Search Results (1,654)

In a systematic explorative study of genetic patterns on chromosome 19, we discovered a pattern comprising 23 SNP alleles that is significantly associated with late-onset Alzheimer’s disease (AD). This association was validated using two independent datasets. The pattern includes thimet oligopeptidase (THOP1), which has a long and disputatious relationship with AD. It also spans solute carrier family 39 member 3 (SLC39A3) and small glutamine-rich tetratricopeptide repeat co-chaperone alpha (SGTA) and is upstream from DIRAS family GTPase 1 (DIRAS1). We utilized population data to observe the frequencies of this genetic pattern for 11 different ancestries and noted that it is highly common for Europeans and relatively infrequent for Africans. This research provides a distinct genetic signature for AD risk, as well as insights into the complicated relationship between this disease and THOP1. Full article

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, ¹³C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte–SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomics analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in three-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment. Full article

Background/Objectives: Gamma-Aminobutyric Acid (GABA) and glutamate are the main inhibitory and excitatory neurochemicals of the central nervous system. Recently, increased GABA+ (GABA+ macromolecules) and Glx (glutamate and glutamine) levels have been reported in migraine. Conversely, decreased GABA+ and Glx levels have been reported in conditions such as chronic musculoskeletal pain and other chronic widespread pain conditions. This has led to the hypothesis that unique neurochemical profiles may underpin different headache and pain conditions. What is currently unknown is how neurochemical levels correlate with different clinical presentations of local and widespread pain sensitivity. The aims of this study were therefore to (i) explore the relationship between brain neurochemicals and clinical presentations of different headache and pain conditions and (ii) use a novel approach to explore how participants cluster based on their neurochemical profiles and explore the clinical characteristics of the participants in these neurochemical clusters. Methods: In this exploratory secondary analysis of a cross-sectional study, participants with migraine (n = 20), whiplash-headache (n = 20), and low back pain (n = 20), and healthy controls (n = 21) completed pain, disability and psychological distress questionnaires, received Magnetic Resonance Spectroscopy (MEGAPRESS), and underwent cervical musculoskeletal and quantitative sensory testing. Participants were classified based on cervical musculoskeletal impairment, increased cervical pain sensitivity, and central sensitization. Correlations between neurochemical levels and clinical classifications were explored. Cluster analysis was used to determine how participants grouped based on their neurochemical profiles. Pain, disability and psychological distress scores and clinical classifications were then compared between the resultant clusters. Post hoc testing explored increased cervical pain sensitivity within the clusters. Results: GABA+ levels moderately correlated with increased cervical pain sensitivity (r² = 0.31, p = 0.006), with no other significant correlations. Cluster analysis revealed three neurochemical profiles, Cluster 1 (Low GABA+ levels) had moderate disability, Cluster 2 (highest Glx levels) had the lowest pain and disability, and Cluster 3 (highest GABA+ levels) had the highest pain and disability. Post hoc testing demonstrated that the cluster with the highest GABA+ levels (Cluster 3) had the most cervical pain sensitivity. Conclusions: This study suggests that considering the pain condition or presence of central sensitization alone is not sufficient to explain GABA+ and Glx levels. Our findings suggest that increased cervical pain sensitivity might be more reflective of GABA+ levels than pain condition or central sensitization and would benefit from further investigation to further elucidate the relationship between brain neurochemicals and clinical characteristics of pain sensitivity. Full article

Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance. Full article

Background: Malnutrition is a clinical condition that leads to unfavourable changes in health. It affects 35–55% of hospitalized patients, and in the case of cancer, this prevalence rises to 40–90% of patients. Screening nutritional status is essential for preventing undernutrition, which is crucial as its treatment. Undernutrition in patients after severe injuries significantly increases catabolic changes. Cytokines and hormones, such as epinephrine, glucagon, and cortisol, are released, which can increase energy expenditure by 50%. Properly conducted nutritional treatment aims to maintain or improve the nutritional status of patients whose nutrition with a natural diet is insufficient, moreover, in some cases, treatment of the underlying disease. Methods: This study is a narrative review focused on immunonutrition. The search for source articles, mainly from the last 10 years, was conducted in the PubMed and Google Schoolar databases, as well as in printed books. The key words used were “malnutrition”, “inflammation”, “clinical nutrition”, “immunomodulatory components”, “nutritional status assessment”, “enteral nutrition”, “parenteral nutrition”, and their combinations. Results: Providing substances such as omega-3 fatty acids, glutamine, arginine, nucleotides, antioxidants, and prebiotic fiber has a beneficial impact on immunological and anti-inflammatory pathways. The above-mentioned ingredients may inhibit the secretion of pro-inflammatory cytokines, activate anti-inflammatory cytokines, stimulate immune cells, and have a beneficial effect in allergic diseases, respiratory infections, or wound healing. Conslusion: Immunonutrition can be administrated via oral, enteral, and parenteral routes. It is crucial to highlight the importance of proper nutritional status in patients. The relationship between inflammation and malnutrition creates a vicious cycle, where one negatively affects the other due to increased metabolic demand, loss of appetite, weakened immune system, and gut dysbiosis. Full article

Amino acids are crucial components of proteins, key molecules in cellular physiology and homeostasis. However, they are also involved in a variety of other mechanisms, such as energy homeostasis, nitrogen exchange, further synthesis of bioactive compounds, production of nucleotides, or activation of signaling pathways. Moreover, amino acids and their metabolites have immunoregulatory properties, significantly affecting the behavior of immune cells. Immunotherapy is one of the oncological treatment methods that improves cytotoxic properties of one’s own immune system. Thus, enzymes catalyzing amino acid metabolism, together with metabolites themselves, can affect immune antitumor properties and responses to immunotherapy. In this review, we will discuss the involvement of tryptophan, glutamine, and asparagine metabolism in the behavior of immune cells targeted by immunotherapy and summarize results of the most recent investigations on the impact of amino acid metabolites on immunotherapy. Full article

Magnesium-doped hydroxyapatite/chitosan composite coatings produced by the radio-frequency magnetron sputtering technique were exposed to 5 MeV electron beams of 8 and 30 Gy radiation doses in a linear electron accelerator. The surfaces of unirradiated layers are smooth, while the irradiated ones exhibit nano-structures with sizes that increase from 60 nm at a 8 Gy dose to 200 nm at a 30 Gy dose. Young’s modulus and the stiffness of the layers decrease from 58.9 GPa and 10 µN/nm to 5 GPa and 2.2 µN/nm, respectively, when the radiation doses are increased from 0 to 30 Gy. These data suggest the diminishing of the contribution of the chitosan to the elasticity of the magnesium-doped hydroxyapatite/chitosan composite layers after electron beam irradiation. The biological capabilities of the coatings were assessed before and after their immersion in RPMI-1640 cell culture medium for 7 and 14 days, respectively, and further cultured with a MG63 cell line (ATCC CRL1427) in Dulbecco’s Modified Eagle Medium supplemented with fetal bovine serum, penicillin–streptomycin, and L-glutamine. Thus, 1 µm spherical structures were developed on the surfaces of the layers exposed to a 30 Gy radiation dose and immersed for 14 days in the RPMI-1640 biological medium. The molecular structures of all the RPMI-1640 immersed samples were modified by the growth of a carbonated hydroxyapatite layer characterized by a B-type substitution, as Fourier Transform Infrared Spectroscopy revealed. The biological assay proved the increased biocompatibility of the layers kept in RPMI-1640 medium and enhanced MG63 cell attachment and proliferation. Atomic force microscopy analysis indicated the elongated fibroblastic cell morphology of MG63 cells with minor alteration at 30 Gy irradiation doses as a result of layer biocompatibility modifications. Full article

Ammonium and nitrate nitrogen are the two main forms of inorganic nitrogen (N) available to crops. However, it is not clear how mixtures of ammonium and nitrate N affect N uptake and partitioning in major rice cultivars in southern China. This study investigated the effects of different ammonium nitrogen and nitrate nitrogen mixture treatments (100:0, 75:25, 50:50, 25:75, and 0:100) on the growth, photosynthetic characteristics, nitrogen uptake, gene expression, and yield of different rice cultivars (Mei Xiang Zhan NO. 2: MXZ2; Nan Jing Xiang Zhan: NJXZ). Rice root biomass, tiller number, and yield were increased by 69.5%, 42.5%, and 46.8%, respectively, in the 75:25 ammonium-nitrate mixed treatment compared to the 100:0 ammonium-nitrate mixed treatment. The nitrogen content in rice roots, stems, leaves, and grains increased by 69.5%, 64.0%, 65.5%, and 17.5%, respectively. In addition, compared with MXZ2, NJXZ had a greater proportion of N allocated to leaves and grains. Analysis of root enzyme activities revealed that the 75:25 ammonium-nitrate mixed nutrient treatment increased rice root glutamine synthetase activity by an average of 35.0% and glutamate synthetase activity by an average of 52.0%. Transcriptome analysis revealed that the 75:25 mixed ammonium-nitrate nutrient treatment upregulated the expression of genes related to the nitrogen metabolism transporter pathway. Weighted correlation network analysis revealed that some differentially expressed genes (HISX and RPAB5) regulated the activities of nitrogen-metabolizing enzymes in rice and some (SAT2, CYSKP, SYIM, CHI1, and XIP1) modulated amino acid synthesis; greater expression of these genes was detected in the 75:25 ammonium-nitrate mixed nutrient treatment. The expression characteristics of the above genes were further confirmed by RT‒qPCR. Interestingly, the expression levels of the above genes were significantly correlated with the glutamate synthase activity, photosynthetic rate, and root volume. It is noteworthy that increasing the expression of the aforementioned genes coupled with nitrogen uptake was observed in the three main rice cultivars. These results suggest that the 75:25 ammonium-nitrate mixture may have increased nitrogen-metabolizing enzyme activities and promoted nitrogen uptake through the upregulated expression of nitrogen metabolism-related genes, thereby increasing tiller number and improving rice yield. Full article

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article

Soil is an important link in the cycling of carbon, nitrogen, and other elements. The soil environment, especially the soil water, nutrients, and salts, undergoes profound changes in the process of oasis evolution. As a key component of the soil ecosystem in an oasis, soil microbial communities are strongly influenced by environmental factors and have feedback effects on them. However, the response of the soil microbial community structure and function to the process of oasis evolution and its mechanism is still unclear. In this study, the effects of different land-use types, including cotton field (CF), orchard (OR), forest land (FL), waste land (WL) and sand land (SL), on the soil microbial community structure and function were analyzed by metagenomic sequencing. The results showed that the cotton field had the highest soil water content, showing a significant difference compared with the other land-use types. Forest land had the highest soil pH, also showing a significant difference compared with the other land-use types. Among the land-use types with different degrees of oasis evolution, Pseudarthrobacter and Actinomycetota were the dominant phyla, with higher relative abundance. The main metabolic pathways in the cotton field, sand land, and waste land were L-glutamine biosynthesis, ornithine cycle, and nitrate reduction V. The soil total salt, moisture content, pH, and available potassium were the important soil physicochemical factors influencing soil microorganisms. This study will deepen our understanding of the role of soil microbial communities in the process of oasis evolution and provide a scientific basis for ecological restoration and desertification control in arid areas. Full article

FMD poses a significant threat to animal husbandry and public health security. This study aims to investigate an innovative method for producing FMD vaccines. Wild-type BHK-21 cells were subjected to heavy ion irradiation. Following the optimization of irradiation parameters, the mutant cell line BHK-7 was selected using the limited dilution method. The concentration of FMDV 146S in the BHK-7 cells was markedly elevated, significantly enhancing FMDV replication. The suspension culture and domestication experiments demonstrated that BHK-7 exhibited characteristics like those of the control BHK-21 cells, thereby improving production efficiency and reducing costs. The metabolic analysis of the BHK-7 suspension cultures indicated that glutamine (GLN) may play a crucial role in FMDV replication, with the addition of an appropriate amount of GLN enhancing viral replication levels. Ten successive generations of BHK-7 cells showed stability in FMDV replication post-domestication, indicating good genetic stability. In this study, we obtained a mutant somatic cell line, BHK-7, which promotes FMDV replication through heavy ion irradiation technology. Through suspension culture domestication and metabolic analysis, this study provides a novel approach and concept for FMD vaccine production, as well as a reference for the development of other vaccine cell lines. Full article

Natamycin is a polyene macrocyclic antibiotic extensively used in food, medical, and agricultural industries. However, its high production cost and low synthetic efficiency fail to meet the growing market demand. Therefore, enhancing the production of natamycin-producing strains is crucial for achieving its industrial-scale production. This study systematically evaluated 16 mutagenesis methods and identified atmospheric and room temperature plasma mutagenesis combined with 2-deoxyglucose tolerance screening as the optimal strategy for enhancing natamycin production. A high-yield mutant strain, AG-2, was obtained, achieving an 80% increase in natamycin production (1.53 g/L) compared to the original strain. Metabolic analysis revealed that glycolysis and the pentose phosphate pathway were enhanced in AG-2, while the tricarboxylic acid cycle was weakened, significantly increasing the supply of precursors such as acetyl-CoA, methylmalonyl-CoA, and the reducing power of NADPH. Additionally, overexpression of the nitrogen metabolism regulatory gene glnR promoted the supply of glutamate and glutamine, further increasing natamycin production in AG-2 to 1.85 g/L. In a 5 L fermenter, the engineered strain AG-glnR achieved a final natamycin production of 11.50 g/L, 1.67 times higher than the original strain. This study is the first to combine mutagenesis with nitrogen metabolism regulation, effectively enhancing natamycin production and providing a novel approach for the efficient synthesis of other polyene antibiotics. Full article

Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that share similar clinical features but have different etiologies, making a differential diagnosis particularly challenging. Background/Objectives: Utilizing advanced machine learning (ML) techniques on metabolomic data, this study aimed to identify key metabolites in synovial fluid (SF) that could aid in distinguishing between OA and RA. Methods: Metabolite data from the MetaboLights database (MTBLS564), analyzed using nuclear magnetic resonance (NMR), were processed using normalization, a principal component analysis (PCA), and a partial least squares discriminant analysis (PLS-DA) to reveal prominent clustering. Results: Decision forests and random forest classifiers, optimized using genetic algorithms (GAs), highlighted a selection of a few metabolites—primarily glutamine, pyruvate, and proline—with significant discriminative power. A Shapley additive explanations (SHAP) analysis confirmed these metabolites to be pivotal predictors, offering a streamlined approach for clinical diagnostics. Conclusions: Our findings suggest that a minimal set of key metabolites can effectively be relied upon to distinguish between OA and RA, supported by an optimized ML model achieving high accuracy. This workflow could streamline diagnostic efficiency and enhance clinical decision-making in rheumatology. Full article

Oyster mushrooms (Pleurotus ostreatus) are one of the most commonly grown edible mushrooms using compost, which contains high concentrations of ammonia. In this study, inoculation of the oyster mushroom culture substrate with ammonia-assimilating bacterium Enterobacter sp. B12, either before or after composting, reduced the ammonia nitrogen content, increased the total nitrogen content of the compost, and enhanced the mushroom yield. Co-cultivation with P. ostreatus mycelia on potato dextrose agar (PDA) plates containing 200 mM NH₄⁺, B12 reduced reactive oxygen species (ROS) accumulation in the mycelia and downregulated the expression of the ROS-generating enzymes NADPH oxidase A (NOXA) and the stress hormone ethylene synthase 1-aminocyclopropane-1-carboxylate oxidase (ACO). It also downregulated the expression of the ammonia-assimilating related genes in the mycelia, such as glutamate dehydrogenase (GDH), glutamate synthase (GOGAT), glutamine synthetase (GS), ammonia transporter protein (AMT), and amino acid transporter protein (AAT), while upregulating its own ammonia-assimilation genes. These findings suggest that the mechanism by which B12 promoted oyster mushroom growth was that B12 assimilated ammonia, alleviated ammonia stress, mitigated ROS accumulation in the mycelia, and supplied ammonia and amino acids to the mycelia. To our knowledge, ammonia-assimilating bacteria are a novel type of mushroom growth promoter (MGP). Full article

Olive trees are a cornerstone of Mediterranean agriculture but face significant threats from diseases such as Verticillium wilt and olive anthracnose. These diseases, caused by Verticillium dahliae and Colletotrichum spp., respectively, result in significant economic losses and degrade olive oil quality. While traditional chemical treatments present environmental risk, sustainable alternatives such as biological control agents (BCAs) are gaining attention. Epicoccum nigrum, an antagonistic fungus, has shown potential as a BCA due to its production of antimicrobial secondary metabolites. This study aimed to observe whether E. nigrum has an antagonistic ability against V. dahliae and C. acutatum, and to elucidate the metabolic interactions between these fungi using NMR-based metabolomics. E. nigrum showed inhibitory effects on the growth of C. acutatum and V. dahlia of 44.97% and 38.73% respectively. Metabolomic profiling revealed distinct biochemical responses in E. nigrum, V. dahliae, and C. acutatum under mono- and dual-culture. Multivariate statistical analysis highlighted the metabolic shifts in mycelia and identified the primary metabolites, such as glutamine, 4-aminobutyrate, and phenylalanine that are involved in adaption for survival in stress conditions such as the presence of a competitor. The results could be important for a better understanding of the primary fungal metabolism, which is still poorly characterized. Further investigation is needed, but these results suggest that E. nigrum could serve as a BCA, offering a more sustainable approach to managing olive diseases. Full article