Search Results (1,406)

Pharmaceuticals can be found in the aquatic environment and cause unwanted effects on organisms. The present work aimed to characterize the toxic mode of action of the antidepressant fluoxetine (FLX) on the freshwater microalga Raphidocelis subcapitata. With this aim, the microalga was exposed to low levels (µg/L) of FLX for 72 h. Exposure to 20–30 µg/L FLX arrested algal growth, which can be explained by the blockage of algal nuclear division. In addition, FLX (15–30 µg/L) deeply altered the alga’s metabolism, which was reflected by an increase in esterase activity, mitochondrial dysfunction (hyperpolarization of inner mitochondrial membrane), and reduction in the content of photosynthetic pigments: chlorophyll a (chla) and carotenoids (car). A sharp decline in photosynthetic performance, revealed by the reduction in maximum photochemical quantum yield (F_v/F_m), effective photochemical quantum yield (ΦPSII), and photosynthetic electron transport rate (ETR) of photosystem II (PSII), was also observed. FLX, at 30 µg/L, induced the intracellular accumulation of reactive oxygen species (ROS) and lipid peroxidation, with a marginal loss (1%) of cell membrane integrity. The results presented here contribute to the elucidation of the toxic mode of action of FLX on the microalgae R. subcapitata and, simultaneously, warn of the negative impact of the presence of pharmaceutical compounds in freshwater aquatic environments. Full article

Reactive oxygen species (ROS) are formed by the incomplete reduction of oxygen and play a crucial role in both physiological function and pathological process, being controlled by enzymatic and non-enzymatic antioxidant systems. However, excessive ROS production can exceed the body’s antioxidant capacity, resulting in oxidative stress and causing cell death and oxidation of important biomolecules. In this context, the inhibition and/or modulation of ROS has been shown to be effective in reducing pain, oxidative stress, and inflammation. Among ROS, superoxide anion (O₂^•−) is the first free radical to be formed through the mitochondrial electron transport chain (ETC) or by specific enzymes systems, such as the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) complex. O₂^•− plays a significant role in the development and maintenance of pain associated with inflammatory conditions through direct or indirect activation of primary nociceptive neurons and, consequently, peripheral and central sensitization. Experimentally, potassium superoxide (KO₂, a O₂^●− donor) is used to initiate O₂^●− mediated inflammatory and nociceptive responses, making it important for studying the mechanisms associated with ROS-induced pain and evaluating potential therapeutic molecules. This review addresses the production and regulation of O₂^•−, highlighting its biosynthesis, redox control, and its physiological and pathological roles in the development of inflammatory pain, as well as the pharmacological therapies under development aimed at its generation and/or action. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

The ability of common carp to withstand both short-term and long-term oxygen deprivation has been well documented; however, the potential genetic mechanisms behind common carp’s hypoxia response remain unclear. Therefore, to understand the possible genetic foundation of their response to hypoxia, comparative genomic analyses were conducted among six common carp varieties: Color, Songpu, European, Yellow, Mirror, and Hebao common carps. We identified 118 single-copy orthologous positively selected genes (PSGs) (dN/dS > 1) in all common carps under study, with GO functions directly related to the cellular responses to hypoxia in Color and European common carp PSGs, such as oxygen transport activity, oxygen binding activity, respiratory burst activity, and superoxide anion production. The Bayes Empirical Bayes (BEB) technique identified possible amino acid substitutions in mitochondrial and hypoxic genes under positive selection. Exonic and intronic structural variations (SVs) were discovered in the CYGB2 hypoxia-related gene of Color and European common carps, as well as in several mitochondrial genes, including MRPL20, MRPL32, NSUN3, GUF1, TMEM17B, PDE12, ACAD6, and COX10 of Color, European, Songpu, Yellow, and Hebao common carps. Moreover, Color common carp and Songpu common carp were found to share the greatest percentage of collinear genes (49.8%), with seven Songpu common carp chromosomes (chr A2, chr A9, chr A13, chr B13, chr B15, chr B2, and chr B12) showing distinct translocation events with the corresponding chromosomes of Color common carp. Additionally, we found 570 translocation sites that contained 3572 translocation-related genes in Color common carp, some of which are directly relevant to mitochondrial and hypoxic GO functions and KEGG pathways. Our results offer strong genome-wide evidence of the possible evolutionary response of Cyprinus carpio to hypoxia, providing important insights into the potential molecular mechanisms that explain their survival in hypoxic environments and guiding future research into carp hypoxia tolerance. Full article

Methylphenidate (MPH) and its active enantiomer, dexmethylphenidate, are widely prescribed as first-line therapies for attention deficit hyperactivity disorder (ADHD), yet their increasing non-medical use highlights significant clinical and toxicological challenges. MPH blocks dopamine (DAT) and norepinephrine (NET) transporters, thereby elevating synaptic catecholamine levels. While this underpins therapeutic efficacy, prolonged or abusive exposure has been associated with mitochondrial impairment, disrupted bioenergetics, and excessive reactive oxygen species (ROS) production, which collectively contribute to neuronal stress and long-term neurotoxicity. Growing evidence suggests that the gut–brain axis may critically influence MPH outcomes: diet-induced shifts in microbiome composition appear to regulate oxidative stress, neuroinflammation, and drug metabolism, opening potential avenues for dietary or probiotic interventions. From a forensic perspective, the detection and monitoring of MPH misuse require advanced methodologies, including enantioselective LC–MS/MS and analysis of alternative matrices such as hair or oral fluids, which enable retrospective exposure assessment and improves abuse surveillance. Despite its established therapeutic profile, MPH remains a compound with a narrow balance between clinical benefit and toxicological risk. Future directions should prioritize longitudinal human studies, biomarker identification for abuse monitoring, and the development of mitochondria-targeted therapies to minimize adverse outcomes and enhance safety in long-term treatment. Full article

Skeletal muscle, constituting 40–50% of total body mass, is vital for mobility, posture, and systemic homeostasis. Muscle contraction heavily relies on ATP, primarily generated by mitochondrial oxidative phosphorylation. Mitochondria play a key role in decoding intracellular calcium signals. The endocannabinoid system (ECS), including CB₁ receptors (CB₁Rs), broadly influences physiological processes and, in muscles, regulates functions like energy metabolism, development, and repair. While plasma membrane CB₁Rs (pCB₁Rs) are well-established, a distinct mitochondrial CB₁R (mtCB₁R) population also exists in muscles, influencing mitochondrial oxidative activity and quality control. We investigated the role of mtCB₁Rs in skeletal muscle physiology using a novel systemic mitochondrial CB₁ deletion murine model. Our in vivo studies showed no changes in motor function, coordination, or grip strength in mtCB₁ knockout mice. However, in vitro force measurements revealed significantly reduced specific force in both fast-twitch (EDL) and slow-twitch (SOL) muscles following mtCB₁R ablation. Interestingly, knockout EDL muscles exhibited hypertrophy, suggesting a compensatory response to reduced force quality. Electron microscopy revealed significant mitochondrial morphological abnormalities, including enlargement and irregular shapes, correlating with these functional deficits. High-resolution respirometry further demonstrated impaired mitochondrial respiration, with reduced oxidative phosphorylation and electron transport system capacities in knockout mitochondria. Crucially, mitochondrial membrane potential dissipated faster in mtCB₁ knockout muscle fibers, whilst mitochondrial calcium levels were higher at rest. These findings collectively establish that mtCB₁Rs are critical for maintaining mitochondrial health and function, directly impacting muscle energy production and contractile performance. Our results provide new insights into ECS-mediated regulation of skeletal muscle function and open therapeutic opportunities for muscle disorders and aging. Full article

Background/Objectives: Poor glycemic control is reaching an epidemic prevalence globally. It is associated with significantly morbid health concerns including retinopathy, neuropathy, nephropathy, cancer, and cardiovascular disease. Probiotics have shown promise in reducing health complications associated with poor blood glucose control. We tested a novel approach to designing a precision probiotic cocktail for improving blood glucose homeostasis. Methods: We tested the in vitro glucose consumption rate of twelve mouse microbiome bacterial strains and selected three with the greatest glucose consumption for the probiotic cocktail. The in vivo metabolic impact of ingesting the selected probiotic cocktail was evaluated in twelve C57BL/6J male mice fed a high-fat diet for eight weeks. Results: Compared to a control group, the probiotic group (L. rhamnosus, L. reuteri, and L. salivarius) exhibited significantly lower blood glucose levels, body weight, and body fat percentage. Moreover, the probiotic cocktail also demonstrated the ability to reduce serum insulin, total cholesterol, very-low-density lipoprotein/low-density lipoprotein cholesterol, and total cholesterol to high-density lipoprotein ratio. For further mechanistic investigation, untargeted metabolomics analyses uncovered overall downregulations in energy substrates and producing pathways like gluconeogenesis, acylcarnitine synthesis, glycolysis, the mitochondrial electron transport chain, the TCA cycle, and the building blocks for ATP formation. Partial least squares-discriminant analyses also confirmed clear group differences in metabolic activity. 16S rRNA sequencing from extracted gut microbiota also showed significant increases in Faith’s phylogenetic diversity, Lachnospiraceae bacterium 609-strain, and the genus Muribaculaceae as well as group β-diversity differences after probiotic intake. Conclusions: As such, we successfully developed a blend of three probiotics to effectively reduce blood glucose levels in male mice, which could further mitigate adverse health effects in the host. Full article

Chronic social isolation (CSIS), a known risk factor for the development of major depressive disorders, is associated with hippocampal dysfunction. In rodent models, CSIS produces two phenotypes: CSIS-susceptible, which develop depressive- and anxiety-like behaviors, and CSIS-resilient, which maintain normal behavior despite stress. However, the biological mechanisms underlying resilience to stress remain elusive. Mitochondria, as central regulators of neuronal energy metabolism and redox balance, are potential mediators of stress susceptibility and resilience. This review summarizes comparative proteomic analyses of hippocampal nonsynaptic mitochondria (NSM) and synaptosome-enriched mitochondria from CSIS-susceptible and CSIS-resilient rats along with controls. In NSM of resilient rats relative to susceptible rats, remodeling enhanced energy production, limited reactive oxygen species, stabilized phosphate transport, and promoted removal of damaged components. Compared with controls, these changes optimized energy production, and selectively downregulated oxidative stress-promoting proteins. Conversely, synaptosome-enriched mitochondria from resilient rats showed downregulation of proteins related to synaptic energy metabolism and redox balance relative to CSIS-susceptible rats, but demonstrated upregulation of bioenergetic and antioxidant enzymes, molecular chaperones, and neuroprotective factors compared with controls. These proteomic signatures both highlight mitochondrial adaptability in promoting stress resilience and identify mitochondria as promising targets for the development of novel antidepressant therapies. Full article

Mitochondria possess their own genome, which encodes subunits of the electron transport chain, rendering mitochondrial protein translation essential for cellular energy metabolism. Mitochondrial dysfunction affects nuclear transcription through the retrograde response. We applied RNA-seq to investigate whether and how the inhibition of mitochondrial translation by chloramphenicol (CAP) affects transcriptome regulation in proliferating or stationary-phase cells of Schizosaccharomyces pombe growing in fermentative or respiratory media. Stationary-phase cells in glucose medium exhibited the strongest transcriptome response to CAP, characterized by expression signatures similar to those observed under other stresses, including the retrograde response. The induced genes were also significantly enriched in cytoplasmic carbon metabolism pathways, reflecting a transcriptional reprogramming from respiration to fermentation. The transcription factors Scr1 and Rst2, regulators of carbon catabolite repression (CCR), controlled a common set of carbon metabolism genes in CAP-treated stationary-phase cells, and they showed opposing effects on the lifespan of these cells. Rst2 was required for the induction of carbon metabolism genes and maintained nuclear localization in CAP-treated stationary-phase cells. A systematic genetic interaction screen revealed functional relationships of Rst2 with processes related to stress and starvation responses. These findings uncover a complex transcriptional program in stationary-phase cells that adapt to inhibited mitochondrial translation, including stress- and retrograde-like responses, contributions of the CCR factors Scr1 and Rst2, and adjustment of carbon metabolism to deal with mitochondrial dysfunction. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoisomerase 1 (TOP1)-DNA complexes. Previously, we obtained HEK293A cells with homozygous knockout of the TDP1 gene by the CRISPR/Cas9 method and used them as a cell model to study the mechanisms of anticancer therapy and to investigate the effect of TDP1 gene knockout on gene expression changes in the human HEK293A cell line by transcriptome analysis. In this study, we investigated the effect of a TDP1 inhibitor ((R,E)-2-acetyl-6-(2-(2-(4-bromobenzyliden) hydrazinyl) thiazol-4-yl)-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d] furan-1(9bH)-one, OL9-119, an usnic acid derivative), capable of potentiating the antitumor effect of topotecan, as well as its combination with topotecan, on the transcriptome of wild-type and TDP1 knockout HEK293A cells. OL9-119 was found to be able to reduce cell motility by decreasing the expression of a number of genes, which may explain the antimetastatic effect of this compound. Differentially expressed genes (DEGs) related to electron transport, mitochondrial function, and protein folding were also identified under TDP1 inhibitor treatment. Full article

Statins are the first-line therapy for managing elevated cholesterol levels that represent a risk of acute cardiovascular events. However, the use of statins is associated with several side effects, likely due to the depletion of Coenzyme Q₁₀ (CoQ₁₀), a key component of the mitochondrial electron transport chain and a membrane antioxidant. In our study, we present evidence of the cytotoxic effects of Atorvastatin on human dermal fibroblasts in terms of oxidative stress and mitochondrial impairment. Interestingly, CoQ₁₀ supplementation in statin-treated cells significantly reduced ROS levels and restored mitochondrial oxygen consumption rate and the intracellular ATP/ADP ratio. Moreover, our data suggest that the mechanism for Atorvastatin off-target effects at high concentrations involves the inhibition of respiratory complexes I and III, leading to reverse electron transport and ROS production by Complex I. These findings highlight the potential benefits of CoQ₁₀ supplementation in mitigating statin-induced cytotoxicity and propose a mechanistic basis for the adverse effects associated with Atorvastatin therapy. Full article

Background: Despite advances in gene-targeted and immunotherapies, many aggressive cancers—including glioblastoma and triple-negative breast cancer—remain refractory to treatment. Mounting evidence implicates metabolic reprogramming, especially dysregulation of glucose and glutamine metabolism, as a core hallmark of tumor progression. Natural compounds with metabolic-modulatory effects have emerged as promising adjuncts in oncology. Research Question and Objectives: This review investigates the following question: How can metabolic-targeted therapies—particularly those modulating the Warburg effect and glutamine metabolism—improve cancer treatment outcomes, and what role do natural compounds play in this strategy? The objectives were to (1) evaluate the therapeutic potential of metabolic interventions targeting glucose and glutamine metabolism, (2) assess natural compounds with metabolic regulatory activity, (3) examine integration of metabolic-targeted therapies with conventional treatments, and (4) identify metabolic vulnerabilities in resistant malignancies. Methods: A qualitative systematic review (QualSR) was conducted following PRISMA guidelines. A total of 87 peer-reviewed studies published between 2000 and 2024 were included. Inclusion criteria required clearly defined mechanistic or clinical endpoints and, for clinical trials, sample sizes ≥ 30. Data extraction focused on tumor response, survival, metabolic modulation, and safety profiles. Results: Curcumin significantly reduced serum TNF-α and IL-6 (both p = 0.001) and improved antioxidant capacity (p = 0.001). EGCG downregulated ERα (p = 0.002) and upregulated tumor suppressors p53 and p21 (p = 0.001, p = 0.02). High-dose intravenous vitamin C combined with chemoradiotherapy yielded a 44.4% pathologic complete response rate in rectal cancer. Berberine suppressed Akt/mTOR signaling and glutamine transporter SLC1A5 across tumor types (q < 10⁻¹⁰). However, poor bioavailability (e.g., EGCG t½ = 3.4 ± 0.3 h) and systemic toxicity limit their standalone clinical application. Conclusions: Metabolic-targeted therapies—particularly natural compounds acting on glucose and glutamine pathways—offer a viable adjunct to standard cancer therapies. Clinical translation will require biomarker-driven patient stratification, improved delivery systems, and combination trials to optimize the therapeutic impact in treatment-resistant cancers. Full article

Neural function relies on tightly regulated lipid metabolism to sustain membrane integrity, synaptic signaling, and energy production. Myelinating glia, particularly Schwann cells, require continuous lipid flux to build and maintain myelin, rendering them vulnerable to imbalances between lipid entry and oxidative capacity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), widely studied in hepatic cholesterol regulation, has emerging roles in the nervous system. In the central nervous system (CNS), local PCSK9 expression influences low-density lipoprotein receptor (LDLR) family abundance, neuronal survival pathways, and neuroinflammatory tone, although circulating PCSK9 has limited parenchymal access due to the blood–brain barrier (BBB). In the peripheral nervous system (PNS), recent evidence highlights a PCSK9–CD36 axis in Schwann cells; genetic Pcsk9 loss elevates CD36, increases fatty-acid influx, promotes lipid droplet expansion and acylcarnitine accumulation, and triggers mitochondrial stress that manifests as hypomyelination, C-fiber pathology, and selective small-fiber neuropathy. These findings suggest that PCSK9 normally restrains CD36-dependent transport to align lipid supply with metabolic demand. Clinically, PCSK9 inhibitors have demonstrated cardiovascular benefit without major neurocognitive signals, yet small-fiber outcomes have not been systematically assessed. This review integrates current evidence on PCSK9 biology across neural compartments, highlights mechanistic links to Schwann cell lipid handling, and outlines research priorities to resolve neural safety and therapeutic potential in lipid-driven neuropathies. Full article

Epigenetic modifications are long-lasting changes to the genome that influence a cell’s transcriptional potential, thereby altering its function. These modifications can trigger adaptive responses that impact protein expression and various cellular processes, including differentiation and growth. The primary epigenetic mechanisms identified to date include DNA and RNA methylation, histone modifications, and microRNA-mediated regulation of gene expression. The intricate crosstalk among these mechanisms makes epigenetics a compelling field for the development of novel control strategies, particularly through the use of epigenetic drugs targeting arthropod vectors such as ticks. In this study, we identified the Rhipicephalus microplus orthologs of canonical histone-modifying enzymes, along with components of the machinery responsible for m⁵C and ⁶mA-DNA, and m⁶A-RNA methylations. We further characterized their transcriptional profiles and enzymatic activities during embryonic development. To explore the functional consequences of epigenetic regulation in R. microplus, we evaluated the effects of various epigenetic inhibitors on the BME26 tick embryonic cell line. Molecular docking simulations were performed to predict the binding modes of these inhibitors to tick enzymes, followed by in vitro assessment of their effects on cell viability and morphology. Tick cells exposed to these inhibitors presented phenotypic and molecular alterations. Notably, we observed high levels of DNA methylation in the nuclear genome. Importantly, inhibition of DNA methylation using 5′-azacytidine (5′-AZA) was associated with increased activity of the mitochondrial electron transport chain and ATP synthesis but reduced cellular proliferation. Our findings highlight the importance of epigenetic regulation during tick embryogenesis and suggest that targeting these pathways may constitute a novel and promising strategy for tick control. Full article

Iron is an essential micronutrient integral to ocular physiology, supporting biochemical processes such as mitochondrial respiration, DNA synthesis and phototransduction. Disruptions in systemic or local iron homeostasis, whether due to overload or deficiency, have been increasingly implicated in the pathogenesis of a broad range of anterior and posterior segment ocular disorders. Iron deficiency may compromise retinal bioenergetics, impair cellular repair, and increase susceptibility to oxidative stress, while iron overload facilitates the generation of reactive oxygen species, contributing to lipid peroxidation, mitochondrial dysfunction, and ferroptosis. Dysregulated iron metabolism has been associated with several ocular pathologies, including age-related macular degeneration, diabetic retinopathy, glaucoma, retinal detachment, cataracts, and anemic retinopathy. The eye possesses specialized iron regulatory mechanisms involving proteins such as transferrin, ferritin, ferroportin, and hepcidin that govern iron transport, storage, and export across ocular barriers. Aberrations in these pathways are now recognized as contributing factors in disease progression. This narrative review explores the complex dual role of iron overload and deficiency in ocular diseases. It highlights the molecular mechanisms underlying iron-mediated pathologies in both the posterior and anterior segments of the eye, along with the clinical manifestations of iron imbalance. Current therapeutic approaches are discussed, including oral and parenteral iron supplementation for deficiency and emerging chelation-based or antioxidant strategies to address iron overload, while highlighting their limitations. Key challenges remain in developing targeted ocular delivery systems that optimize bioavailability and minimize systemic toxicity. Hence, maintaining iron homeostasis is critical for visual function, and further research is needed to refine therapeutic interventions and clarify the mechanistic role of iron in ocular health and disease. Full article