Search Results (119)

Statins are commonly used cholesterol-lowering drugs, but their effects on astrocyte oxidative metabolism are poorly understood. To investigate this, rat astrocytes were exposed to 200 nM atorvastatin or simvastatin for 6 days and then assessed for changes in coenzyme Q (CoQ) homeostasis, mitochondrial function, and energy metabolism. Both statins comparably decreased cellular CoQ9 and CoQ10 levels (~35%), with greater losses of their reduced antioxidant forms (60–75%). Lower intracellular and mitochondrial levels of reactive oxygen species (ROS) were accompanied by the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant pathways (superoxide dismutase 1 and glutathione reductase) and metabolic stress response factors, including hypoxia-inducible factor 1-alpha (HIF1α) and brain-derived neurotrophic factor (BDNF). Both statins promoted glycolytic reprogramming, mitochondrial fission, and biogenesis while impairing oxidative phosphorylation, as evidenced by reduced ATP-linked respiration, increased proton leak, and lower ATP levels. These findings suggest that statin-treated astrocytes adapt by prioritizing redox homeostasis over ATP production. CoQ10 supplementation increased cellular CoQ10 levels and restored ATP levels without further decreasing ROS, suggesting that its primary benefit is bioenergetic support, not additional antioxidant protection. Overall, statin-induced CoQ deficiency induces adaptive metabolic remodeling of astrocytes, while CoQ10 supplementation may help maintain energy metabolism under these conditions. Full article

Primary coenzyme Q10 (CoQ10) deficiency results from mutations in genes involved in the CoQ10 biosynthetic pathway. In humans, at least 10 genes (PDSS1, PDSS2 to COQ10) are required for the biosynthesis of functional CoQ10, a mutation in any one of which can result in a deficit in CoQ10 status and present as primary CoQ10 deficiency. Furthermore, the genes NDUFA9 and HPDL, whilst not part of the PDSS1, PDSS2 to COQ10 gene sequence, have also been shown to have a crucial role in CoQ10 biosynthesis. A major problem in treating primary CoQ10 deficiencies is the poor bioavailability of supplemental CoQ10, both in terms of lack of absorption from the digestive tract and inability to cross the human blood–brain barrier. Bypass strategies aim to circumvent this problem by using more bioavailable precursor analogues that can enter the cell and be incorporated into the CoQ10 synthesis pathway downstream of the affected enzyme, examples being 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid or vanillic acid, which, in contrast to CoQ10, are small, water-soluble molecules. In this article, we have, therefore, reviewed potential bypass mechanisms for primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10, together with NDUFA9 and HPDL, using such precursors. Most of the published data relating to the bypass therapy of primary CoQ10 deficiency is derived from cell lines or animal models, and few human studies have so far been undertaken. In addition, further research is required to investigate the potential mechanisms by which bypass compounds such as 4-HB may access the human blood–brain barrier (BBB), for example, using in vitro co-culture BBB model systems incorporating CoQ10-deficient neurons. Overall, the objective of this article is, therefore, to systematically review the available data for each of the primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10 together with NDUFA9 and HPDL, in particular to identify the clinical potential of such studies. Full article

Congenital heart diseases (CHDs) are characterized by profound metabolic remodeling of mitochondrial pathways. However, data regarding mitochondrial respiration, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO) in patients with Ebstein anomaly (EA) are currently unavailable. This study evaluated 14 EA patients and 18 healthy volunteers. In accordance with the 2020 ESC guidelines, patients were stratified into two cohorts: EA-0 (patients currently without an indication for intervention) and EA-1 (patients meeting Class Ia or IIb indications for surgical intervention). Platelet OXPHOS and FAO parameters were determined simultaneously via high-resolution respirometry. CI-linked LEAK respiration (substrates: pyruvate and malate) and FAO-linked LEAK respiration (substrates: octanoylcarnitine and malate) were significantly elevated in EA patients. Furthemore, the EA-1 group showed significantly lower coenzyme Q₁₀ (CoQ₁₀) and γ-tocopherol levels than EA-0. Differences in the measured parameters between groups suggest a state of myocardial adaptation and transient metabolic reprogramming in EA-0 patients, whereas in EA-1 patients, a significant change in mitochondrial metabolism and bioenergetics was found. We hypothesize that increased platelet LEAK mitochondrial respiration and CoQ₁₀ deficiency could be key signals of mitochondrial reprogramming and serve as potential biomarkers for right ventricular dysfunction. The analysis of platelet mitochondrial bioenergetics represents a novel area of translational mitochondrial cardiology, contributing to personalized diagnostics, risk stratification and optimal surgical timing in EA patients. Full article

Objective: Dental professionals are routinely exposed to infectious agents through contact with blood, saliva, and aerosols. This cross-sectional survey aimed to evaluate and compare knowledge, attitudes, and self-reported practices related to infectious diseases among dental students and practicing dentists in the post-COVID era. Methods: This web-based cross-sectional survey was conducted between January and March 2024 at a single dental faculty. Fourth- and fifth-year dental students and practicing dentists were invited to participate. A 30-item questionnaire assessed knowledge of infectious disease transmission and immunological markers (Questions Q1–Q19), as well as attitudes and self-reported practices toward patients with infectious diseases (Q20–Q30). Descriptive statistics were calculated, and comparisons between groups were performed using Pearson’s chi-square or Fisher’s exact tests (α = 0.05). Internal consistency of the questionnaire was acceptable (Cronbach’s alpha: 0.81 for knowledge items and 0.88 for attitude/practice items). Results: A total of 221 dental students and 33 dentists were included in the final analysis. Both groups demonstrated high awareness of respiratory transmission routes for COVID-19 and influenza. In contrast, recognition of bloodborne transmission pathways was limited, with approximately half of participants identifying blood contact and blood-contaminated instruments as potential sources of infection. Significant differences were observed between students and dentists in the interpretation of SARS-CoV-2 IgG antibodies, with dentists more frequently associating IgG positivity with prior infection (p = 0.009) and immunity (p < 0.001). Cautious behavior toward treating patients with infectious diseases was common in both groups, whereas reluctance to provide treatment and lower self-perceived knowledge were more frequently reported among students. Conclusions: Despite adequate awareness of respiratory infection transmission, important deficiencies persist in bloodborne pathogen knowledge, serological interpretation, and confidence in managing infected patients, particularly among dental students. These findings underscore the need for targeted, practice-oriented infection control education that integrates immunological principles and hands-on training to enhance clinical preparedness in the post-COVID era. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, yet adequate in vitro models mimicking the tumor immune microenvironment (TIME) are rare. Specifically, the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating interactions between tumor cells and tumor-associated macrophages (TAMs) is not fully understood. We established a 3D multicellular tumor spheroid (MCT) model using murine N-HCC25 cells with CRISPR/Cas9-mediated knockouts of Nrf2 and its negative regulator Kelch-like ECH-associated protein 1 (Keap1), the latter mimicking constitutive activation. N-HCC25 cells were co-cultured with bone marrow-derived macrophages (BMDMs) isolated from wild-type and Nrf2-knockout C57BL/6J mice. We compared co-culture setups (conditioned media, transwell systems, direct contact) using RT-qPCR, flow cytometry, and invasion assays. 3D spheroid systems better preserved stemness than 2D cultures and revealed functional Nrf2-dependent effects such as increased Vegf-α secretion in Keap1-deficient spheroids. Among the different co-cultivation models, the most profound effects were observed in the MCT model. Macrophages successfully integrated into the spheroids and triggered invasive outgrowth, whereas MCTs containing Nrf2-deficient macrophages displayed markedly reduced tumor spheroid growth and lower programmed cell death ligand-1 expression. These findings demonstrate that Nrf2 signaling in macrophages fosters an immunosuppressive and pro-invasive microenvironment. The established MCT model provides a suitable platform to further unravel Nrf2-dependent mechanisms in the HCC TIME. Full article

In grid-deficient environments, residential energy systems face severe carbon emission penalties due to mandatory reliance on diesel standby generators during supply interruptions. In Iraq, summer peak loads routinely exceed grid capacity, triggering prolonged generator operation and dramatically increasing household carbon footprints. This study presents a deep Q-network (DQN) reinforcement learning framework for intelligent battery energy storage system (BESS) scheduling, targeting carbon emissions reduction through strategic peak shaving. The DQN agent learns optimal battery dispatch strategies by internalizing diurnal patterns in load and solar generation through temporal state features, enabling anticipatory control without requiring explicit external forecasting models. The system is trained on one-year operational data from a representative Iraqi residential installation and evaluated over the critical summer period (122 days, 35.5% grid unavailability). The results demonstrate a 54.8% ${\mathrm{CO}}_2$ reduction (306.5 kg versus 677.4 kg baseline), a 25.5% reduction in generator runtime, and a 23.7% reduction in operating costs for the studied configuration. The learned policy approaches 89.6% of perfect-foresight MILP performance while executing 35,000 times faster. A reward function sensitivity analysis across five weighting schemes confirms that the 20:1 carbon-to-cost priority ratio optimally balances environmental and economic objectives. Ablation studies quantify the mechanism contributions: anticipatory pre-charging accounts for 58% of the total improvement, discharge optimization for 44%, and real-time PV coordination for 22%. These findings establish DQN-based BESS optimization as a practically deployable decarbonization approach for residential systems in grid-constrained developing regions. Full article

Coenzyme Q₁₀ (CoQ₁₀) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ₁₀ participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ₁₀ deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ₁₀ biosynthesis. These defects lead to reduced CoQ₁₀ levels and impaired mitochondrial functions. Clinically, primary CoQ₁₀ deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ₁₀, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ₁₀ biology, biosynthesis, and the clinical spectrum of primary CoQ₁₀ deficiencies, and we discuss emerging mechanisms linking CoQ₁₀ depletion to mitochondrial dysfunctions and human diseases. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder with limited effective therapeutic options. Emerging lipidomic studies suggest that alterations in membrane-associated lipids contribute to MASH pathophysiology; however, nutritional interventions capable of modifying these lipid alterations remain poorly defined. This study aimed to investigate the effects of coenzyme Q10 (CoQ) supplementation on hepatic lipidomic remodeling in a methionine- and choline-deficient (MCD) diet-induced mouse model of MASH. Methods: Male C57BL/6J mice were fed a methionine- and choline-sufficient diet or an MCD diet for 4 weeks, with MCD-fed mice receiving vehicle or CoQ (100 mg/kg body weight/day). Hepatic lipid profiles were assessed using untargeted LC–MS-based lipidomics, and expression of genes involved in phospholipid and sphingolipid metabolism was quantified by quantitative real-time PCR. Results: CoQ supplementation significantly attenuated liver injury induced by the MCD diet, as evidenced by reduced histological severity and decreased serum ALT and AST levels. Lipidomic analyses revealed marked alterations in hepatic phospholipid and sphingolipid profiles during MASH development. CoQ was associated with remodeling of phospholipid composition, increasing phosphatidylcholine (PC) species and reducing phosphatidylethanolamine (PE) species, resulting in an increased hepatic PC to PE ratio. This change was accompanied by upregulation of Pemt (phosphatidylethanolamine N-methyltransferase). In contrast, sphingolipid accumulation induced by the MCD diet remained largely unchanged by CoQ, and Smpd1 (sphingomyelin phosphodiesterase 1) expression was not altered. Conclusions: CoQ supplementation was associated with attenuation of MCD diet-induced MASH and modulation of hepatic phospholipid homeostasis, supporting its potential as a nutritional intervention targeting membrane lipid dysregulation in MASH. Full article

Leaf color mutants are commonly characterized by altered chlorophyll content and aberrant chloroplast development, making them valuable models for investigating photosynthetic mechanisms and chloroplast biogenesis. In this study, an albino mutant was isolated from a population of transgenic maize breeding lines. Genetic analysis indicated that the mutant phenotype is inherited in a Mendelian manner and is controlled by a single nuclear locus. This was supported by a χ² test performed on the T₂ generation, which confirmed a segregation ratio consistent with 3:1 (176:68, χ² = 1.07 < χ²_0.05 = 3.84, p > 0.05). Microscopic examination revealed the absence of normally developed chloroplasts in mutant cells. Further expression analysis of chloroplast genes via Northern blotting and quantitative real-time PCR (qRT-PCR) suggested that the mutation impairs the regulation of plastid-encoded polymerase (PEP)-dependent chloroplast gene expression. Notably, PCR-based co-segregation analysis indicated that the mutant phenotype is associated with the entire inserted vector sequence, rather than a point mutation or a small genomic deletion. In conclusion, this paper reports the isolation and phenotypic characterization of an etiolated mutant from a transgenic maize breeding population, including comparative ultrastructural analysis of chloroplasts, co-segregation validation, and chloroplast gene expression profiling. These results enhance our understanding of the physiological and molecular mechanisms underlying chlorophyll-deficient mutations in plants. Full article

The disparity in outcomes between preclinical and clinical studies supplementing coenzyme Q10 (CoQ10) in neurological disorders may be a reflection of the differences in the ability of supplemental CoQ10 to access the blood–brain barrier (BBB) in rodents and in humans, which is, in turn, a consequence of contrasting structures of the BBB. The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. In this article, we have, therefore, reviewed the role of model systems to study the access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. In addition, the use of such model systems to study the interactions of CoQ10 with vitamin E and selenium has been reviewed. Finally, the practical application of a neuronal model system to investigate the effect of CoQ10 supplementation on CoQ10 status and mitochondrial metabolism in a CoQ10 deficiency state has been described. Full article

Probiotics are widely used as feed additives in livestock production, yet the overall safety of commercially available veterinary probiotics remains insufficiently assessed. In this study, 33 probiotic products marketed in Northern China were systematically evaluated with respect to strain composition, label accuracy, antimicrobial resistance, and the diversity of resistance genes. A total of 32 Bacillus spp. were isolated, many of which showed resistance to multiple antibiotics. Labeling inaccuracies were prevalent: none of the products specified strain names and numbers, 33% (11/33) failed to report viable bacterial counts, 9% (3/33) lacked their claimed key ingredients, and 21% (7/33) contained isolated strains that did not match the label. High-throughput quantitative PCR (HT-qPCR) analysis further revealed that all 27 tested products harbored abundant antibiotic resistance genes (ARGs), with 241 ARGs and seven mobile genetic elements (MGEs) detected. The ARGs were primarily associated with tetracycline, aminoglycosides, β-lactams, and macrolide–lincosamide–streptomycin B (MLSB) antibiotics, and co-occurrence analysis showed a strong positive correlation between ARG and MGE abundance, with Clostridium and Enterococcus identified as potential hosts. These findings underscore significant quality and safety deficiencies in veterinary probiotics and highlight potential risks to animal, human, and environmental health, emphasizing the relevance of a One Health perspective in probiotic evaluation and regulation. Full article

Understanding the molecular crosstalk between drought and iron (Fe) homeostasis is crucial for developing drought-tolerant wheat cultivars with enhanced nutrient quality. In this study, transcriptomic data mining identified 23,271 and 5933 differentially expressed genes (DEGs) under drought and Fe deficiency, respectively, with 2479 DEGs in response to both stresses. Notably, this overlapping set included significant numbers of genes encoding transcription factors (TFs) (149 genes), Fe homeostasis components (274 genes), and those involved in phytohormones pathways (245 genes), particularly the abscisic acid (ABA) pathway. Gene Ontology (GO) analysis revealed specific and commonly affected biological processes, such as response to abiotic stimulus and heme binding. Furthermore, co-expression network analysis revealed modules highly enriched with genes involved in transcriptional regulation and Fe uptake, enabling the identification of key hub regulatory genes, belonging to the MYB, NAC, BHLH, and AP2/ERF families, involved in the shared stress response. Finaly, the expression of a set of candidate TF-encoding genes was validated using qRT-PCR in durum wheat under drought and Fe starvation, providing a detailed overview of the possible shared regulatory mechanisms linking drought and Fe deficiency responses. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients—those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors—derive little benefit from current immunotherapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal accumulation of lipid peroxides, has emerged as a promising antitumor mechanism that can interact with and modulate antitumor immunity. Concurrently, the gut microbiota exerts powerful control over host metabolism and immune tone through microbial community structure and metabolite production; accumulating evidence indicates that microbiota-derived factors can either sensitize tumors to ferroptosis (for example, via short-chain fatty acids) or confer resistance (for example, indole-3-acrylic acid produced by Peptostreptococcus anaerobius acting through the AHR→ALDH1A3→FSP1/CoQ axis). In this review we synthesize mechanistic data linking microbial ecology, iron and lipid metabolism, and immune regulation to ferroptotic vulnerability in CRC. We discuss translational strategies to exploit this “microbiota–ferroptosis” axis—including precision microbiome modulation, dietary interventions, pharmacologic ferroptosis inducers, and tumor-targeted delivery systems—and we outline biomarker frameworks and trial designs to evaluate combinations with ICIs. We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges. Full article

Estrogen is a key regulator of skeletal muscle growth and metabolism in birds, yet its specific roles in female chickens remain poorly defined. To address this gap, we established an estrogen-deficient model by surgically removing the ovaries of Wuding hens, a Chinese indigenous slow-growing breed. Growth traits, carcass yield, and meat quality were evaluated across different ages, complemented by histological examination, serum biochemical analysis, and multi-omics approaches (transcriptomics, proteomics, and lipidomics). Ovariectomized hens maintained somatic growth for a longer period and reached greater body weight and carcass yield at 330 days compared with intact controls. Thigh muscle tenderness was also enhanced in the absence of estrogen, despite no long-term differences in muscle fiber morphology. Lipidomic analysis revealed a transient increase in intramuscular triglyceride content at mid-growth (240 days), pointing to altered lipid storage and distribution. Integrated omics profiling further demonstrated significant changes in the mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling pathways, accompanied by differential expression of key metabolic and structural genes, including mitogen-activated protein kinase 8 (MAPK8), fatty acid binding protein 4 (FABP4), ankyrin 1 (ANK1), and coenzyme Q6 monooxygenase (COQ6). These molecular adjustments suggest that estrogen withdrawal triggers broad reprogramming of muscle signaling and lipid metabolism. Overall, this study highlights the multifaceted role of estrogen in coordinating growth, muscle quality, and lipid homeostasis in hens and provides a functional model for studying estrogen deficiency in poultry with implications for meat quality improvement. Full article

Rootstock choice offers a powerful lever for tailoring economically important trees to adverse environments. Camellia oleifera Abel., a premier oil-producing species cultivated widely on red-soil hills, suffers large yield losses under chronic phosphorus deficiency. We grafted a single elite scion (CL4) onto three contrasting rootstocks (CL4, CL3, CL53) and monitored growth and root transcriptomes for 1.5 years under adequate (1 mM) or limiting (0 mM) P supply. Under low-P stress, the rootstock identity reshaped the root architecture: CL4/CL3 produced the longest, most extensive network, increasing the total root length by 49.7%, the surface area by 52.9%, and the volume by 42.6% relative to the control, whereas leaf morphology responded solely to P supply, not to the graft combination. CL4/CL3 also accumulated up to more than 17.5% of root biomass and 28.25% of whole-plant biomass than any other combination. Physiologically, CL4/CL3 acted as an aggressive P miner, accumulating 67.8% more P in its roots than the self-grafted control under P limitation, while CL4/CL4 maximized the internal P use efficiency, showing a 44.74% higher root P use efficiency than CL4/CL53—two contrasting yet effective strategies for coping with low-P stress. Transcriptome profiling uncovered 1733 DEGs in the CL4/CL3 and 2585 in the CL4/CL4 roots, with 150 and 255 uniquely co-expressed genes, respectively. CL4/CL3 up-regulated organic-acid and phenylpropanoid pathways; CL4/CL4 activated defense and phosphate transport networks. qRT-PCR of six genes confirmed that CL4/CL3 mounted a stronger low-P response via MAPK, hormonal, and lipid–metabolic signaling. These results provide a mechanistic framework for rootstock-mediated P efficiency and establish a foundation for the molecular breeding of C. oleifera under nutrient-limited conditions. Full article