Search Results (2,598)

Icariin (ICA), a prenylated flavonoid glycoside from Epimedium (Yin Yang Huo), exhibits multi-organ pharmacological effects and has emerged as a promising candidate for osteoporosis therapy and bone tissue regeneration because of its capacity to modulate diverse osteogenic, anti-inflammatory, and angiogenic signaling pathways. Preclinical studies in osteoporotic models suggest that ICA improves trabecular microarchitecture and increases bone mineral density. Mechanistically, ICA modulates bone remodeling bidirectionally: it promotes osteoblast differentiation and extracellular matrix mineralization via activation of pro-osteogenic pathways, including Wnt/β-catenin and PI3K/Akt signaling, while simultaneously inhibiting osteoclastogenesis and bone resorption by suppressing RANKL-mediated NF-κB activation, thus reestablishing remodeling equilibrium. Despite these benefits, clinical advancement is hindered by the suboptimal oral bioavailability of ICA, stemming from poor intestinal absorption and extensive first-pass metabolism. To address this, innovative delivery systems have been engineered to enhance localized bioavailability and sustain therapeutic efficacy, such as hydrogel depots, nanoparticle formulations, and 3D-printed scaffolds enabling precise, controlled release. In bone tissue engineering applications, ICA-incorporated biomaterials—either standalone or in combination with osteogenic factors or exosomes—foster a regenerative niche by mitigating inflammation and oxidative stress, while synergistically promoting osteogenesis and angiogenesis, thereby expediting bone defect healing and osseointegration. Overall, these mechanistic elucidations and delivery advancements underscore ICA’s potential as a translational candidate for osteoporosis treatment and bone regenerative therapies. This review aims to critically and systematically synthesize current evidence on ICA-mediated bone repair and regeneration, with a particular emphasis on the molecular regulation of osteogenic signaling, the restoration of bone-remodeling homeostasis, and delivery-system-enabled strategies that may facilitate translational application. Full article

Intraoperative fluorescence-guided surgery is an important adjunct to brain tumor resection. However, fluorescent probe performance varies across molecularly and histopathologically distinct entities, including IDH-wildtype glioblastoma, metastatic brain tumors (MBTs), and primary central nervous system lymphoma (PCNSL), and the mechanisms underlying this variability remain poorly understood. We propose a mechanistic framework integrating biomechanical constraints, molecular barrier heterogeneity, and probe-specific pharmacokinetics to explain cross-tumor differences in fluorescence signal. Probe performance is conceptualized through three sequential bottlenecks: extravasation (blood–brain barrier/blood–tumor barrier permeability and transcytosis), interstitial penetration (extracellular matrix density and hydraulic resistance), and retention/clearance (efflux transporters and metabolic processing). An overlying optical layer, including tissue absorption, scattering, and autofluorescence, further modulates the detected signal. Tumor-specific molecular heterogeneity critically shapes these processes. In IDH-wildtype glioblastoma and legacy high-grade glioma cohorts, heterogeneous expression of ATP-binding cassette transporters has been associated with reduced intracellular accumulation of protoporphyrin IX after 5-aminolevulinic acid administration and may contribute to false-negative fluorescence in selected tumor regions. In MBTs, stage-dependent blood–tumor barrier integrity and vascular programs influence probe delivery, whereas in PCNSL, corticosteroid-sensitive restoration of endothelial barrier function may compromise the performance of leakage-dependent tracers. Together, this framework highlights how tumor biology, barrier function, and probe pharmacology jointly shape fluorescence contrast. Rational probe selection informed by tumor-specific transport and barrier constraints may improve intraoperative visualization of brain tumors and optimize surgical decision-making. Full article

(1) Background: Cinnamaldehyde exhibits a broad spectrum of biological activities, and its α,β-unsaturated aldehyde scaffold serves as a versatile platform for the design of hydrazone derivatives with improved pharmacological properties. (2) Methods: In this study, eight cinnamaldehyde-based hydrazones were synthesized via a one-step condensation reaction between cinnamaldehyde and para-substituted acylhydrazides. Prior to synthesis, an in silico assessment of physicochemical, pharmacokinetic, ADME (absorption, distribution, metabolism, elimination), lead-likeness, and drug-likeness properties was conducted using SwissADME, ACD/Labs v. 9.10, and MDL QSAR v2.2.0.0.446 software. Structural characterization by IR, ¹H NMR, ¹³C NMR, and HR ESI–MS confirmed successful formation of the hydrazone linkage. Cytotoxic activity was evaluated using the MTT assay against selected cancer cell lines. (3) Results: All compounds exhibited favorable lead-like characteristics, including suitable molecular weight, moderate lipophilicity, and acceptable predicted ADME profiles. Biological evaluation revealed moderate, structure-dependent antiproliferative activity with clear cell line selectivity. Among the series, compound CA8 showed the most promising profile, displaying the highest cytotoxic activity against T-cell leukemia KE-37 cells (IC₅₀ = 20.3 ± 2.8 μM), comparable to reference drug melphalan (IC₅₀ = 21.40 ± 3.9 μM), and the highest selectivity index (≥19.7). Structure–activity analysis suggests that an amino substituent enhances both potency and selectivity. (4) Conclusions: Overall, these findings identify cinnamaldehyde hydrazones as a promising scaffold for anticancer drug development and provide a strong basis for further structural optimization. Full article

Selenium (Se) is an important micronutrient that is required in very small amounts and plays a significant role in enhancing plant growth, stress resistance, and fruit quality. In this study, we investigated the effects of different sodium selenite concentrations (CK, 0 mg/L; Se1, 0.50 mg/L; Se2, 1.00 mg/L, Se3, 2.00; and Se4, 3.00 mg/L) on the growth, nutrient absorption, antioxidant capacity, and leaf metabolome of blueberry (Vaccinium corymbosum L. ‘Brigitta’) in hydroponic culture. Our results showed that moderate Se concentration (1.00 mg/L, Se2) had noticeable enhancements in key traits like taller plants, thicker stems, a greater number of leaves, and stem fresh weight, with increases of 60.23%, 61.90%, 36.05%, and 87.97%, respectively, compared to the CK. In addition, the appropriate application of Se fertilizer (1.0 mg/L, Se2) can enhance the absorption of macronutrients by plants, with the total contents of nitrogen (N), phosphorus (P), and potassium (K) increasing by 48.11%, 15.85%, and 14.25%, respectively, compared to CK. In comparison to CK, the content and accumulation of total Se rose dramatically under the Se4 treatment, showing increases of 2300% and 2514%. The contents of chlorophyll and antioxidant enzyme activities were maximized at Se2, while excessive Se (Se4) led to oxidative damage, as indicated by elevated MDA, H₂O₂, and O₂⁻ levels. Moreover, metabolomic analysis revealed that moderate Se concentration (Se2) significantly altered metabolic pathways related to aminoacyl-tRNA biosynthesis, arachidonic acid metabolism, and ABC transporters, with downregulation of key metabolites in sugar and organic acid metabolism (e.g., α-D-glucose-6-phosphate, L-lactic acid, maleic acid). In contrast, high Se concentration (Se4) disrupted these pathways and promoted volatile compound accumulation. These findings demonstrate that moderate Se application enhances blueberry growth and quality by regulating nutrient uptake, antioxidant defense, and primary metabolism, whereas excessive Se induces metabolic imbalance and oxidative stress. Overall, moderate Se fertilizer (1.00 mg/L) can significantly enhance the growth and quality of blueberries, while excessive selenium may have adverse effects. Full article

Metabolic changes in saliva are known to be closely associated with the presence of non-oral cancers, particularly breast cancer. The diagnostic and prognostic potential of salivary biomarkers in breast cancer has been demonstrated, but their applicability for assessing therapy response has not yet been established. The aim of this study was to comprehensively analyze clinical, pathological, molecular, and salivary characteristics when assessing the response to neoadjuvant chemotherapy for breast cancer. The study included 361 breast cancer patients undergoing their first course of chemotherapy and 127 healthy volunteers without breast pathologies. Saliva samples were collected from all volunteers before treatment. Saliva analysis results for amino acids, lipids, and tumor markers were compared with tumor pathomorphism assessment after breast cancer surgery. The proportion of patients with a complete response to therapy was statistically significantly lower after menopause, and in those with HER2-negative breast cancer, moderate tumor differentiation, and high estrogen and progesterone receptor expression. For the first time, a body mass index (BMI) greater than 25 and low HER2 expression (HER2-low) were shown to have an unfavorable prognosis. The criterion for selecting informative salivary metabolites was a multidirectional change in minimal and complete pathological responses to therapy compared to healthy controls. Thus, prognostically favorable signs were a decrease in the concentration of urea below 7.5 mmol/L (OR = 1.921; 95% CI 1.061–4.270; p = 0.0342), a decrease in the area of the absorption band at 2957 cm⁻¹ below 24 (OR = 3.875; 95% CI 1.160–12.70; p = 0.0003), and an increase in the concentration of cancer antigen CA27.29 above 3 U/L (OR = 2.138; 95% CI 1.021–7.273; p = 0.0343) and CA-15-3 above 39 U/L (OR = 3.896; 95% CI 1.062–14.07; p = 0.0072). With a simultaneous increase in both CA27.29 and CA15-3, the probability of a complete response to therapy increased (OR = 4.288; 95% CI 1.056–17.09; p = 0.0013). Multivariate analysis showed that an independent prognostic indicator, along with the expression status of HER2, estrogen receptors, differentiation degree, BMI, and menopause status, was the concentration of CA15-3 in saliva (AUC = 0.789, 95% CI: 0.737–0.842, p = 0.0001). Identifying new markers will help physicians formulate treatment plans tailored to a patient’s individual risk factors, leading to increased survival and improved quality of life. Full article

Background: To investigate the effect of angiotensin-(1-7) [Ang-(1-7)] on serum metabolomics in obese type 2 diabetic (T2DM) mice. Methods: Four-week-old male C57BL/6 mice were fed a high-fat diet and intraperitoneally injected with streptozotocin (35 mg/kg) to establish an obese T2DM model. Mice were randomized into control, T2DM and T2DM+Ang-(1-7) groups (n = 6). Body weight and blood glucose were recorded weekly. At 10 weeks, blood glucose, serum inflammatory factors, lipid profiles, and pancreatic β-cell insulin secretion were detected; serum metabolite alterations were analyzed via untargeted metabolomics. Results: 1. Ang-(1-7) intervention decreased blood glucose (p < 0.05) and CRP levels (p < 0.01), and alleviated dyslipidemia (p < 0.05 or p < 0.01), as well as β-cell morphology and insulin expression in obese T2DM mice. 2. Non-targeted metabolomics analysis suggested that Ang-(1-7) may alleviate abnormal amino acid metabolic pathways by regulating levels of metabolites such as L-valine, L-proline, L-histidine, and glutamic acid. This intervention also tended to reduce multiple lipid metabolites, including Omega-3 Arachidonic Acid Ethyl Ester, phosphatidylcholine, and glycerophosphocholine, thereby participating in the modulation of lipid metabolism balance. KEGG enrichment analysis further indicated that Ang-(1-7) was involved in the regulation of protein digestion and the absorption pathway, as well as the HIF-1 signaling pathway related to oxidative stress, bile acid metabolism pathway, and other signaling pathways, and improving the insulin secretion pathway, pyrimidine metabolism, and TCA cycle energy metabolism pathway. Conclusions: Ang-(1-7) may partially improve metabolic disturbances in obese T2DM mice, which is potentially associated with the modulation of multiple metabolic processes, including amino acid metabolism, lipid metabolism, insulin secretion, and TCA cycle energy metabolism. Full article

Boswellic acids (BAs), the major bioactive constituents of Boswellia serrata oleo–gum resin, exhibit well-documented anti-inflammatory and antioxidant activities, which correspond to their healing effects in arthritis, inflammatory bowel disease, asthma, metabolic syndrome, liver disorders, and certain cancers. However, their therapeutic potential is hindered by their poor aqueous solubility, low intestinal absorption, extensive metabolism, and overall low oral bioavailability. This review provides a comprehensive analysis of conventional Boswellia serrata products and advanced drug delivery systems designed to enhance the biological performance of BAs. We summarize recent developments in formulation strategies, including phytosomes, micelles, self-emulsifying drug delivery systems, solid lipid particles, polymeric nanoparticles, hydrogels, cyclodextrin complexes, metal-based nanocarriers, and hybrid delivery platforms. Available in vivo and cellular studies are critically evaluated, with a focus on disease-specific outcomes. Results indicate that emerging formulation technologies significantly increase the oral absorption, systemic exposure, and biological effectiveness of BAs. However, despite promising preclinical data, challenges remain regarding the standardization of Boswellia extracts, the stability of novel formulations, their safety, and limited clinical evaluation. By comparing the advantages and limitations of conventional preparations with modern drug delivery systems, this review outlines the most effective strategies to enhance the bioavailability of BAs and highlights future research directions for their translational development. Full article

This study evaluated the effects of two silicon sources (silicic acid and Agrisil) and increasing Si concentrations on physiological responses, total polyphenol content, photochemical performance, nutrient uptake, and phenolic metabolism in sour passion fruit (Passiflora edulis Sims) grown under soilless culture conditions. The experiment was conducted in a greenhouse using increasing concentrations of Si applied through the nutrient solution. Gas exchange parameters, chlorophyll index (SPAD), chlorophyll fluorescence variables, leaf temperature, and the contents of Si, nitrogen, and total polyphenols in leaves and roots were evaluated. Moderate Si concentrations enhanced stomatal conductance and transpiration, improving intrinsic water use efficiency, and maintaining higher chlorophyll levels and photochemical performance. In contrast, higher Si concentrations increased Si deposition in leaf tissues, reduced stomatal regulation and transpiration, and increased leaf temperature. These changes were associated with reductions in chlorophyll index and photochemical performance index (PI), as well as increased F₀/Fm. Net CO₂ assimilation remained relatively stable. Silicon uptake differed between sources, with silicic acid showing faster absorption and Agrisil a more gradual release. Silicon fertilization also increased nitrogen uptake and stimulated the accumulation of phenolic compounds in roots. Overall, moderate silicon supplies enhanced physiological stability, whereas excessive accumulation imposed photochemical constraints. Full article

Background/Objectives: Early childhood caries (ECC) remains a major public health concern, with Streptococcus mutans as a primary etiological agent. Current treatments rely on broad-spectrum antimicrobials, which can disrupt the oral microbiome and promote resistance. This study applied a structure-based in silico pipeline to identify molecule modulators of Toll-like receptor 2 (TLR2), a key host receptor implicated in ECC, and to explore their binding potential against major S. mutans proteins. Methods: ECC-related genes were collected from public databases and analyzed by functional enrichment and protein–protein interaction (PPI) network analysis. Hub genes were ranked using centrality algorithms. Virtual screening on TLR2 (DrugCLIP) was followed by molecular docking of selected compounds against the TLR1/TLR2 heterodimer and 50 S. mutans proteins, complemented by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Results: Fifty-four ECC-related genes and nine hub genes were identified, with TLR2 and cathelicidin antimicrobial peptide (CAMP) as central nodes. Virtual screening yielded five lead compounds fulfilling drug-likeness and toxicity criteria. Docking to TLR1/TLR2 showed favorable binding energies, with Z7684613096 showing the most consistent binding. V026-2549 displayed the highest number of strong interactions with S. mutans targets, including dTDP-glucose 4,6-dehydratase (rmlB), NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (gapN), glucosyltransferase C (gtfC), and 5-methyltetrahydropteroyltriglutamate-homocysteine methyltransferase (metE). Conclusions: Five candidate compounds with promising dual activity against TLR1/TLR2 and S. mutans proteins were prioritized for experimental validation, including TLR2 functional assays and in vitro anti-biofilm studies. Full article

Background/Objectives: Genetic generalized epilepsies (GGE) often remit in childhood, yet a subset of adults remain pharmacoresistant with substantial morbidity. The genetic basis of adult pharmacoresistant GGE is poorly defined. This descriptive study used whole-genome sequencing (WGS) to identify recurrent coding variants and pathways associated with pharmacoresistant adult GGE. Methods: WGS was performed in ten racially diverse adults (mean age 37.2 years; range 20–52) with electroencephalographically confirmed, pharmacoresistant GGE (mean onset 13.7 years). Analysis prioritized variants present in at least 80% of participants and which were either (i) missense variants predicted deleterious with ANNOVAR or (ii) loss-of-function variants predicted high-impact from snpEff. Pathway enrichment and overlap with a commercial clinical epilepsy gene panel were assessed. Results: Filtering identified 133 unique, deleterious coding variants across 69 genes shared by at least eight participants. Four genes (APOL4, KMT2C, SON, VDR) overlapped a clinical epilepsy panel, supporting the capacity of WGS to recover clinically relevant loci. Prioritized loci implicated gastrointestinal and metabolic regulators (e.g., MUC6, PNLIPRP2), chemosensory receptors (OR10D3, OR8U1, TAS2R19), neuroimmune mediators (LILRA2, SIGLEC12, OAS2), and ion transporters (KCNJ12, P2RX5, RHBG), consistent with multifactorial mechanisms of pharmacoresistance. Conclusions: This exploratory WGS study focused exclusively on adults with pharmacoresistant GGE, revealing shared high-impact variants and convergent pathways spanning absorption/metabolism, vitamin D signaling, immunity, and ion transport. Findings broaden the genetic landscape of pharmacoresistant GGE while motivating validation in larger, multiethnic cohorts. Full article

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O exposure. Method: In this study, we investigated the effects of chronic N₂O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N₂O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites. Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism. Conclusions: Our data indicate that chronic N₂O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B₁₂, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N₂O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N₂O exposure. Full article

The gut microbiota, often referred to as the “forgotten organ”, plays an indispensable role in maintaining host physiological metabolism, immune function, and nutrient absorption. Moreover, the gut microbiome serves as a critical biological barrier against viral infections and is increasingly recognized as a potential target to augment antiviral therapies. Recent studies have revealed that microbial ligands and metabolites derived from the gut microbiota are pivotal in modulating respiratory immune responses, providing compelling evidence of the complex interaction network between microorganisms and the host, particularly the signaling pathways linking the gut to distal organs such as the lungs. This review examines the communication and regulatory mechanisms between the gut microbiota and pulmonary mucosal surfaces during influenza virus infection, emphasizing how gut microbial communities and probiotics influence host immune responses, promote the production of immune-related molecules, and enhance antiviral defenses. The aim is to provide comprehensive insights into the gut–lung axis and its implications for respiratory health. Full article

Brown seaweeds are recognized for their rich content of phlorotannins with promising antidiabetic properties through multi-targeted modulation of glucose metabolism. This study investigated the antidiabetic potential of the ethyl acetate fraction of Ecklonia cava (EC-ETAC) and its major phlorotannin, dieckol, focusing on inhibition of carbohydrate-digesting enzymes, intestinal glucose absorption, dipeptidyl peptidase-IV (DPP-IV) activity, and hepatic glucose metabolism. EC-ETAC potently inhibited α-glucosidase (IC₅₀ = 2.2 ± 0.2 µg/mL) and α-amylase (IC₅₀ = 41.0 ± 1.2 µg/mL), outperforming acarbose by 26-fold and 6-fold, respectively. Pure dieckol showed strong activity with IC₅₀ values of 2.213 ± 0.04 µM (α-glucosidase) and 156.87 ± 0.124 µM (α-amylase). In differentiated Caco-2 cells, both EC-ETAC and dieckol downregulated SGLT1 and GLUT2 protein expression to ~0.5-fold of control and suppressed 2-NBDG glucose uptake by 46–53% over 120 min, effects not seen with acarbose. Dieckol inhibited DPP-IV activity (IC₅₀ = 12.12 ± 0.021 µM), reducing in situ activity to 53.89% at 25 µM without changing DPP-IV protein levels. Molecular docking revealed high-affinity binding of dieckol to DPP-IV (−10.396 kcal/mol), directly occluding the catalytic triad (Ser630, His740). In insulin-resistant HepG2 cells, dieckol restored glucose uptake to 108.97% of control via AMPK activation (1.21-fold), GLUT2 normalization (0.84-fold), and PGC-1α recalibration (0.96-fold), matching or surpassing 1 mM metformin. These results demonstrate dual-inhibition mechanism combined with hepatic AMPK restoration, establishing dieckol as a promising marine-derived multi-targeted agent for T2DM management. Full article

Glycerophosphocholine (GPC) is a well-known choline-containing compound commonly found in nature and has demonstrated potential therapeutic effects in aging-related conditions, such as neurodegenerative disorders, skeletal muscle performance, and eye disorders. Despite being widely used as a supplement, the mechanism by which GPC is absorbed and metabolized in the digestive system remains elusive. Furthermore, growing evidence suggests that high intake of choline-containing compounds, including GPC, is linked with trimethylamine N-oxide (TMAO) production, a metabolite associated with atherosclerosis progression. However, there has been an inconsistency that is not commonly discussed, and thus, the adverse effect of TMAO remains debatable. These warrant a better understanding of the physiological significance and metabolism of GPC in the body and how it is linked to TMAO and its potential risk. Through a comprehensive literature search, this narrative review aims to fill these gaps by providing a summary of the physiological significance and supplementation evidence of GPC. Further, the review also highlights the absorption mechanisms and relationship of GPC with intestinal microbiota and its relationship with TMAO production. Lastly, this review addresses and discusses the challenge of GPC supplementation and provides a brief view on future perspectives on GPC as a bioactive compound. Full article

The hybrid sturgeon (HS, Acipenser baerii Brandt ♀ × A. schrenckii Brandt ♂) was compared with its parental varieties (Siberian sturgeon (SS) and Amur sturgeon (AS)) to evaluate muscle quality differences. Three sturgeon species were bred from the same batch, reared under identical conditions until three years of age, and then male fish from each species (AS, 3.2 ± 0.18 kg; SS, 2.5 ± 0.14 kg; HS, 3.5 ± 0.21 kg) were sampled for analysis of muscle nutritional composition, texture, microstructure, and metabolomics. Results showed no significant differences in proximate composition, hydrolyzed amino acids, pH, or water-holding capacity among the three groups. However, HS exhibited higher gumminess and chewiness than both parent species, as well as greater hardness and springiness compared with the SS. Muscle fiber density was higher in HS than in the AS, but no significant difference was observed between HS and SS. Levels of free amino acids (Val, Ile, Ala) were lower in HS than in AS. In terms of fatty acid profiles, HS showed elevated polyunsaturated fatty acids compared with SS, resembling the pattern observed in AS. Muscle color of HS was similar to that of SS, whereas its a* value differed from those of AS. Metabolomics identified differential metabolites (GABA, D-glucosaminic acid, AP4) enriched in pathways such as ABC transporters, protein digestion and absorption, and amino acid metabolism. Overall, HS combines improved texture traits with meat quality attributes resembling SS (muscle color, free amino acids) and AS (polyunsaturated fatty acids). These characteristics suggest that HS possesses a distinctive combination of meat quality traits. Full article