATP and its metabolites, including adenosine, accumulate under stress and act through purinergic receptors to influence angioinflammatory processes. We recently showed that systemic caffeine administration suppressed CNV in vivo, an effect partly reproduced by the adenosine receptor A_2A antagonist Istradefylline. Here, we investigated the cell-autonomous effects of caffeine on mouse choroidal endothelial cells, focusing on its role as an adenosine receptor antagonist and its potential to inhibit pathological neovascularization. Full article

Fibrosis manifests as an excessive accumulation of fibrillar collagen in tissues where secreted collagen exceeds degradation. Myofibroblasts are important contributors to the excessive collagen seen in fibrotic lesions. Accordingly, targeting signaling pathways that enhance collagen degradation and subdue myofibroblast differentiation has the potential to optimize collagen remodeling and improve organ fibrosis. One of the most promising molecular targets for therapeutic development is the G protein-coupled receptor (GPCR) family, which is diverse, cell-type-specific, multi-pass transmembrane receptors that participate in the regulation of extracellular matrix remodeling. GPCRs are categorized into multiple subclasses, some of which activate signaling cascades that can augment or reduce pro-fibrotic processes, depending on which Gα class is activated. Specifically, activation of Gαs GPCR stimulates production of the second messenger, cyclic adenosine monophosphate (cAMP), which generally inhibits pro-fibrotic mediators. A related, second approach for control of fibrosis is the blockade of a specific mechanosensitive, Ca²⁺-permeable channel that is implicated in fibrosis and contributes to myofibroblast differentiation, the transient receptor potential vanilloid type 4 (TRPV4). In health, TRPV4 activation regulates collagen remodeling, but when dysregulated, it promotes pro-fibrotic gene expression through mechanosensitive transcription factors. In this review, we focus on the functions of the Gαs GPCR pathway and TRPV4 activation through the interplay of the second messengers cAMP and Ca²⁺ ions. Ca²⁺ influx modulates cAMP levels by regulating phosphodiesterases and adenylyl cyclases. We consider evidence that Gαs GPCR and TRPV4 signaling pathways interact antagonistically to either promote collagen degradation or to increase the formation of myofibroblasts through signaling that involves cAMP and Ca²⁺ conductance. Coordinated activation of the Gαs GPCR pathway and inhibition of TRPV4 could provide a novel, bimodal approach to control tissue fibrosis. Full article

Polydeoxyribonucleotide (PDRN), a DNA fragment mixture, exerts biological effects via adenosine A2A receptor and salvage pathway activation. Here, Paeonia lactiflora-derived PDRN (Peony PDRN) is proposed as a plant-based alternative to salmon-derived PDRN. While P. lactiflora is known for its medicinal properties, the biological functions of Peony PDRN have not been characterized. To validate and optimize its efficacy, we systematically compared the biological activities of three molecular weight groups of Peony PDRN (high, medium, and low) using in vitro assays and clinical studies. The low-molecular-weight fraction (Low-Peony PDRN) markedly enhanced skin cell proliferation and migration, upregulated extracellular matrix-related genes (COL1A1, COL5A1, ELN, and FBN1), and promoted keratinocyte differentiation and epidermal barrier formation by increasing COL7A1, IVL, FLG, and OCLN expression. It also reduced reactive oxygen species levels and suppressed key inflammatory mediators. Clinically, topical application of Low-Peony PDRN for 2 weeks markedly reduced transepidermal water loss in a sodium lauryl sulfate-induced skin damage model, enhancing barrier recovery (n = 10). Periorbital skin elasticity improved after 4 weeks of treatment (Approval No. Intertek IRB-202505-HR(1)-0001, 20 June 2025). These results indicate that Low-Peony PDRN is a promising plant-derived biomaterial of pharmacological and cosmetic significance, with potential to address skin aging. Full article

Glucagon is an endogenous peptide that is produced in the pancreas. Via glucagon receptors, glucagon increases the beating rate in cultured rat neonatal cardiomyocytes and also in isolated right atrial preparations from adult rats. Moreover, in living adult mice, injections of glucagon can elevate the heart rate. It is unknown whether these effects of glucagon in living adult mice are mediated via central glucagon receptors or via a direct effect on cardiac glucagon receptors. Thus, we tested the hypothesis that glucagon can exert a direct positive chronotropic effect in the adult mouse heart. We measured the contractile effects of cumulatively increasing concentrations of glucagon (0.1–100 nM) in isolated paced (1 Hz) left atrial preparations, in isolated spontaneously beating right atrial preparations and in isolated spontaneously beating retrogradely perfused whole hearts. We detected in isolated right atrial preparations time- and concentration-dependent positive chronotropic effects of glucagon that were reversed by the glucagon receptor antagonists SC203972 and desglucagon. The positive chronotropic effects of glucagon were also attenuated by 1 µM of ivabradine, an inhibitor of the hyperpolarization-activated cation channels (HCN), but not by 100 nM rolipram, a phosphodiesterase 4 inhibitor, nor by 10 µM of propranolol, a β-adrenoceptor antagonist. Moreover, the positive chronotropic effects of glucagon were also attenuated by stimulation of the A₁-adenosine receptor or muscarinic receptors. Glucagon decreased the force of contraction in right atrial preparations. In left atrial preparations, glucagon failed to alter the force of contraction. In isolated adult mouse hearts perfused in the Langendorff mode, 10 nM of glucagon increased the beating rate and reduced left ventricular force of contraction. The gene expression of the glucagon receptors was lowest in the left atrium, higher in the ventricle and highest in the right atrium of adult mice. In summary, glucagon exerted a positive chronotropic effect in the mouse heart via glucagon receptors, mediated, at least in part, via HCN channels in the sinus node. Full article

Background: Ticagrelor is a reversible, direct inhibitor of the platelet adenosine diphosphate (P2Y12) receptor, widely used in combination with acetylsalicylic acid (ASA) as dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS) to prevent cardiovascular events. Despite its well-established efficacy, ticagrelor may cause adverse effects ranging from common ones (e.g., bleeding, dyspnea) to rare but potentially serious reactions such as bradyarrhythmias. These rare events are likely related to elevated adenosine levels secondary to inhibition of the human equilibrative nucleoside transporter 1 (hENT1). Methods: We describe two clinical cases of ticagrelor-associated bradyarrhythmia observed in patients following ACS. Both cases were analyzed in terms of clinical presentation, ECG findings, management strategy, and outcomes after discontinuation of the drug. Results: The first case concerns a 67-year-old woman with non-ST-segment elevation myocardial infarction (NSTEMI) who developed complete atrioventricular block (third degree) with a 45 s asystolic pause and syncope. The second case involves a 67-year-old man with anterior ST-segment elevation myocardial infarction (STEMI) who experienced recurrent sinus pauses lasting up to 5 s. In both cases, symptoms resolved following ticagrelor discontinuation and theophylline administration. No recurrence of arrhythmia was observed after switching to prasugrel. Conclusions: Ticagrelor-induced bradyarrhythmias, although rare, represent an important and reversible adverse effect that clinicians should be aware of, particularly during the early post-ACS phase. Prompt recognition and drug withdrawal may prevent severe outcomes and avoid unnecessary interventions such as pacemaker implantation. Further studies are warranted to identify patient-specific risk factors predisposing to ticagrelor-related conduction disturbances. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article

The aim of this study is to investigate the A_2BAR-dependence of okhotoside A₁-1 cytotoxic and antiproliferative action on triple-negative MDA-MB-231 breast cancer cells using monolayer and 3D culture approaches. Earlier triterpene glycoside okhotoside A₁-1 (Okh) was isolated from the sea cucumbers Cucumaria djakonovi and C. conicospermium and its selective cytotoxicity against MDA-MB-231 vs. non-tumorigenic MCF-10A cells was reported. Now it has been found that the A_2B adenosine receptor (A_2BAR) is one of the molecular targets for Okh and its antiproliferative effect is A_2BAR-dependent. Molecular docking studies suggested a unique behavior for Okh demonstrating two highly probable binding modes with comparable affinity, when the aglycone is immersed in the binding pocket, or alternatively, the carbohydrate moiety occupies the site. The glycoside modulated cAMP and intracellular Ca²⁺ levels in an A_2BAR-dependent manner, which accompanied by the suppression of p38 MAPK and ERK1/2 phosphorylation, and blocked cell cycle progression. Okh induced mitochondrial dysfunction, characterized by increased ROS production and loss of the mitochondrial membrane potential (ΔΨm), which led to the upregulation of APAF-1 and cytochrome C, activation of caspases-9 and -3, and initiation of apoptosis. The antitumor potential of Okh was confirmed in a 3D culture of MDA-MB-231 cells and was more significant than those of another A_2BAR-targeted triterpene glycoside cucumarioside A₀-1 and cisplatin. Full article

Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments. Full article

Introduction/Objectives: Ginsenoside F1, a pharmacologically active saponin derived from Panax ginseng, exhibits diverse bioactivities, but its use is limited because it is difficult to purify and has high production costs. To overcome these challenges, a ginsenoside F1-enriched extract named SGB121 was developed. This study aimed to evaluate the therapeutic efficacy of SGB121 in a high-fat, high-carbohydrate (HFHC) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mouse model and to elucidate its mechanism of action using F1-based cellular assays. Methods: Male C57BL/6 mice (6 weeks old) were fed an HFHC diet to induce MAFLD and were treated with SGB121. Hepatic lipid accumulation, oxidative stress markers, and metabolic parameters were analyzed. In parallel, human hepatocellular carcinoma (HepG2) cells exposed to free fatty acids (FFAs) were used to assess oxidative stress and lipid accumulation. Mechanistic studies were conducted using purified F1 to examine adenosine monophosphate-activated protein kinase (AMPK) activation and related pathways. Results: SGB121 reduced hepatic lipid accumulation, malondialdehyde (MDA) levels, and fasting insulin while restoring glutathione (GSH) content and improving the homeostasis model assessment of insulin resistance (HOMA-IR) in MAFLD mice. In FFA-treated HepG2 cells, both SGB121 and F1 decreased reactive oxygen species (ROS), suppressed sterol regulatory element-binding protein 1 (SREBP1), enhanced peroxisome proliferator-activated receptor-α (PPARα) and β-oxidation, and restored insulin receptor substrate (IRS)/protein kinase B (Akt)/glucose transporter 2 (GLUT2) signaling. Conclusions: SGB121 ameliorates MAFLD and related metabolic dysfunction through antioxidant, lipid-regulating, and insulin-sensitizing actions, highlighting its potential as a safe multifunctional nutraceutical for MAFLD management. Full article