Search Results (9,063)

Efficient enrichment and rapid determination of trace cadmium (Cd²⁺) in complex environmental and food matrices remain challenging because of severe matrix interference and insufficient sample pretreatment efficiency. Herein, a thiol-functionalized silica-coated magnetic biochar (MBC@SiO₂–SH) was developed as a selective magnetic adsorbent and integrated with a homogeneous chemiluminescence immunoassay (CLIA) to establish an enrichment-assisted analytical strategy for trace Cd²⁺ determination in environmental water and aquatic products. Owing to its abundant thiol coordination sites, large specific surface area, and excellent magnetic responsiveness, MBC@SiO₂–SH exhibited a high practical Cd²⁺ enrichment capacity (82.65 mg/g) under high-loading conditions, remarkable selectivity, and good reusability toward Cd²⁺. Adsorption kinetic, isotherm, thermodynamic, and X-ray photoelectron spectroscopy analyses revealed that Cd²⁺ uptake was predominantly governed by Cd–S coordination accompanied by physical adsorption. Under the optimized fixed-bed enrichment conditions, the proposed column achieved a preconcentration factor of approximately 40, enabling efficient matrix cleanup and selective enrichment prior to CLIA. The integrated method exhibited excellent analytical performance for both environmental water and aquatic products, with recoveries of 92.26–118.64% and 92.41–108%, respectively, and showed good agreement with ICP-MS. By coupling selective magnetic preconcentration with rapid homogeneous immunodetection, the proposed strategy provides a simple, sensitive, and efficient analytical platform for routine monitoring of trace Cd²⁺ and offers a generalizable framework for enrichment-assisted rapid analysis of trace contaminants in complex environmental and food matrices. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with lymph node metastasis (LNM) being a key predictor of recurrence and poor prognosis. Preoperative detection of LNM remains challenging due to the limitations of imaging modalities, leading to inadequate surgical resection in 20–30% of patients. While immune checkpoint molecules have been implicated in PTC progression, the heterogeneity of CD8⁺ T cell exhaustion subsets and their specific association with LNM remain poorly defined. In this study, we aimed to perform an exploratory characterization of the distinct immune landscape of PTC prone to LNM, with a focus on terminal immune exhaustion, in order to generate hypotheses for improved risk stratification and therapeutic strategies. Methods: Fresh PTC tissues from 40 patients (22 LNM-positive and 18 LNM-negative) were analyzed via flow cytometry (FCM) to quantify immune cell subsets, inflammatory cytokines, and chemokines. Immunohistochemistry (IHC) validated CD45⁺ immune cell infiltration. Transcriptomic and clinical data from 448 PTC patients in The Cancer Genome Atlas (TCGA-PTC) cohort were used for bioinformatic analysis consistent with the observed phenotype, including Gene Set Variation Analysis (GSVA) of terminal exhaustion gene signatures. Results: LNM-positive PTC exhibited a unique inflammatory milieu with significantly elevated IL-6, IL-1ra, CCL5, and IL-9 levels (all p < 0.05) in tumor interstitial fluid. FCM analysis revealed that LNM-positive PTC had increased infiltration of total CD45⁺ immune cells, CD3⁺ T cells, and CD3⁺CD8⁺ T cells (all p < 0.05). Critically, terminally exhausted PD-1^hiTIM-3⁺ CD8⁺ T cells were significantly enriched in LNM-positive PTC (p = 0.022) and positively correlated with extrathyroidal extension (p = 0.044). Additionally, LNM risk was associated with increased CD4⁺ regulatory T (Treg) cell frequency (p = 0.023) and elevated CTLA-4 expression on CD4⁺ T cells (p = 0.047). In TCGA-PTC validation, the terminal exhaustion gene signature was predominantly enriched in LNM-positive (p < 0.0001) and advanced-stage PTC (p < 0.001) and strongly correlated with BRAF mutation (predominantly V600E) (p < 0.0001)—the most common oncogenic driver in aggressive PTC. Conclusions: Our findings suggest a terminal immune exhaustion phenotype (characterized by PD-1^hiTIM-3⁺ CD8⁺ T cells and Treg enrichment) as a potential key feature associated with LNM-prone PTC. This phenotype shows consistency across clinical samples and TCGA datasets, linking BRAF mutation (predominantly V600E) to immune suppression and metastatic potential. These insights provide a novel exploratory immune-based biomarker for LNM risk stratification and support the potential of combining anti-PD-1/TIM-3 therapy with BRAF inhibitors for high-risk PTC, which should be confirmed in future studies. Full article

Methotrexate (MTX) remains central to the treatment of rheumatoid arthritis and several malignancies, yet its use is complicated by dose-dependent toxicity, variable oral exposure, photolability, and pH-dependent solubility. Cyclodextrins (CDs) can alter the molecular environment of MTX, but the literature often conflates true inclusion complexes with formulations in which CD merely forms part of a larger carrier. This review critically distinguishes direct MTX–CD complexes, dosage forms built from a preformed complex, CD-containing carriers without direct evidence of cavity occupancy, and covalent MTX–CD conjugates. Particular attention is given to binding stoichiometry, apparent association constants, guest orientation, preparation methods, and the evidence needed to establish inclusion. Both solution-state host–guest association and isolated solid products are considered; however, solid-state changes are treated as supportive evidence rather than as stand-alone proof of cyclodextrin cavity occupancy. Among the limited head-to-head comparisons of native cyclodextrins, β-CD generally showed more favorable MTX recognition than α- or γ-CD, although the magnitude of this difference is method- and condition-dependent. Complexation can improve dissolution, photostability, and oral or local delivery; however, greater solubilization does not necessarily enhance membrane transport. In carrageenan hydrogels, β-CD increased MTX loading and release while reducing membrane permeation, illustrating the importance of the equilibrium between complexed and freely permeating drug. The most promising systems remain preclinical. Progress toward translation will require clearer nomenclature, orthogonal structural characterization, mechanism-resolving controls, and standardized pharmacokinetic and safety studies. Full article

Background: Endometriosis-associated ovarian cancers (EAOCs), including ovarian clear cell (OCCC) and endometrioid ovarian carcinoma (EnOC) subtypes, frequently exhibit transcriptomic dysregulation of the PI3K/AKT/mTOR signalling axis. While genomic aberrations are well-documented, the coordinated microRNA (miRNA)-mediated networks governing post-transcriptional remodelling of this pathway across these subtypes remain poorly defined. Methods: We conducted an integrative in silico meta-analysis of independent mRNA and small RNA sequencing datasets. The mRNA analysis included 120 EAOC samples, of which 68 were OCCC and 52 were EnOC, compared with 149 normal ovarian tissues. The miRNA analysis included 170 samples comprising 55 OCCC, 82 EnOC and 33 normal ovarian tissues. Differential expression analysis, dimensionality reduction (UMAP), functional enrichment, and topologically unweighted miRNA–mRNA interaction networks were evaluated. Results: Both subtypes showed significant transcriptomic dysregulation of the core pathway machinery, including PIK3CB and mTOR, while preserving mTORC2 components. Post-transcriptional concurrent downregulation of IRS1, GRB10, DDIT4, and PIK3CD, which were identified as candidate targets of the hub miRNAs hsa-miR-30a-5p, hsa-miR-30d-5p, and hsa-miR-7-5p, suggests further refined control of the pathway. The identification of highly connected hub genes linking mTOR, MAPK, and Wnt signalling pathways within the mTOR-regulatory network suggests that pathway modulation occurs through extensive crosstalk across multiple oncogenic signalling pathways in EAOCs. Conclusions: Transcriptomic dysregulation of the mTOR pathway in EAOCs reflects not only genomic alterations but also potential post-transcriptional regulation. Despite subtype-specific transcriptomic differences, both exhibited transcriptional upregulation of components of the canonical PI3K/AKT/mTOR signalling axis. Pathway modulation through the miRNA regulatory network exhibited potential crosstalk across oncogenic pathways and hub genes. Full article

Background/Objectives: Sjögren’s Syndrome (SS) is an autoimmune disorder with impaired exocrine gland function. Its pathogenesis remains elusive, but aberrant innate/adaptive immunity and dysregulated interferon signaling are core features. Current SS research lacks exploration of innate immune mechanisms and therapeutic targets. Phloretin, a natural dihydrochalcone derivative, inhibits excessive innate immune activation, yet its role and mechanism in SS remain unreported. Methods: This study aimed to explore the therapeutic efficacy of phloretin against Sjögren’s syndrome (SS) and elucidate the regulatory mechanism underlying its effects on dendritic cells (DCs) and the Stimulator of Interferon Genes (STING)-driven innate immune cascade. Clinical specimens were utilized to analyze DC infiltration and STING expression in the labial glands of SS patients. In vivo experiments were conducted on NOD/Ltj SS mice with phloretin treatment, using hydroxychloroquine as a positive control. For in vitro studies, DCs were stimulated with poly I:C to verify the functional effects of phloretin and its regulatory role in the STING/TANK-binding kinase 1 (TBK1)/Interferon Regulatory Factor 3 (IRF3) signaling. Salivary secretion, glandular inflammatory responses, and systemic immune overactivation were evaluated in SS mice. In poly I:C-stimulated DCs, cell activation, migration, and co-stimulatory molecule expression were measured. The regulatory effects of phloretin on the STING signaling cascade and STING ubiquitin-mediated degradation were examined by Western blotting. Phloretin, initially identified as a candidate compound via virtual screening, was subjected to thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulation (MD) for direct binding verification with STING. The STING overexpression rescue experiment further corroborates that phloretin modulates innate immune responses in a STING-dependent manner. Results: Clinical results revealed obvious infiltration of CD11c⁺STING⁺ DCs and CD11c⁺p-TBK1⁺ DCs in labial gland lesions of SS patients. In NOD/Ltj SS mice, phloretin treatment recovered salivary secretion, relieved glandular inflammatory injury, and restrained excessive activation of innate and adaptive immune responses, showing comparable therapeutic effects compared with hydroxychloroquine. In vitro experiments confirmed that phloretin could alleviate poly I:C-induced abnormal activation and migration of DCs, as well as reduce the expression of co-stimulatory molecules. Mechanistically, phloretin was found to interfere with the STING signaling cascade, alter the ubiquitination level of STING protein, and further inhibit the abnormal activation of DCs, which may contribute to its protective effects against Sjögren’s syndrome. Notably, results from MD, CETSA and DARTS collectively validate the interaction between phloretin and STING protein, providing solid molecular-level evidence for its regulatory effect on STING signaling transduction. Conclusions: DCs and STING-driven innate immunity critically contribute to SS progression. Phloretin effectively ameliorates SS-related immune disorders by restraining DC overactivation and STING signaling, supporting it as a promising candidate agent for SS treatment. Full article

Background/Objectives: Adequate dietary intake is essential for supporting growth, health, and athletic performance in adolescent athletes. Handball is a high-intensity intermittent team sport characterised by repeated running, sprinting, jumping, and physical contact, placing substantial physiological and nutritional demands on young athletes. This study examined associations between eating behaviour dimensions, sport anxiety, resilience, and dietary intake in adolescent elite female handball players. Methods: This cross-sectional study included 74 adolescent elite female handball players; after exclusion of two dietary-intake outliers, 72 participants were included in the analyses (mean age: 15.6 ± 1.7 years; BMI: 21.2 ± 2.4 kg/m²). Eating behaviour, sport anxiety, and resilience were assessed using the TFEQ-R21, SAS-2, and CD-RISC-10, respectively. Dietary intake was estimated using a semi-quantitative food frequency questionnaire. Pearson correlation and linear regression analyses were performed. Results: Cognitive Restraint was negatively correlated with energy (r = −0.266, p = 0.024), fat (r = −0.288, p = 0.014), carbohydrate (r = −0.257, p = 0.029), and sugar intake (r = −0.255, p = 0.031). Uncontrolled Eating was positively associated with energy (β = 0.338, p = 0.030; R² = 0.134) and fat intake (β = 0.366, p = 0.017; R² = 0.157) in the regression analyses. Higher resilience was associated with lower sugar intake in the regression analysis (β = −0.318, p = 0.007; model R² = 0.101) and with lower sport anxiety in the Pearson correlation analysis (r = −0.559, p < 0.001). Conclusions: The findings indicate associations between eating behaviour dimensions, selected psychological characteristics, and dietary intake in adolescent elite female handball players. Uncontrolled Eating and Cognitive Restraint showed distinct patterns of association with dietary intake, while resilience was associated with sugar intake and sport anxiety. Given the cross-sectional and exploratory nature of the study, these findings warrant cautious interpretation and replication in larger independent samples. Full article

Background/Objectives: Inflammatory bowel diseases (IBDs) are an increasingly important global health problem, yet Central Asia remains underrepresented in international IBD data. To evaluate the clinical and demographic characteristics of patients included in the national multicenter clinical IBD registry of the Republic of Kazakhstan (IBD Registry) according to disease activity at registry enrollment visit and to identify factors associated with active IBD at that time. Methods: We conducted a cross-sectional analysis of the registry enrollment visit data from the national multicenter clinical IBD registry of the Republic of Kazakhstan. The study included patients with ulcerative colitis (UC) and Crohn’s disease (CD) registered between 2021 and 2024. Disease activity at the registry enrollment visit was assessed using the full Mayo score for UC and the Harvey–Bradshaw index for CD. Univariable and multivariable logistic regression analyses were performed to identify factors associated with active disease. Results: The analysis included 1521 patients with IBD, 68.4% with ulcerative colitis and 31.6% with Crohn’s disease. At the registry enrollment visit, 77.5% of patients had clinically active disease. In UC, active disease was independently associated with rural residence (aOR 2.11; 95% CI 1.25–3.56), ≥2 exacerbations per year (aOR 3.47; 95% CI 2.18–5.51), current corticosteroid therapy (aOR 5.96; 95% CI 3.04–11.69), and immunosuppressive therapy (aOR 2.71; 95% CI 1.15–6.38), whereas rare exacerbations were associated with lower odds of activity (aOR 0.41; 95% CI 0.23–0.73). In CD, active disease was independently associated with ≥2 exacerbations per year (aOR 2.41; 95% CI 1.47–3.95), colonic (L2) location (aOR 2.32; 95% CI 1.25–4.30), ileocolonic (L3) location (aOR 2.24; 95% CI 1.25–4.04), extraintestinal manifestations (aOR 2.88; 95% CI 1.68–4.93), and current corticosteroid therapy (aOR 1.77; 95% CI 1.03–3.05), whereas immunosuppressive therapy was associated with lower odds of active disease (aOR 0.46; 95% CI 0.24–0.89). Biologic therapy was not independently associated with disease activity in either UC or CD. Conclusions: A high proportion of patients treated at participating secondary and tertiary centers had clinically active IBD at registry enrollment. The profiles of factors associated with activity differed between UC and CD, while frequent exacerbations were consistently associated with active disease in both conditions. These findings should be interpreted as cross-sectional associations rather than causal or prognostic relationships, particularly for treatment-related factors. Full article

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by marked clinical heterogeneity. Existing prognostic frameworks, including the International Staging System (ISS) and FISH-defined cytogenetic risk, are anchored at diagnosis and do not capture the evolutionary dynamics of disease or treatment response, leaving an unmet need for risk models that retain prognostic validity longitudinally. Methods: Using transcriptomic data from 762 CD138-selected MM plasma cells from newly diagnosed patient samples in the MMRF CoMMpass study (NCT01454297), we computed single-sample pathway activity scores for 469 curated cancer-relevant pathways (MSigDB Hallmark; Reactome) and learned a Bayesian causal network linking pathway activity to survival. The model was validated in five independent diagnostic cohorts (n = 1255) and in two independent treatment and relapsed/refractory cohorts (n = 319). Longitudinal risk tracking was additionally assessed in a 46-patient subset of the discovery cohort with serial pre- and post-treatment sampling. Results: The network identified five pathways associated with survival: unfolded protein response (UPR), FLT3 signaling through SRC family kinases, G2M DNA replication checkpoint, metabolism of selenium compound (SeMet), and nicotinate metabolism. The composite survival score stratified patients into high-risk (n = 76; 10%) and standard-risk groups with markedly divergent survival (median 1170 days vs. not reached; p < 0.0001). The score remained an independent prognostic factor after adjustment for age, sex, ISS stage, and KRAS, TP53, and UBR5 mutational status (HR 4.93; 95% CI 2.96–8.19; p < 0.001), and replicated across all five external diagnostic cohorts. Critically, the model retained prognostic discrimination in previously treated (GSE57317; p < 0.0001) and relapsed/refractory (GSE9782; p < 0.0001) settings, and patients transitioning from standard- to high-risk between serial samples exhibited significantly inferior survival compared to standard-risk patients. Conclusions: This pathway-based Bayesian network provides a reproducible, dynamically applicable risk model for MM that captures information complementary to ISS and FISH-defined cytogenetics. The framework supports longitudinal patient monitoring and may inform trial enrichment strategies and closer surveillance for high-risk subpopulations. Full article

Background: Myelodysplastic neoplasms (MDSs) are clonal hematopoietic stem cell disorders associated with ineffective hematopoiesis, chronic inflammation, and increased cardiovascular morbidity. Although metabolic dysregulation has been implicated in MDS pathogenesis, systemic metabolic alterations remain incompletely characterized. Methods: Plasma samples from treatment-naïve patients with MDS or chronic myelomonocytic leukemia (CMML) and age-matched healthy controls were analyzed using quantitative nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Metabolomic profiles were compared using unsupervised and supervised multivariate analyses, validated in an independent external MDS cohort, and integrated with re-analysis of publicly available RNA-sequencing datasets from purified CD14⁺ CMML monocytes. Results: Patients with MDS and CMML exhibited broad reductions in circulating lipoprotein-associated metabolites, including HDL-, LDL-, IDL-, and apolipoprotein-associated fractions, indicating disturbed systemic lipoprotein homeostasis. Within the discovery cohort, CMML samples showed higher concentrations of the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as succinate. LC-MS analysis demonstrated selective increases in C18:1 acylcarnitine, oleic and isopalmitic acids, whereas free carnitine abundance remained unchanged. Elevated 3-hydroxybutyrate levels were not associated with mutational burden, hematologic parameters, disease risk, or immunophenotypic features. Re-analysis of public CMML monocyte transcriptomes demonstrated increased expression of genes involved in lipid uptake and intracellular lipid trafficking, including FABP5, APOE, LPL, and SLC27A2, without coordinated activation of fatty acid oxidation pathways. External cohort analysis confirmed the overall MDS-associated plasma metabolomic profile. Conclusions: MDSs and CMML are associated with reproducible alterations in systemic lipid metabolism characterized by reduced circulating lipoprotein-associated metabolites, while CMML showed more pronounced ketone body- and acylcarnitine-associated metabolic phenotype accompanied by changes in lipid-handling transcriptional programs. These findings support altered systemic lipid metabolism and carnitine-dependent fatty acid handling as characteristic features of myeloid neoplasms and provide a rationale for future functional studies investigating lipid metabolism in disease pathogenesis. Full article

Rapid identification of free thiols is essential in pharmaceutical quality control and food safety. Herein, we demonstrate the sensing concept of “two signals from one event” by exploiting the intrinsic dual functionality of selenium (Se) nanomaterials to construct a signal-on, dual-mode sensing platform for free thiols. The single event is thiol-triggered seeded growth: free thiols interact with L-cysteine-modified Se seeds, driving seed fusion and crystallization into chiral trigonal Se structures. This same event yields two readouts simultaneously: a colorimetric response arising from particle size enlargement (UV-Vis red-shift) and a turn-on circular dichroism (CD) signal from long-range chiral ordering. The method achieves a detection threshold of 10 μmol/L for various free thiols and can be completed within 60 min from seed preparation to signal readout without complex instrumentation. It serves as a general indicator of total free thiols rather than distinguishing individual thiol species. Above the threshold, concentration-dependent color deepening and spectral redshifts provide semi-quantitative estimation of the concentration range. Its practicality was validated by detecting D-penicillamine in commercial tablets. This strategy offers an approach for on-site free thiol screening and highlights the potential of chiral inorganic nanomaterials in multi-mode sensing via chiral transfer and amplification. Full article

The continual spermatogenesis throughout adulthood is ensured by a rare and unique cell group named spermatogonial stem cells (SSCs), which undergo self-renewal and/or differentiate into sperm cells. SSCs also become a promising genetic source for the protection of animal biodiversity. However, the isolation and culture of SSCs in vitro is still a big challenge and poorly explored in rabbits. The main objective of this study was to isolate, culture, and deeply characterize SSCs obtained from rabbit testes. Briefly, rabbit testicular tissue was mechanically and enzymatically dissociated, and obtained testicular somatic and germ cells were cultured for a short term in culture media supplemented with specific molecular factors maintaining SSC self-renewal and proliferation (GDNF, GFRα-1, FGF2, etc.). Immunofluorescent and PCR techniques were used for molecular profiling of cultured SSCs, while TEM analysis revealed their ultrastructure. After a few weeks, round and grape-like SSC colonies emerged, growing on the feeder cell layer. Rabbit SSCs showed positive staining for DBA, GFRA1, PLZF, RET, PGP9.5, DAZL, and DDX4. Increased expression of additional SSC markers was noticed using RT-qPCR and dd PCR (RET, PLZF, PGP9.5, DAZL, DDX4, CDH1, CD9, CD14, CD90, c-kit, ALDH, SSEA-4, SALL4, OCT4, and SOX2), while ultrastructure typical for primitive undifferentiated cells was observed under TEM. In conclusion, we successfully established a method for rabbit SSC isolation, culture, and phenotyping, which might facilitate their collection for further cryopreservation. However, the self-renewal, proliferative, and differentiation capacities of cultured SSCs still need to be confirmed through an in vivo SSC transplantation experiment. Full article

Background: This study aims to investigate the impact of chronic endometritis (CE) diagnosis and treatment on pregnancy outcomes during hysteroscopic fallopian tube catheterization combined with laparoscopy in infertility patients with pelvic endometriosis (EMS) and proximal tubal obstruction (PTO). Methods: A retrospective study was conducted between July 2020 and March 2022, including patients with PTO who underwent hysteroscopy–laparoscopy. CE was diagnosed via CD138 immunohistochemical staining and treated with oral doxycycline. The study further assessed the prevalence of CE and evaluated the effect of its diagnosis and treatment on pregnancy outcomes. Results: A total of 454 participants with PTO were enrolled, of whom 158 had concomitant pelvic EMS. Among EMS patients, 78 underwent CD138 staining for CE diagnosis (Group A), while the rest were classified as Group B. The incidence of CE in Group A was 62.8%. These affected individuals were treated with doxycycline. The natural pregnancy rate was significantly higher in Group A than Group B (46.2% vs. 26.3%, p = 0.009). The clinical pregnancy rate and live birth rate were higher in Group A, although the differences were not statistically significant. Additionally, Group A demonstrated a significantly higher cumulative natural pregnancy rate (p < 0.05). Notably, the diagnosis and treatment of CE emerged as a protective factor for cumulative natural pregnancy (HR, 1.78; 95% CI, 1.06–2.97; p = 0.028). Conclusions: In infertility patients with pelvic EMS complicated by PTO undergoing hysteroscopic tube catheterization combined with laparoscopy, prioritizing the diagnosis and treatment of CE is crucial for enhancing natural pregnancy outcomes. Full article

Background/Objectives: Chronic metabolic inflammation is associated with pro-inflammatory macrophage activation and mitochondrial dysfunction. Semaglutide, a widely used GLP-1 receptor agonist, has been reported to possess systemic anti-inflammatory properties, but its action on human macrophages, especially in the context of mitochondrial regulation, remains poorly understood. The aim of the study was to evaluate the direct effect of semaglutide on macrophage polarization and to investigate the roles of cAMP signaling and mitochondrial regulation in this process. Methods: THP-1 and U-937 monocytic cell lines were differentiated into macrophages and polarized into the M1-like phenotype using LPS/IFN-γ. Cells were treated with 100 nM semaglutide in the presence or absence of the adenylyl cyclase inhibitor SQ22536. Intracellular cAMP levels, mRNA expression of macrophage markers and key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), and levels of pro- and anti-inflammatory cytokines were determined. The COX-1/SDH-A and mtDNA/nDNA ratios were analyzed as markers of mitochondrial biogenesis. Results: Semaglutide induced cAMP accumulation in M0- and M1-like macrophages derived from both cell lines. This response was significantly attenuated by GLP-1R antagonist exendin(9–39), supporting the presence of functional GLP-1R signaling. Semaglutide supplementation during inflammatory polarization resulted in reduced levels of pro-inflammatory markers (CD80/CD86, TNF-α, IL-6) and increased expression of M2-associated genes CD206 and CD163 and secretion of the anti-inflammatory cytokine IL-10. Semaglutide also increased SIRT1 and PGC-1α expression, the COX-1/SDH-A ratio, and the mtDNA/nDNA ratio, suggesting activation of processes associated with mitochondrial biogenesis. All of the effects of semaglutide described above were attenuated by SQ22536, supporting an important contribution of cAMP signaling to these responses. Conclusions: Semaglutide acts directly on human monocytic cell line-derived macrophages, attenuating the M1-like program and promoting a shift toward a less inflammatory phenotype. These effects strongly depend on cAMP signaling and are accompanied by increased expression of SIRT1 and PGC-1α and mitochondrial changes consistent with enhanced biogenesis. Full article

Objectives: Nasopharyngeal carcinoma (NPC) arises in an immune-suppressive milieu that frequently undermines treatment efficacy. TPPP3 has been implicated as a negative regulator of NPC aggressiveness, yet its relevance to immune modulation or chaperone networks remains poorly defined. We therefore sought to determine how TPPP3 shapes the NPC immune landscape and to identify its interacting protein partners. Methods: Public single-cell RNA-sequencing datasets from head and neck squamous cell carcinoma and nasopharyngeal carcinoma were analyzed using R. HK-1 and C666-1 cells stably overexpressing TPPP3 were established. These cells were used to construct humanized xenograft tumor models, with intratumoral immune cell infiltration evaluated by immunohistochemistry. In vitro, the same cells and their controls were indirectly co-cultured with peripheral blood mononuclear cells. Cellular lysates from TPPP3-overexpressing cells were subjected to immunoprecipitation–mass spectrometry and immunofluorescence staining, which identified HSPA8 as a TPPP3-interacting protein. Three groups—control, TPPP3-overexpressing, and TPPP3-overexpressing plus the HSPA8 inhibitor VER155008—were then compared in wound healing, colony formation, cell-cycle, and xenograft assays, with immunohistochemical staining for Ki67, TPPP3, and CD3 performed on tumor sections. Results: TPPP3 transcripts were barely detectable across most tumor cell subsets but showed preferential enrichment in NPC epithelial clusters. Enforced TPPP3 expression curtailed xenograft outgrowth while increasing intratumoral abundance of CD3⁺ T cells, CD8⁺ T cells, and CD11c⁺ dendritic cells. Pharmacological blockade of HSPA8 with VER155008 further enhanced TPPP3-driven suppression of migration, clonogenicity, and tumor expansion, and also altered cell-cycle progression while boosting CD3⁺ T-cell accumulation within grafts. Conclusions: These findings suggest a functional association between TPPP3 and HSPA8 that may contribute to tumor growth suppression and immune microenvironment remodeling in NPC. Pharmacological disruption of HSPA8-dependent proteostasis enhanced TPPP3-associated antitumor activity in both in vitro and in vivo models, indicating that this chaperone pathway represents a candidate mechanism worthy of further mechanistic investigation and therapeutic exploration. Full article

Looking at the demand for precise matching between the mechanical properties of similar materials and natural soft clay in soft ground visual model tests, this paper proposes a preparation method for graded transparent soil based on optical testing principles and geotechnical similarity theory. Using n-dodecane and 15# white oil as pore fluids, combined with nano-fumed silica and optimally graded fused quartz sand, a graded transparent soil material system with accurately matched refractive indices was constructed. The synergistic effect of nano-fumed silica and graded quartz sand enables dual optimization of material transparency and mechanical performance. The feasibility of simulating soft ground was verified through load-plate tests, jacked pile penetration model tests, and consolidated-drained (CD) triaxial tests. The consolidation compression and direct shear test results show that the material has a compression coefficient of 1.43 MPa⁻¹, a compression modulus of 1.72 MPa, a total internal friction angle φ ranging from 16.53° to 23.21°, and a total cohesion c ranging from 5.42 to 11.34 kPa. Further CD triaxial test results verified that the developed transparent soil exhibits effective shear strength parameters (c′ = 9.65 kPa, φ′ = 16.01°), which are highly consistent with the effective strength indices of natural Shaoxing silty clay (c′ = 12.94 kPa, φ′ = 13.52°), with a relative error of ultimate deviator stress less than 5% under various confining pressures. Moreover, different strength levels can be obtained by adjusting the pre-consolidation pressure. During shear loading, the material presents stable volumetric contraction without dilatancy, conforming to the typical contractive mechanical characteristics of normally consolidated soft clay. PIV velocity-field analysis of the indoor plate load test under constant-settlement-rate conditions revealed that the transparent soil displays a typical Prandtl failure mode, consistent with the failure characteristics of natural soft clay. The model test of jacked-pile penetration further confirmed that this material can effectively simulate the stress-deformation behavior of soft ground under the test conditions adopted in this study. The developed material offers a viable alternative simulant and relevant test reference for laboratory visual model investigations into soft ground deformation, pile–soil interaction and failure evolution in geotechnical model tests. Full article