Search Results (512)

Curcuminoids from Curcuma longa L. (curcumin, demethoxycurcumin, bisdemethoxycurcumin) are attractive bioactives yet constrained by low water solubility and chemical instability. Herein, we introduce a Supramolecular Deep Eutectic Solvent (SupraDES) as a “Janus” green platform, combining extraction and stabilization with a subsequent solvent-to-material strategy. Eight NaDES/SupraDES formulations based on choline chloride (ChCl) or betaine with glycerol (Gly) or citric acid (CitA), with/without β-cyclodextrin (βCD), were assessed. The extinction coefficients of the most promising solvents were extrapolated at 425 nm for the UV–vis quantification of curcuminoids, to determine extraction performance. The SupraDES ChCl:Gly:βCD gave the best performance during the first solvent screening, improving at the same time the bioactive stability (after 30-day, 47.5% loss vs. 62.8% of ChCl:Gly alone). Subsequent microwave-assisted extraction (MAE) optimization identified 80 °C as the optimal process temperature, with near-equilibrium reached within 15 min (3139.4 µgCurc/gEXT). Peleg modelling (R² = 0.997) indicated a fast extraction rate and limited benefit from longer residence times. Finally, the curcuminoid-loaded SupraDES was incorporated into polyvinyl alcohol (PVA) networks crosslinked with CitA and 2,5-bis(hydroxymethyl)furan (BHMF); thermal analysis confirmed the formation of a stable crosslinked structure. To the best of our knowledge, this is the first report of a βCD-based SupraDES acting as a Janus platform that couples supramolecular extraction of lipophilic bioactives with their direct incorporation into bio-based polymeric materials, exemplifying an integrated green chemistry approach aligned with circular bioeconomy principles. Full article

Background/Objectives: Mucinous adenocarcinoma (MAC) is a rare and clinically problematic subtype of rectal cancer, tending to present at an advanced stage and to respond poorly to neoadjuvant therapy. The consistently worse prognosis than that of not-otherwise-specified adenocarcinoma (NOS-AC) is not fully understood, potentially owing to intrinsically more aggressive biology or specific immune evasion mechanisms. We used the IMMUNOREACT multicentre cohort, with external validation in TCGA, to investigate the clinical and immunological features of rectal MAC in detail. Methods: Two hundred patients with rectal adenocarcinoma (16 MAC, 184 NOS-AC) from the IMMUNOREACT 1 (NCT04915326) and IMMUNOREACT 2 (NCT04917263) prospective cohorts were included. To account for the imbalance in baseline characteristics, propensity score matching (PSM) was performed on age, sex, neoadjuvant treatment and TNM stage. The immune microenvironment was characterised using immunohistochemistry (CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, PMS2, CD80), flow cytometry and NanoString PanCancer IO 360™ transcriptomics of adjacent healthy mucosa. Findings were externally validated against TCGA rectal and colon adenocarcinoma datasets. Results: MAC presented at significantly more advanced stage than NOS-AC across all TNM parameters: higher T stage (p = 0.006), N stage (p < 0.001), M stage (p = 0.039) and overall TNM stage (p < 0.001). In the unmatched cohort, MAC was associated with worse overall survival (HR 2.53; 95% CI 1.03–6.23; p = 0.043) and disease-free survival (HR 2.86; 95% CI 1.25–6.55; p = 0.013), but both differences became non-significant after PSM. MAC patients had higher haemoglobin after adjusting for confounders (mean difference [MD] 1.26 g/dL, 95% CI 0.30–2.31, p = 0.012), consistent with a hypothesis of reduced chronic rectal bleeding as a possible mechanism for late presentation. Transcriptomically, MAC showed suppression of HLA class II antigen presentation genes (HLA-DQA1, HLA-DQB1, HLA-DRB1) and myeloid activation genes (S100A8/A9/A12) in adjacent healthy mucosa. Loss of MMR proteins MSH6 and PMS2 in histologically normal mucosa was significantly more frequent in MAC. These findings were replicated in the TCGA cohort, which also showed lower tumour mutational burden and a distinct mucin-associated transcriptomic profile in MAC. Conclusions: The worse outcomes of rectal MAC appear to be driven largely by late-stage presentation, possibly owing to later diagnosis. MAC nonetheless carries a distinct immune phenotype, detectable even in histologically normal surrounding mucosa, that likely contributes to its treatment resistance. These observations provide a basis for developing histotype-specific approaches to both early detection and treatment in this uncommon but clinically challenging tumour subtype. Full article

Expansin-like A (EXLA) proteins belong to one of the four main families within the expansin superfamily, a group of plant proteins essential for cell wall loosening. Here, we report, for the first time, the purification of a novel EXLA, named cpEXLA, from canihua seeds. cpEXLA (yield ~0.16 mg per 100 g of seeds) is a 29 kDa glycoprotein with a high melting temperature (Tm of 86.75 ± 1.06 °C). Elucidation of its primary structure reveals that the mature protein consists of 246 amino acids, ten of which are cysteine residues forming five disulphide bridges. Structural studies based on 3D model prediction reveal the presence of N- and C-terminal domains, which are typical of EXLAs and rich in β-sheets, as confirmed by circular dichroism (CD) spectroscopy. Furthermore, comparative analysis of amino acid sequences between cpEXLA and 219 similar EXLAs, retrieved from dicotyledonous genomes and transcriptomes, identified eighteen invariant amino acid residues: eleven in the N-terminal domain and seven in the C-terminal domain. Finally, phylogenetic analysis of EXLAs in dicotyledonous species shows a close relationship with other EXLAs from the Amaranthaceae family, confirming that EXLA proteins are highly conserved among dicotyledonous plants. Overall, cpEXLA represents an intriguing native tool for studying cell wall evolution and the functional role of EXLAs. Full article

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy. Full article

Background and Objectives: Early progression (PFS < 90 days) in NSCLC patients undergoing ICI treatment constitutes a significant clinical challenge. Although predictive biomarkers have been extensively investigated, specific transcriptomic and immune microenvironment characteristics contributing to early progression remain inadequately characterized. Materials and Methods: We analyzed RNA-seq data from 27 NSCLC patients receiving anti-PD-1/PD-L1 therapy (GSE135222). Patients were categorized as Early Progression (PFS < 90 days; n = 17) or Clinical Benefit (PFS ≥ 90 days; n = 10). GSEA was performed with Hallmark and C7 ImmuneSigDB gene sets. Immune cell deconvolution was performed using EPIC. An 87-gene immunosuppressive risk score was derived from TGF-β, WNT/β-catenin, and EMT pathway leading-edge genes. Results: GSEA identified 17 significantly enriched Hallmark pathways in early progressors, predominantly immunosuppressive (TGF-β, WNT/β-catenin) and oncogenic (MYC targets, E2F targets, G2M checkpoint) programs. C7 ImmuneSigDB analysis revealed 131 enriched immune signatures including CD8 T cell dysfunction, Treg activation, and M2 macrophage polarization. An 87-gene immunosuppressive risk score demonstrated a significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006) and a trend toward poorer survival outcomes (HR = 2.12, p = 0.093). Conclusions: In NSCLC patients receiving ICI, early disease progression is marked by simultaneous activation of TGF-β/WNT-mediated immunosuppressive pathways, oncogenic signaling, and CD8 T cell dysfunction. The 87-gene immunosuppressive risk score demonstrates a statistically significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006); however, given the small sample size (n = 27) and absence of external validation, these findings should be interpreted as exploratory and hypothesis-generating, warranting prospective validation in independent cohorts. Full article

Myocardial infarction (MI) triggers excessive oxidative stress, a detrimental immune response, and insufficient angiogenesis, which collectively impede effective cardiac repair. This study developed a multifunctional composite polysaccharide hydrogel, termed KgXd^gel, based on konjac glucomannan (KGM) and xanthan gum (XG) functionalized with gallic acid (GA) and dopamine (DA), respectively, to integrate reactive oxygen species (ROS) scavenging, macrophage polarization, and pro-angiogenic activities. In vitro assays demonstrated that the KgXd^gel hydrogel exhibited excellent cytocompatibility, effectively scavenged ROS, promoted the polarization of macrophages towards the reparative M2 phenotype, and enhanced the migration and tube formation of human umbilical vein endothelial cells. In a rat MI model, treatment with KgXd^gel significantly improved cardiac function (e.g., left ventricular ejection fraction, LVEF; left ventricular fractional shortening, LVFS), attenuated left ventricular dilation (LVIDs), and favorably modulated the post-infarction microenvironment. This was evidenced by the upregulation of the M2 marker CD163 and the angiogenic factor VEGF, alongside the downregulation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and the M1 marker iNOS. These findings conclusively demonstrate that the KgXd^gel hydrogel synergistically promotes cardiac repair post-MI through its integrated antioxidant, immunomodulatory, and pro-angiogenic functions, presenting a promising multi-targeted therapeutic strategy. Full article

This study evaluates β-cyclodextrin (β-CD) and malonic acid functionalized pine sawdust biochar for organic pollutant removal, benchmarking efficacy against commercial Norit GSX activated carbon for sustainable water treatment. Characterization revealed that β-CD modification successfully developed porous structures, with Sawdust Activated Carbon (SDAC) and Norit GSX Activated Carbon (GSXAC) achieving Brunauer–Emmett–Teller (BET) surface areas of 438.36 m²/g and 1223.79 m²/g, respectively. Adsorption kinetics and isotherm studies demonstrated the superiority of β-CD-modified materials over traditional acid-functionalized variants. The adsorption kinetics were exceptionally well-described by the Pseudo-Second-Order model R² > 0.99, indicating that the process is governed by chemical interactions rather than simple physical attachment. In contrast, the Pseudo-First-Order and Elovich models provided poor descriptions of the system (R² = 0.54 and 0.11, respectively). An isotherm analysis further confirmed the heterogeneous nature of the SDAC surface, with the Freundlich model exhibiting an excellent fit (R² > 0.99) and an n value of 0.79. For GSXAC, the Freundlich model also outperformed the Langmuir model, yielding a K_F of 441.72 mg/g and n = 0.77, reflecting high adsorption intensity on a heterogeneous surface. The comparative advantage of β-CD is in line with its unique truncated cone structure, which is consistent with guest–host inclusion complex formation, multi-modal hydrogen bonding, and enhanced pH resilience. These findings validate β-CD-modified sawdust-derived adsorbents as potential, sustainable, high-capacity alternatives to industrial-grade carbons. Full article

Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet because of its presence in nearly all food types, including potatoes, vegetables, cereals, grains, legumes, shellfish, and organ meat. Cd has no physiological role or nutritional value in the body and causes toxicity to multiple tissues and organs via oxidative stress and chronic inflammation; as such, at high prevalence, it is frequently associated with diseases, notably cancer, heart disease, diabetes, osteoporosis, and chronic kidney disease. Using kidneys and bones as critical toxicity targets, current dietary Cd exposure guidelines vary from 0.21 to 0.83 μg/kg b.w./d. There is a widespread concern about these guidelines because they were based on the excretion of β₂-microglobulin (β₂M) at a rate of 300 µg/g of creatinine as an endpoint. Concerningly, rice is a staple food for over 50% of the world’s population; however, the permissible Cd level in this commodity has not been adequately addressed. This narrative review focuses on critiquing existing food standards and exposure guidelines for Cd. It discusses the threshold-based risk assessment that was used to define the no-observed-adverse-effect level (NOAEL) for Cd, when β₂M excretion was used with Cd excretion at a rate of 5.24 µg/g of creatinine being a threshold. The estimated glomerular filtration rate (eGFR) is recommended as an appropriate kidney disease endpoint. The current view around how Cd uses various transport proteins to enter and induce toxicity to its target cells are summarized. The strategies to minimize Cd accumulation and mitigate its nephrotoxicity are highlighted. Full article

Background: High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68⁺ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68⁺ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. Methods: Immunohistochemistry scoring of Regnase-1 and CD68⁺ TAMs was performed in 91 patients. Overall survival (OS) was assessed by Kaplan–Meier and Cox regression, and findings were validated in an independent “The Cancer Genome Atlas” Sarcoma (TCGA-SARC) cohort (n = 212). Results: In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate hazard ratio (HR) = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68⁺ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1–3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. Regnase-1-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. Conclusions: Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy. Full article

Oncomodulin (OCM) is the most abundant Ca²⁺ buffering protein found in mature outer hair cells (OHCs). Cadherin 23 (CDH23) is a crucial component of the tip-links in hair cell stereocilia. The absence or dysfunction of these two proteins contributes to the early onset of age-related hearing loss (AHL). In this study, we investigated the effects of the Cdh23^753G→A mutation on OHC function using new Ocm-knockout (KO) mouse models (Ocm^tm1a/tm1a) with or without the Cdh23^753G→A mutation. Despite having the same genetic background, Ocm-KO mice carrying the Cdh23^753G→A mutation displayed a notable decline in OHC function across all measured frequencies as early as three months of age. In contrast, Ocm-KO mice without the Cdh23^753G→A mutation did not exhibit comparable hearing loss until they reached twelve months of age. Additionally, we examined the role of OCM in preserving OHC function under ototoxic stress induced by HPβCD (2-hydroxypropyl-β-cyclodextrin). The distortion product otoacoustic emission data show that the administration of HPβCD resulted in a more pronounced decline in OHC function in Ocm-KO mice compared to wild-type (WT) mice. Time-lapse recording also shows that HPβCD treatment led to greater structural deterioration and more rapid rupture events in OHCs from Ocm-KO mice than in those from WT mice. These findings suggest that the Cdh23^753G→A mutation, rather than other potential strain-specific genetic factors associated with AHL, significantly exacerbates the early onset of AHL phenotypes in Ocm-KO mice. Furthermore, our data indicates that the OCM protein in OHCs enhances their ability to withstand ototoxic stimuli. Full article

In this study, we prepare N–doped biochar loaded with β-CD, using cotton stalks as a carbon source, and evaluate its removal efficiency for tetracycline (TC) and methylene blue (MB) from aqueous solutions. This composite uniquely integrates molten salt activation, nitrogen doping, and β-CD grafting, resulting in an exceptionally high specific surface area of 1943 m²/g and abundant active sites. The findings reveal that β-CD-NKBC-1.5 (5 g of N–doped biochar loaded with 1.5 g of β-CD) demonstrates remarkable capabilities for both TC and MB removal across an extensive pH spectrum, reaching peak adsorption levels of 1269.8 and 969.4 mg/g at 308.15 K, respectively—outperforming most previously reported biochar-based adsorbents. The adsorption process is well described by the pseudo-second-order and Langmuir models, indicating that monolayer chemisorption is the dominant mechanism. β-CD-NKBC-1.5 exhibits preferential adsorption for TC and MB and maintains high adsorption efficiency even with coexisting ions (Na⁺, K⁺, Ca²⁺, Mg²⁺, and SO₄²⁻) at concentrations up to 500 mg/L. The adsorption mechanism involves Lewis acid–base interactions, hydrogen bonding, π–π stacking, and pore filling. Full article

Objectives: This study aimed to investigated the role of Giardia extracellular vesicles (EVs) in intercellular communication and to evaluated their potential as vaccine candidates. Methods: The immunomodulatory effects of Giardia EVs were assessed in mouse macrophages and human monocyte-derived dendritic cells (Mo-DCs), with a particular focus on key inflammatory signaling pathways. In vivo immunogenicity was evaluated following EV administration, and the antigenic composition of EV cargo was characterized by proteomic analysis. Results: Giardia EVs activated pro-inflammatory signaling pathways in mouse macrphages, including SAPK/JNK, ERK1/2, and NF-κB. This activation was associated with IκB-α degradation and nuclear translocation of p65. Furthermore, EV stimulation significantly upregulated the expression of pro-inflammatory genes, including Il1β, Il6, Il4, Ptgs2, Nos2, and Tnf, with log₂ fold changes ranging from 3.9 to 15.8. Consistently, EVs increased iNOS protein expression (28–45%) and nitrite production (9.6–12.3-fold). In human Mo-DCs, Giardia EVs promoted cellular maturation, as evidenced by increased expression of MHC-II, CD80, and CD86, and enhanced T-cell proliferation with a Th1-skewed profile. In vivo immunization induced antigen-specific antibody responses, with IgG subclass distribution indicative of a balanced Th1/Th2 response. Proteomic analysis identified immunoreactive EV-associated proteins, including elongation factor 1-alpha, α-7.3 giardin, tubulin, and variant surface proteins (VSPs), which are well-established antigens in Giardia infection, with prominent bands observed at approximately 22 kDa and 50 kDa. Conclusions: Collectively, these findings demonstrate that Giardia EVs modulate innate immune responses in vitro, elicit antigen-specific humoral immunity in vivo, and contain conserved immunogenic proteins. These properties support their potential as a promising cell-free vaccine platform against giardiasis. Full article

Background: CD8A-related CD8α deficiency (Immunodeficiency 116) is a rare autosomal recessive primary immunodeficiency disease characterized by absent CD8⁺ T cells and variable sinopulmonary disease. Case Presentation: A seven-year-old boy from a consanguineous family was referred for chronic wet cough and “uncontrolled asthma” despite being prescribed high-dose inhaled corticosteroids and montelukast. He was hospitalized seven times over a two-year period for presumed asthma exacerbations complicated by pneumonia. An examination revealed bilateral crackles without wheezing. Throat culture tested positive for Haemophilus influenzae. CT imaging showed signs of chronic rhinosinusitis (maxillary mucosal thickening) and chronic airway disease with bronchiectatic changes. The patient’s immunoglobulin levels were within normal ranges for his age group. Flow cytometry revealed profound CD8⁺ T-cell lymphopenia (CD8⁺ 0.21%; 11 cells/µL; near-absent after excluding dual-positive cells) with expansion of CD3⁺CD4⁻CD8⁻ T cells (29.5%). CD8A gene sequencing identified a novel homozygous nonsense variant NM_001768.7:c.319C>T (p.Arg107Ter; GRCh38: chr2:86790412G>A), consistent with loss of CD8α and secondary loss of CD8β surface expression. A literature review identified three previously reported symptomatic patients (and two asymptomatic sisters in the first family), all with recurrent respiratory infections and variable structural lung disease. Conclusions: This case highlights CD8A deficiency as a rare mimic of pediatric asthma and expands the genotype spectrum with a truncating CD8A variant. Early lymphocyte immunophenotyping in children with recurrent sinopulmonary infections may prevent delayed diagnosis and progressive airway damage. Full article

Immunosenescence is characterized by an age-associated decline in immune function, particularly involving T-cell dysfunction, which increases susceptibility to infections and chronic diseases. This study investigated the anti-aging and immunomodulatory effects of American ginseng extract (G1899) using in vitro and in vivo models of aging. Cellular senescence was induced in HepG2 cells by D-galactose treatment, followed by exposure to G1899 (20 and 100 μg/mL). Senescence-associated markers were assessed to evaluate cellular aging. An aging mouse model was established in male C57BL/6 mice through intraperitoneal administration of D-galactose (500 mg/kg) and tert-butyl hydroperoxide (0.4 mmol/kg), and G1899 was orally administered at 400 mg/kg. Thymic immune cell subsets and aging-related protein expression were analyzed using flow cytometry and Western blotting. G1899 significantly reduced p21 expression and senescence-associated β-galactosidase activity in senescent HepG2 cells. In aging-induced mice, G1899 restored CD4⁺ and CD8⁺ T-cell populations, normalized naïve T-cell levels, and reduced anergic CD28-negative T cells. Furthermore, G1899 regulated the expression of key aging-related proteins, including FOXO1, Sirt1, p53, and CD38. These findings demonstrate that G1899 attenuates age-related immune alterations by restoring thymic T-cell homeostasis and regulating aging-associated molecular pathways. Full article

Antrodia cinnamomea is a rare medicinal and edible macrofungus, and its triterpenoids (ACT, A. cinnamomea triterpenoids) exhibit notable hepatoprotective, antioxidant, anticancer, and immunomodulatory activities. However, their poor aqueous solubility and low dispersibility in aqueous media have limited their practical applications. In this study, the conditions for ultrasonic treatment and xylo-oligosaccharide (XOS)-mediated glycation for soy protein isolate (SPI) were optimized; ACT was then encapsulated into the modified SPI carrier to prepare XOS-SPI-ACT nanoparticles. The delivery system was systematically characterized in terms of encapsulation efficiency (74.22 ± 2.15)%, drug-loading capacity (71.19 ± 4.67)%, storage stability, thermal stability, Fourier transform infrared (FTIR) spectroscopy, UV fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and surface morphological features. The results showed that ACT was effectively embedded in XOS-SPI to form a stable complex with excellent thermal stability and favorable storage stability over a 28-day period. The in vitro antioxidant activities of XOS-SPI-ACT, XOS-SPI, and free ACT were comparatively evaluated. XOS-SPI-ACT exhibited significantly higher scavenging capacities against DPPH radicals, ABTS radicals, hydroxyl radicals, and superoxide anions, as well as higher FRAP values (94%, 74%, 75%, 68%, and 2 mmol/g), compared with free ACT (48%, 17%, 21%, 32%, and 1 mmol/g). Furthermore, XOS-SPI-ACT effectively inhibited lipid peroxidation in the β-carotene/linoleic acid oxidation model, with an overall antioxidant performance of 72%, markedly higher than the 20% of free ACT. This study effectively improves the aqueous solubility and dispersibility of ACT, expands their application potential, and provides a foundation for developing ACT-based natural antioxidants and functional foods. Full article