Search Results (38)

Magnesium (Mg²⁺) is a key regulator of cellular biochemical processes and an essential cofactor in skeletal muscle physiology. Although Mg²⁺ deficiency has been linked to reduced muscle strength, its role in the regulation of calcium (Ca²⁺) signaling and in inflammation remains incompletely understood. In this study, we examined the effects of Mg²⁺ availability using the murine myoblast cell line C2C12. Cells were differentiated under low, normal, or high Mg²⁺ conditions, and myotube formation, intracellular Ca²⁺ fluxes, and resistance to inflammatory stimuli were assessed. Mg²⁺ deficiency impaired myotube differentiation, while Mg²⁺ supplementation preserved Ca²⁺ response during stimulation and contributed to protect myotubes against inflammation-induced damage. Collectively, these findings highlight a dual role of Mg²⁺ in sustaining functional performance under repeated stress and protecting myotubes against inflammatory injury. This study supports the importance of adequate dietary Mg²⁺ intake as a potential strategy to mitigate muscle loss associated with aging and chronic inflammation. Full article

Keloids are abnormal fibroproliferative responses in the skin that often occur without an apparent injury. Their pathogenesis remains incompletely understood, though genetic, environmental, and biochemical factors are believed to contribute. Topical medications (mostly TCA injection) are the most used treatments followed by surgery, alone or in association with other therapeutic options. In most cases, improvement has been described. A combination of altered collagen synthesis, overactive fibroblasts, and immune response contributes to keloid formation. Genomic studies have identified specific mutations, and the role of growth factors such as TGF-β has been confirmed as a key player in keloid pathogenesis. Although great improvements have been made from the molecular point of view and keloids are more easily diagnosed and treatable nowadays, they remain very challenging, having a great impact on quality of life. Their recurrence is still very high. Understanding genetic predisposition and microenvironmental influences is critical for developing more effective therapies. Advances in molecular research and clinical strategies are improving our understanding of keloids, but further studies are needed to establish precise diagnostic markers and more effective long-term treatments. Full article

Global climate change has intensified temperature fluctuations, significantly impacting insect populations. Thermal tolerance has emerged as a critical determinant of species distribution and invasion potential. Liriomyza trifolii, an economically important invasive pest, has been rapidly expanding in southeastern coastal regions of China, gradually displacing its congeners L. sativae and L. huidobrensis. This competitive advantage is closely associated with its superior thermal adaptation strategies. Here, we first examine the temperature-mediated competitive dominance of L. trifolii, then systematically elucidate the physiological, biochemical, and molecular mechanisms underlying its temperature tolerance, revealing its survival strategies under extreme temperatures. Notably, L. trifolii exhibits a lower developmental threshold temperature and higher thermal constant, extending its damage period, while its significantly lower supercooling point confers exceptional overwintering capacity. Physiologically, rapid cold hardening (RCH) enhances cold tolerance through glycerol accumulation and increased fatty acid unsaturation, while heat acclimation improves thermotolerance via a trade-off between developmental processes and reproductive investment. Molecular analyses demonstrate that L. trifolii combines the low-temperature inducible characteristics of L. huidobrensis with the high-temperature responsive advantages of L. sativae in heat shock protein (Hsp) expression patterns. Transcriptomic studies further identify differential expressions of lipid metabolism and chaperone-related genes as key to thermal adaptation. Current research limitations include incomplete understanding of non-Hsp gene regulatory networks and laboratory–field adaptation discrepancies. Future studies should integrate multi-omics approaches with ecological modeling to predict L. trifolii’s expansion under climate change scenarios and develop temperature-based green control strategies. Full article

The etiology and pathophysiology of allergic diseases remain incompletely understood. Current immunological paradigms, while insightful, often fall short in fully elucidating the mechanisms underlying allergic and autoimmune disorders. Under the protein–homeostasis–system (PHS) hypothesis, allergic diseases have etiological substances, and immune reactions against them are responsible for clinical manifestations of allergic diseases. The etiological substances are mainly external in origin and very small with each biochemical property and react to target cells in various organ tissues. Eosinophils, mast cells, and immunoglobulin Es as major immune effectors in allergic diseases control toxic substances according to the chemical or biochemical properties of these substances. Mast cells in the central nervous system may be associated with allergic episodes through connection to peripheral mast cells, and this connection is proposed as the mast cell-associated network. The toxic and/or bioactive proteins/peptides and other non-protein substances, which are derived from injured cells caused by allergic reactions, induce activation of adaptive and innate immune components for controlling the substances. New insights into the etiology and pathophysiology of allergic diseases are introduced with the PHS hypothesis. Full article

Pharmaceuticals such as fluoxetine, paroxetine, sertraline, and mianserin occur in aquatic environments at low yet persistent concentrations due to their incomplete removal in wastewater treatment plants. Although frequently detected, these neuroactive compounds remain underrepresented in ecotoxicological assessments. Given their pharmacodynamic potency, environmentally relevant concentrations may induce sublethal effects in non-target organisms. In this study, we applied untargeted LC-MS-based metabolomics to investigate the sublethal effects of four widely used antidepressants—paroxetine, sertraline, fluoxetine (SSRIs), and mianserin (TeCA)—on two ecologically relevant freshwater invertebrates: S. ambiguum and D. magna. Organisms were individually exposed to each compound for 48 h at a concentration of 100 µg/L and 25 µg/L, respectively. Untargeted metabolomics captured the sublethal biochemical effects of these antidepressants, revealing both shared disruptions—e.g., in glycerophospholipid metabolism and cysteine and methionine metabolism—and species-specific responses. More pronounced pathway changes observed in D. magna suggest interspecies differences in metabolic capacity or xenobiotic processing mechanisms between taxa. Among the four antidepressants tested, sertraline in D. magna and fluoxetine in S. ambiguum exerted the most extensive metabolomic perturbations, as evidenced by the highest number and pathway impact scores. In D. magna, fluoxetine and mianserin produced similar metabolic profiles, largely overlapping with those of sertraline, whereas paroxetine affected only a single pathway, indicating minimal impact. In S. ambiguum, paroxetine and mianserin elicited comparable responses, also overlapping with those of fluoxetine, while sertraline triggered the fewest changes. These results suggest both compound-specific effects and a conserved metabolic response pattern among the antidepressants used. They also underscore the considerable potential of metabolomics as a powerful and sensitive tool for ecotoxicological risk assessments, particularly when applied across multiple model organisms to capture interspecies variations. However, further research is essential to identify which specific pathway disruptions are most predictive of adverse effects on organismal health. Full article

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct damage and cholestasis. While ursodeoxycholic acid (UDCA) is the first-line therapy, approximately 40% of patients have incomplete responses, necessitating alternative treatments. This systematic review and meta-analysis evaluate the efficacy and safety of novel oral anti-cholestatic agents for PBC. Methods: A systematic literature search was conducted in electronic databases up to September 2024. Randomized controlled trials, cohort studies, and case-control studies evaluating novel oral anti-cholestatic agents in adult PBC patients were included. The primary outcome was a change in alkaline phosphatase (ALP) levels. Safety was assessed by the incidence of serious adverse events. Random-effect meta-analyses were performed. Results: Ten studies involving 878 patients were analyzed. Novel agents included seladelpar, fenofibrate, saroglitazar, bezafibrate, elafibranor, and budesonide. The meta-analysis showed significant reductions in ALP levels with novel agents compared to the controls (SMD −2.80; 95% CI −3.56, −2.03; p < 0.00001), with high heterogeneity (I² = 93%). Saroglitazar achieved the largest effect size. There was no significant difference in serious adverse events between novel agents and controls (OR 1.21; 95% CI 0.81, 1.83; p = 0.35). Conclusions: Novel oral anti-cholestatic agents show promise in improving biochemical markers in PBC patients with suboptimal UDCA responses, with a safety profile comparable to controls. However, study heterogeneity and limited long-term data restrict direct comparisons. Larger standardized trials with extended follow-up are needed to confirm long-term efficacy and safety. Full article

α-Lipoic acid (ALA) is a naturally occurring compound with diverse biological functions, widely distributed in animal and plant tissues. It has attracted considerable attention due to its versatile therapeutic potential. However, despite these promising prospects, the clinical application of ALA remains limited by its low bioavailability and chemical instability and an incomplete understanding of its multifaceted mechanisms across various diseases. This review provides a comprehensive overview of the biochemical properties of ALA, including its direct free-radical-scavenging activity, regeneration of endogenous antioxidants, chelation of metal ions, and modulation of inflammatory responses. We also highlight the current evidence regarding ALA’s therapeutic roles and efficacy in major diseases, such as neurodegenerative disorders, lung diseases, cardiovascular diseases, and diabetes. Furthermore, recent advancements and innovative strategies in ALA-based derivatives and drug-delivery systems are summarized, emphasizing their potential to address complex diseases and the necessity for further translational studies. This review aims to provide a theoretical foundation for the rational design of ALA-based therapies, thereby supporting future clinical applications and the optimization of therapeutic strategies. Full article

Background/Objectives: Structural incomplete response (SIR) (persistence/recurrence) may occur in 2–6% of low-risk differentiated thyroid cancer (DTC)-cases and in 67–75% of high risk. Regarding locoregional disease, surgery is the optimal therapeutic modality if the smallest dimension of the targeted node is ≥8 mm or ≥10 mm (central or lateral compartment). In the presence of smaller nodes, contraindications or the patient’s unwillingness for reoperation, active surveillance (AS) or minimally invasive treatments (MITs) may be considered. Methods: We retrospectively studied eight DTC patients with SIR confirmed by ultrasound (U/S)-guided fine-needle aspiration cytology (FNAC) and the measurement of Thyroglobulin (Tg) in the washout fluid. Fourteen malignant lesions were ablated by radiofrequency (RF). We assessed prior to RF ablation (RFA) and consecutively at one month, three months and, then, every three months the volume of each lesion, serum Tg and Anti-Tg antibodies and calculated the volume reduction ratio (VRR). Results: Patients were followed for a mean period of 13.25 months (range: 4–24) after RFA was performed. The targeted lesions reduced significantly from a median volume of 0.24 mL (range: 0.09–0.9) to 0.02 mL (range: 0–0.03) (p < 0.05), with a median VRR of 94.5% (range: 78–100%) and concomitant significant biochemical remission (decrease in serum Tg from a median of 1.05 ng/mL to 0.2 ng/mL, p < 0.05). In one patient with an aggressive radioiodine (RAI)-refractory histological variant, re-recurrence was documented, which was successfully re-ablated by RF. In two patients, Horner syndrome was diagnosed as an RFA complication, which was totally resolved within six months. Conclusions: RFA may be considered as an effective and safe MIT in selective DTC patients with SIR, especially in cases of smaller lesions. Additional prospective studies are needed, including aggressive DTC histological variants towards a tailored therapeutic approach. Full article

Presbycusis, also referred to as age-related hearing loss (ARHL), is a multifaceted condition caused by the natural aging process affecting the auditory system. Genome-wide association studies (GWAS) in human populations can identify potential genes linked to ARHL. Despite this, our knowledge of the biochemical and molecular mechanisms behind the condition remains incomplete. This study aims to evaluate a potential protective tool for ARHL treatment by comparing human blood-based target gene-miRNA associations regulated in ARHL. To identify promising target genes for ARHL, we utilized an mRNA assay. To determine the role of miRNA in ARHL, we investigated the expression profile of miRNA in whole blood in ARHL patients with real-time polymerase chain reaction (RT-qPCR). A reporter gene assay was performed to confirm the regulation of candidate genes by microRNA. Through RT-qPCR validation analysis, we finally confirmed the relationship between ARHL and the role of the interferon-gamma (IFNG) gene. This gene can be regarded as an age-related gene. Through gene ontology (GO) analysis, it has been found that these genes are enriched in pathways related to apoptosis. Among them, IFNG induces an inflammatory response, apoptotic cell death, and cellular senescence. We found that miR-409-3p downregulates the expression of the IFNG in vitro. In addition, the downregulation of the IFNG by miRNA 409-3p promoted cell apoptosis and suppressed proliferation. In conclusion, our study produced gene signatures and associated microRNA regulation that could be a protective key for ARHL patients. IFNG genes and miR-409-3p should be investigated for their usefulness as a new biomarker for treatment modality. Full article

Xanthomonas campestris pathovar campestris (Xcc) is a significant phytopathogen causing black rot disease in crucifers. Xcc injects a variety of type III effectors (T3Es) into the host cell to assist infection or propagation. A number of T3Es inhibit plant immunity, but the biochemical basis for a vast majority of them remains unknown. Previous research has revealed that the evolutionarily conserved XopL-family effector XopL_Xcc inhibits plant immunity, although the underlying mechanisms remain incompletely elucidated. In this study, we identified proton pump interactor (PPI1) as a specific virulence target of XopL_Xcc in Arabidopsis. Notably, the C-terminus of PPI1 and the Leucine-rich repeat (LRR) domains of XopL_Xcc are pivotal for facilitating this interaction. Our findings indicate that PPI1 plays a role in the immune response of Arabidopsis to Xcc. These results propose a model in which XopL_Xcc binds to PPI1, disrupting the early defense responses activated in Arabidopsis during Xcc infection and providing valuable insights into potential strategies for regulating plasma membrane (PM) H⁺-ATPase activity during infection. These novel insights enhance our understanding of the pathogenic mechanisms of T3Es and contribute to the development of effective strategies for controlling bacterial diseases. Full article

Background: The cornerstone treatment for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), but many patients exhibit an incomplete response, leading to disease progression. Risk prediction models like the GLOBE and UK-PBC scores hold promise for patient stratification and management. We aimed to independently assess the predictive accuracy of these risk scores for UDCA response in a prospective U.S. cohort. Methods: We conducted a prospective cohort study at a U.S. liver center, monitoring UDCA-treated PBC patients over a one-year follow-up. We evaluated the predictive efficacy of the GLOBE and UK-PBC scores for UDCA treatment response, comparing them to the Paris II criteria. Efficacy was assessed using univariate and multivariate analyses, followed by prognostic performance evaluation via receiver operating characteristic (ROC) curve analysis. Results: We evaluated 136 PBC patients undergoing UDCA therapy. Based on the Paris II criteria, patients were categorized into UDCA full-response and non-response groups. The GLOBE score identified a non-responder rate of 18% (p = 0.205), compared to 20% (p = 0.014) with the Paris II criteria. Multivariate analysis, adjusted for age and biochemical markers, showed that both the GLOBE and UK-PBC scores were strongly associated with treatment response (p < 0.001). The area under the ROC curve was 0.87 (95% CI 0.83−0.95) for the GLOBE score and 0.94 (95% CI 0.86−0.99) for the UK-PBC risk score. Conclusions: Our study demonstrates that GLOBE and UK-PBC scores effectively predict UDCA treatment response in PBC patients. The early identification of patients at risk of an incomplete response could improve treatment strategies and identify patients who may need second-line therapies. Full article

Light is a crucial environmental factor that influences the phenotypic development of plants. Despite extensive studies on the physiological, biochemical, and molecular mechanisms of the impact of light on phenotypes, genetic investigations regarding light-induced transgenerational plasticity in Arabidopsis thaliana remain incomplete. In this study, we used thaliana as the material, then gathered phenotypic data regarding leaf number and plant height under high- and low-light conditions from two generations. In addition to the developed genotype data, a functional mapping model was used to locate a series of significant single-nucleotide polymorphisms (SNPs). Under low-light conditions, a noticeable adaptive change in the phenotype of leaf number in the second generation suggests the presence of transgenerational genetic effects in thaliana under environmental stress. Under different lighting treatments, 33 and 13 significant genes associated with transgenerational inheritance were identified, respectively. These genes are largely involved in signal transduction, technical hormone pathways, light responses, and the regulation of organ development. Notably, genes identified under high-light conditions more significantly influence plant development, whereas those identified under low-light conditions focus more on responding to external environmental stimuli. Full article

Roux-en-Y gastric bypass (RYGB) is a treatment for severe obesity. However, many patients have insufficient total weight loss (TWL) after RYGB. Although multiple factors have been involved, their influence is incompletely known. The aim of this exploratory study was to evaluate the feasibility and reliability of the use of machine learning (ML) techniques to estimate the success in weight loss after RYGP, based on clinical, anthropometric and biochemical data, in order to identify morbidly obese patients with poor weight responses. We retrospectively analyzed 118 patients, who underwent RYGB at the Hospital Clínico Universitario of Valencia (Spain) between 2013 and 2017. We applied a ML approach using local linear embedding (LLE) as a tool for the evaluation and classification of the main parameters in conjunction with evolutionary algorithms for the optimization and adjustment of the parameter model. The variables associated with one-year postoperative %TWL were obstructive sleep apnea, osteoarthritis, insulin treatment, preoperative weight, insulin resistance index, apolipoprotein A, uric acid, complement component 3, and vitamin B12. The model correctly classified 71.4% of subjects with TWL < 30% although 36.4% with TWL ≥ 30% were incorrectly classified as “unsuccessful procedures”. The ML-model processed moderate discriminatory precision in the validation set. Thus, in severe obesity, ML-models can be useful to assist in the selection of patients before bariatric surgery. Full article

Salt stress poses a significant threat to crop yields worldwide. Melatonin (MT), an endogenous hormone synthesized in plants, has emerged as a crucial player in plant responses to various abiotic stresses, including drought, salinity, heat, and cold. However, the precise molecular mechanisms underlying MT-mediated abiotic stress responses remain incompletely understood. To elucidate the key genes and pathways involved in MT-mediated alleviation of salt stress, we conducted physiological, biochemical, and transcriptomic analyses on alfalfa seedlings. Our results demonstrated that alfalfa seedlings treated with melatonin exhibited higher germination rates, longer bud lengths, and greater fresh weights compared to those subjected to salt stress alone. Furthermore, the levels of malondialdehyde (MDA) and superoxide anion (O²⁻) were reduced, while the activities and contents of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and glutathione (GSH) increased in response to melatonin treatment. Transcriptome analysis revealed 2181 differentially expressed genes (DEGs) in the salt-treated group, with 780 upregulated and 1401 downregulated genes. In contrast, the MT-treated group exhibited 4422 DEGs, including 1438 upregulated and 2984 downregulated genes. Functional annotation and pathway enrichment analysis indicated that DEGs were primarily involved in the biosynthesis of flavonoids, isoflavones, plant hormones, glutathione (GSH), soluble sugars, and other substances, as well as in ABC transporter and MAPK signaling pathways. Notably, the MT-treated group showed greater enrichment of DEGs in these pathways, suggesting that MT mitigates salt stress by modulating the expression of genes related to phytohormones and antioxidant capacity. Overall, our findings provide valuable insights into the molecular mechanisms underlying MT-mediated salt tolerance in alfalfa, with important implications for breeding salt-tolerant alfalfa and other crops. Full article

The complexity of macrophage (MΦ) plasticity and polarization states, which include classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) MΦ phenotypes, is becoming increasingly appreciated. Within the M2 MΦ polarization state, M2a, M2b, M2c, and M2d MΦ subcategories have been defined based on their expression of specific cell surface receptors, secreted cytokines, and specialized immune effector functions. The importance of immunometabolic networks in mediating the function and regulation of MΦ immune responses is also being increasingly recognized, although the exact mechanisms and extent of metabolic modulation of MΦ subtype phenotypes and functions remain incompletely understood. In this study, proton (¹H) nuclear magnetic resonance (NMR) metabolomics was employed to determine the polar metabolomes of M2 MΦ subtypes and to investigate the relationship between aqueous metabolite profiles and M2 MΦ functional phenotypes. Results from this study demonstrate that M2a MΦs are most distinct from M2b, M2c, and M2d MΦ subtypes, and that M2b MΦs display several metabolic traits associated with an M1-like MΦ phenotype. The significance of metabolome differences for metabolites implicated in glycolysis, the tricarboxylic acid (TCA) cycle, phospholipid metabolism, and creatine–phosphocreatine cycling is discussed. Altogether, this study provides biochemical insights into the role of metabolism in mediating the specialized effector functions of distinct M2 MΦ subtypes and supports the concept of a continuum of macrophage activation states rather than two well-separated and functionally distinct M1/M2 MΦ classes, as originally proposed within a classical M1/M2 MΦ framework. Full article