Search Results (180)

Sphingolipid metabolism has emerged as a regulatory interface between lipid homeostasis, organelle stress, and genome maintenance. Although sphingolipids are essential structural components of cellular membranes, specific metabolites also function as bioactive mediators that shape cellular responses to genotoxic stress. In this review, we examine how canonical and atypical sphingolipid pathways influence the DNA damage response through three mechanistic axes. First, ceramide-centered stress signaling links radiation, chemotherapy, and inflammatory injury to kinase and phosphatase pathways, mitochondrial apoptosis, and checkpoint-associated cell-fate decisions. Second, nuclear sphingolipid metabolism, particularly sphingosine kinase 2-dependent production of sphingosine-1-phosphate, regulates chromatin-associated transcriptional programs through modulation of histone deacetylase activity. Third, persistent sphingolipid imbalance promotes metabolic stress by disrupting lysosomal turnover, mitochondrial function, endoplasmic reticulum homeostasis, and redox balance, thereby increasing endogenous oxidative DNA damage. We also discuss atypical sphingolipids, including 1-deoxysphingolipids generated through altered serine palmitoyltransferase substrate utilization, as emerging mediators of mitochondrial dysfunction and genome instability. Finally, we consider the relevance of these mechanisms to cancer, lysosomal storage disorders, and neurodegenerative diseases, where sphingolipid dysregulation may influence therapeutic responses and disease progression. Together, these position sphingolipid metabolism as an integrated regulatory network connecting cellular stress signaling, chromatin regulation, organelle dysfunction, and genome stability. Full article

In vitro capacitation of boar spermatozoa remains highly variable among laboratories due to differences in media composition, incubation conditions, and previous semen handling. Since capacitation is a dynamic process, identifying how different media modulate specific sperm responses over time is crucial to improving the standardization of porcine in vitro fertilization protocols. This study evaluated the temporal dynamics of membrane lipid disorder, acrosomal integrity, mitochondrial activity, and motility patterns in response to different media. Commercial boar semen doses were centrifuged and resuspended in a non-capacitating control solution or in three capacitation media differing mainly in bicarbonate, caffeine, and energy substrate composition, and evaluated every 15 min using flow cytometry and computer-assisted semen analysis at 38 °C for up to 2 h. Media containing higher bicarbonate and caffeine concentrations induced rapid membrane lipid destabilization and increased acrosomal exocytosis during the initial incubation period. Subsequently, these changes were accompanied by a more rapid decline in cell viability over time. In contrast, the medium containing lower bicarbonate together with lactate and pyruvate preserved higher viability, mitochondrial activity, and a more sustained, linear movement pattern (higher linearity and straightness). Interestingly, training-associated responses were detected immediately at time 0, suggesting that semen storage conditions may prime spermatozoa before incubation. Overall, medium composition and pre-treatment handling conditions should both be considered when standardizing porcine reproductive technologies. Full article

Endogenous bioactive lipids are complex signaling mediators actively involved in a plethora of pathophysiological processes, including energy homeostasis and fibrosis. Energy homeostasis is a stable internal state resulting from a dynamic balance between energy expenditure and storage. Dysregulated energy balance can contribute to fibrosis, exhibiting key metabolic effects on insulin sensitivity, glucose tolerance, lipid accumulation and metabolism, as well as on energy expenditure, ultimately leading to metabolic disorders. In this context, three major classes of endogenous lipid mediators derived from polyunsaturated fatty acids (PUFAs)—eicosanoids, specialized pro-resolving mediators, and endocannabinoids—represent a key signaling network involved in the regulation of energy metabolism. Hence, alterations in their metabolism and signaling are often associated with fibrosis and other related molecular changes. Here, we provide a comprehensive overview of the role of the above-mentioned lipid classes in energy homeostasis and fibrosis by reviewing the available literature spanning nearly four decades, with a primary focus on studies published over the past 20 years. Full article

Tay-Sachs disease is a rare genetic disorder characterized by the accumulation of GM2 ganglioside in neuronal lysosomes due to deficient β-hexosaminidase A (HexA) activity. Progressive GM2 storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons. However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders. To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells. The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production. Transcriptomic analysis revealed significant alterations in pathways associated with neuronal degeneration, synaptic organization, mitochondrial dysfunction, and ganglioside metabolism. In summary, this model reproduces some classical cellular alterations reported in Tay-Sachs disease and could potentially provide novel insight into astrocyte involvement in its pathophysiology. These findings support the relevance of non-neuronal cells in disease pathophysiology and establish this system as a valuable platform for screening potential novel mechanisms and therapeutic approaches. Furthermore, this approach highlights the importance of integrating cell type specific models to better understand disease heterogeneity and providing insights into the progressive neurodegeneration of Tay-Sachs disease, positioning this model as a valuable tool for studying its underlying pathophysiology. Full article

Phosphatidate phosphatase (PAP) governs a critical branchpoint in glycerolipid synthesis by catalyzing the Mg²⁺-dependent dephosphorylation of phosphatidate (PA) to diacylglycerol (DAG), thereby controlling the partitioning of lipid flux between membrane phospholipid synthesis and triacylglycerol (TAG) storage. While the structure, regulation, and function of ScPah1 have been extensively characterized in the non-oleaginous yeast Saccharomyces cerevisiae, far less is known about its ortholog in the oleaginous yeast Yarrowia lipolytica. This review provides a comparative analysis of Pah1 between the two yeasts, encompassing domain architecture, phosphorylation-dependent regulation, enzymatic characterization, and genetic and multi-omics studies. ScPah1 and YlPah1 share a conserved HAD-like catalytic core but diverge substantially in their regulatory domains: YlPah1 features compressed intrinsically disordered regions, an attenuated regulation of phosphorylation (RP) domain, and a massively expanded acidic tail. Unlike ScPah1, which is hyperphosphorylated and cytosolically sequestered during growth, YlPah1 maintains membrane association and increasing protein levels throughout growth. Deletion of PAH1 in Y. lipolytica produces a moderate reduction in TAG levels with evidence of metabolic redundancy, contrasting with the near-complete TAG loss observed in S. cerevisiae. Total PAP activity in Y. lipolytica peaks during exponential growth and does not correlate temporally with TAG accumulation, a dissociation attributable to the contributions of non-Pah1 PAP enzymes. Whether the Nem1–Spo7 homologs in Y. lipolytica form a functional phosphatase complex and the individual contributions of all PAP-encoding genes to lipid homeostasis remain important unresolved questions. Full article

Lipid droplets (LDs) were long thought to be passive organelles merely for neutral lipid storage. Mounting evidence redefines LDs as dynamic metabolic signaling hubs orchestrating cellular stress adaptation, with multifaceted roles in organelle crosstalk, metabolic reprogramming, redox balance and immune signaling. LD function is tightly intertwined with liquid–liquid phase separation (LLPS) and epigenetic remodeling, bridging cellular metabolism to gene expression and cell fate control. LD biogenesis relies on ER lipid structures, phase-separated protein assemblies and lipid regulatory proteins. Via contacts with multiple organelles, LDs regulate lipid catabolism, ferroptosis, inflammation and chromatin accessibility, while their metabolites directly reshape epigenetic modifications and transcription. LLPS-driven biomolecular condensates further coordinate LD-linked metabolic and stress signaling. Dysregulated LD remodeling mediates metabolic flexibility, immune escape and drug resistance in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, viral infection and cancer. This review summarizes progress in LD biogenesis and metabolism, dissects mechanistic crosstalk between LDs, LLPS and epigenetic control, and outlines LD-driven pathogenic reprogramming across human disorders. We also discuss therapeutic approaches targeting LD and LLPS pathways. Despite promising translational prospects, unresolved mechanistic and clinical hurdles persist. Further research on LD biology will reshape our framework linking metabolism, chromatin regulation and stress adaptation. Full article

The skin microbiome plays a central role in maintaining cutaneous homeostasis, and its disruption has been implicated in a wide range of inflammatory and degenerative skin disorders. This review critically evaluates the current evidence on topical probiotics in dermatology, integrating microbiological mechanisms, formulation strategies, and translational and regulatory challenges within a single framework—an angle that remains insufficiently addressed in previous reviews. A targeted search of PubMed and ScienceDirect (2009–2025) was conducted to identify relevant original studies. The results suggest that topical probiotics may promote skin health through three broad, interconnected axes: (i) modulation of host responses (e.g., inflammation, immune signaling, and oxidative stress); (ii) microbial ecology and pathogen control (e.g., competition, acidification, and antimicrobial metabolite production); and (iii) support of barrier function and tissue repair (e.g., lipid metabolism, re-epithelialization, and extracellular matrix remodeling). Efficacy appears to depend strongly on strain specificity, formulation design, and microbial viability during storage and application. In addition to conventional dosage forms, advanced platforms—hydrogels, microgels, microparticles, and microneedle-based systems—have been investigated to improve stability and local delivery. Promising preclinical and clinical results have been reported for acne, wound healing, skin barrier repair, and anti-aging applications. Nevertheless, major translational challenges remain, including limited standardization, instability of live microorganisms, insufficiently representative experimental models, and regulatory uncertainty. Overall, topical probiotics represent a promising microbiome-based strategy in dermatology, but robust clinical validation and formulation optimization are still needed to support broader clinical implementation. Full article

Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gα_q, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. Methods: To explore Gα_q’s role in adipocytes, we generated CRISPR-mediated Gα_q (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes. Results: The absence of Gα_q resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gα_q deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes. Conclusions: These findings support Gα_q as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gα_q as a potential treatment for individuals with obesity and metabolic disorders. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to have beneficial effects in T2D, reducing hepatic lipid storage and improving metabolic dysfunction-associated steatotic liver disease. However, sex and reproductive age may influence their effect. We investigated the effect of liraglutide administration (0.2 mg/kg/day subcutaneously for 8 weeks) on metabolic disorders in relation to sex and reproductive age, using male, female and ovariectomized female hereditary hypertriglyceridemic (HHTg) rats as a prediabetic model. Liraglutide improved glucose tolerance in all HHTg rats. Female and ovariectomized (OVX) female rats showed a stronger effect of lipid metabolism and visceral adiposity than males. Moreover, no changes in hepatic triacylglycerol (TAG) accumulation were observed in males. Liraglutide partially reversed ovariectomy effects, such as increased body weight, visceral obesity and impaired glucose tolerance. Compared with males, female and OVX female rats showed more significant changes in hepatic gene expression involved in lipogenesis (Scd-1, Srebp1, Pparγ), fatty acid and lipid metabolism (Pparα, Hmgcr, Srebp2) and fibrosis (Tgfβ), which may improve hepatic lipid metabolism. Females of fertile age showed greater improvements in insulin sensitivity, reductions in ectopic lipid accumulation, and improvements in lipid metabolism. Depending on sex and reproductive status, liraglutide can mitigate fatty liver before diabetes onset. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which dopaminergic dysfunction plays a central role. Beyond its neurotransmitter function, dopamine is a redox-active molecule capable of generating reactive oxygen species and toxic intermediates, particularly when cytosolic dopamine accumulates because of altered vesicular storage or transporter imbalance. This review examines whether dopamine-derived oxidative stress may represent a biologically plausible and testable framework for ADHD by integrating current evidence on dopamine metabolism, oxidative stress, and neuronal dysfunction, while distinguishing direct evidence from indirect and translational findings. A structured literature search was conducted in PubMed, Scopus, and Web of Science for relevant English-language studies published between January 2000 and March 2026. The available evidence suggests that dopamine-derived oxidative stress may help link disturbed dopamine handling to protein modification, lipid peroxidation, mitochondrial dysfunction, synaptic inefficiency, and circuit-level abnormalities in ADHD. Although direct in vivo evidence remains limited, this framework may help distinguish dopamine-derived oxidative stress from more general oxidative imbalance in ADHD and may guide future biomarker-based, experimental, and translational research. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

Atherosclerotic cardiovascular disease (ASCVD) is increasingly recognized not merely as a lipid-storage disorder but as a chronic, lipid-driven inflammatory condition of the arterial wall. Despite the widespread use of statins and other lipid-lowering therapies, a substantial “residual inflammatory risk” persists, propelling the search for targeted immunopharmacological interventions. At the forefront of this inflammatory cascade is the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which serves as a central orchestrator of vascular inflammation by linking metabolic dysregulation to the innate immune response. Atherogenic danger signals—such as oxidized low-density lipoprotein (ox-LDL) and cholesterol crystals—trigger NLRP3 activation through reactive oxygen species (ROS) generation, lysosomal rupture, and potassium efflux. This, in turn, drives the maturation of pro-inflammatory cytokines (IL-1β and IL-18) and initiates macrophage pyroptosis. In this review, we systematically evaluate the immunomodulatory potential of natural products—both complex extracts and single bioactive compounds—in inhibiting the NLRP3 inflammasome axis. We detail the pharmacological mechanisms by which these natural agents intercept inflammatory signaling at multiple stages: suppressing TLR4/NF-κB-mediated priming, scavenging mitochondrial ROS, and restoring autophagic flux via AMPK/mTOR pathways to prevent inflammasome assembly. By critically analyzing these pathways, we highlight natural product-derived inhibitors as a promising class of immunomodulators capable of attenuating atherosclerotic progression and addressing the persistent challenge of residual inflammatory risk. Full article

Periodontal disease represents a major global health burden, beginning with gingivitis and progressing to periodontitis, which causes connective tissue breakdown, alveolar bone resorption, and eventual tooth loss. Beyond local pathology, periodontitis is a chronic inflammatory condition with systemic associations, including cardiovascular disease, diabetes, and metabolic disorders. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have emerged as promising candidates for periodontal regeneration. This review aimed to map the current evidence on MSC-derived EVs (MSC-EVs) in periodontal regeneration, focusing on their mechanisms of action, therapeutic potential, and translational challenges. A comprehensive literature search was conducted across a major biomedical database (PubMed) to identify preclinical and clinical studies investigating MSC-EVs in the context of periodontitis. Data were charted on EV cargo composition, biological functions, regenerative outcomes, and reported limitations. Evidence indicates that MSC-EVs encapsulate bioactive molecules—including antimicrobial peptides, proteins, lipids, and microRNAs—that modulate immune responses, suppress pro-inflammatory signaling, and promote angiogenesis and tissue repair. In periodontal models, MSC-EVs attenuate osteoclast activity, enhance fibroblast proliferation, and stimulate extracellular matrix remodeling, supporting regeneration of periodontal ligament and alveolar bone. Exosome-based approaches demonstrate advantages such as reduced immunogenicity, improved safety, and feasibility for storage and standardization. However, most findings remain preclinical, with limited human data available. To bridge the translational gap, well-designed clinical trials are needed to confirm efficacy and safety while addressing regulatory challenges, GMP standards, and outcome measures. Harnessing their regenerative capacity while mitigating side effects may guide precision-targeted therapies, and continued mechanistic studies with standardized production will be key to advancing MSC-EVs into clinical practice. Full article

Bone formation requires a substantial energy supply to sustain extracellular matrix production and mineralization, yet the temporal contribution of lipid metabolism during osteoblast maturation remains incompletely characterized. This study investigated the molecular and transcriptional remodeling of lipid metabolism. Intracellular lipid distribution was analyzed by confocal microscopy using Nile Red staining. Transcriptional modulation of lipid synthesis, storage, lipolysis, genes associated with mitochondrial fatty acid oxidation, and osteogenic markers were assessed by quantitative real-time PCR, and the biochemical composition was evaluated by Raman spectroscopy. Early stages of spheroid development showed higher expression of genes involved in lipid synthesis and storage (FASN, DGAT2, and PLIN2) together with intracellular lipid accumulation, whereas later stages displayed increased expression of lipolytic and β-oxidation markers (PNPLA2/ATGL, CPT1A, and HADHA), accompanied by the redistribution of lipid droplets. The Raman analysis revealed a time-dependent variation of lipid-associated CH₂/CH₃ bands and modulation of protein-related Amide I–III signals, consistent with biochemical remodeling during maturation. Overall, the data indicate a coordinated transcriptional shift from lipid accumulation-associated pathways toward lipid mobilization during osteogenic progression in a 3D culture. This model provides a controlled experimental platform for investigating metabolic regulation during bone formation and for studying metabolic alterations associated with skeletal disorders. Full article